We are a biopharmaceutical company with the purpose of bettering the life of each person impacted by kidney disease.
−Removed: Since our initial public offering in 2014, we have built a business focused on developing and commercializing innovative renal therapeutics that we believe serves as a foundation for future growth.
−Removed: As a leader in the kidney community, we remain committed to helping patients and others where we believe our current and future products have the ability to deliver value.
−Removed: Our portfolio includes a late-stage product candidate and a commercial product:
−Removed: • Vadadustat is an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor, or HIF-PHI, designed to mimic the physiologic effect of altitude on oxygen availability.
+Added: Since our initial public offering in 2014, we have built a business focused on developing and commercializing innovative therapeutics that we believe serves as a foundation for future growth.
+Added: We have established ourselves as a leader in the kidney community, and we remain committed to helping patients and others where we believe our current and potential future products have the ability to deliver value.
+Added: We believe that delivering value broadly to the kidney community, as well as others who may benefit from our medicines, will result in delivering value for shareholders.
+Added: Our current portfolio includes a late-stage product candidate and a commercial product:
+Added: • Vadadustat is an investigational oral hypoxia-inducible factor prolyl hydroxylase, or HIF-PH, inhibitor designed to mimic the physiologic effect of altitude on oxygen availability.
At higher altitudes, the body responds to lower oxygen availability with stabilization of hypoxia-inducible factor, or HIF, which stimulates erythropoietin, or EPO, production and leads to red blood cell, or RBC, production and improved oxygen delivery to tissues.
The significance of the HIF pathway was recognized by the 2019 Nobel Prize and the 2016 Albert Lasker Basic Medical Research Award, which honored the three physician-scientists who discovered the HIF pathway and elucidated this primary oxygen sensing mechanism that is essential for survival.
−Removed: We believe that, based on the HIF-PHI mechanism of action and clinical data to date, vadadustat has the potential to set a new oral standard of care for the treatment of anemia due to chronic kidney disease, or CKD.
−Removed: We recently completed the global Phase 3 clinical development program for vadadustat, which included two separate programs, INNO 2 VATE and PRO 2 TECT.
+Added: We believe that, based on the HIF-PH inhibitor mechanism of action and the results of our Phase 3 clinical trials, vadadustat has the potential to become the new oral standard of care for the treatment of anemia due to chronic kidney disease, or CKD.
+Added: We completed the global Phase 3 clinical development program for vadadustat in September 2020 to support regulatory filings in the United States, Europe and other countries, which included two separate programs, INNO 2 VATE and PRO 2 TECT.
INNO 2 VATE evaluated vadadustat for the treatment of anemia due to CKD in adult patients on dialysis, or DD-CKD, and PRO 2 TECT evaluated vadadustat for the treatment of anemia due to CKD in adult patients not on dialysis, or NDD-CKD.
−Removed: In May of 2020, we announced positive top-line results from our Phase 3 INNO 2 VATE program that showed vadadustat was non-inferior to darbepoetin alfa, an injectable erythropoiesis-stimulating agent, or ESA, with respect to hematological efficacy (change in hemoglobin concentration) and cardiovascular safety (assessed in a time to the first occurrence of a major adverse cardiovascular event (MACE) analysis, which is the composite of all-cause mortality, nonfatal myocardial infarction, or a nonfatal stroke) in treating anemia due to CKD in DD-CKD adult patients.
+Added: In May of 2020, we announced positive top-line results from our Phase 3 INNO 2 VATE program that showed vadadustat was non-inferior to darbepoetin alfa, an injectable erythropoiesis-stimulating agent, or ESA, with respect to hematological efficacy (change in hemoglobin concentration) and cardiovascular safety (assessed in a time to the first occurrence of a major adverse cardiovascular event, or MACE, analysis, which is the composite of all-cause mortality, nonfatal myocardial infarction, or a nonfatal stroke) in treating anemia due to CKD in DD-CKD adult patients.
In addition to meeting the primary endpoints of the INNO 2 VATE program, vadadustat met the key secondary hematological efficacy endpoint in each of the two studies in the program and also met the program's key secondary safety endpoints.
−Removed: The results of the INNO 2 VATE program were presented at American Society of Nephrology, or ASN, in October of 2020.
+Added: The results of the INNO 2 VATE program were presented at American Society of Nephrology, or ASN, in October of 2020 and published in the New England Journal of Medicine in April of 2021.
In September of 2020, we announced top-line results from our Phase 3 PRO 2 TECT program that showed vadadustat was non-inferior to darbepoetin alfa with respect to hematological efficacy in treating anemia due to CKD in NDD-CKD adult patients.
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These cardiovascular outcomes contrast with those reported within the INNO 2 VATE program, which evaluated vadadustat for the treatment of anemia due to CKD in DD-CKD adult patients.
−Removed: The results of the PRO 2 TECT program were presented at ASN in October of 2020.
−Removed: S imultaneous with the PRO 2 TECT ASN presentation, we presented additional analyses, conducted by Akebia, of data from the PRO 2 TECT program that revealed that the greater number of MACE events observed among vadadustat patients as compared to the active comparator was primarily related to an excess of non-cardiovascular death and death-of-unknown-cause in regions outside of the United States where significant differences in treatment patterns for NDD-CKD patients were observed.
−Removed: We plan to proceed with the submission of a New Drug Application, or NDA, for vadadustat by the middle of the second quarter of 2021 for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients.
−Removed: We are also working in close collaboration with our collaboration partner, Otsuka Pharmaceutical Co.
−Removed: Ltd., to prepare a Marketing Authorization Application, or MAA, for vadadustat for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients for submission to the European Medicines Agency, or EMA, expected in 2021.
−Removed: However, a s vadadustat did not meet the PRO 2 TECT program's primary safety endpoint, we are remaining cautious in our outlook for potential approval of vadadustat in NDD-CKD adult patients in the United States and Europe.
+Added: The results of the PRO 2 TECT program were presented at ASN in October of 2020 and published in the New England Journal of Medicine in April of 2021.
+Added: We submitted a New Drug Application, or NDA, to the U.S.
+Added: Food and Drug Administration, or FDA, for vadadustat in March of 2021 for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients.
+Added: Our NDA submission was accepted for filing by the FDA in May of 2021 and the FDA has indicated that they are not currently planning to hold an Advisory Committee meeting to discuss the NDA for vadadustat.
+Added: The FDA also assigned the application standard review and a Prescription Drug User Fee Act, or PDUFA, target action date of March 29, 2022.
+Added: Our collaboration partner, Otsuka Pharmaceutical Co.
+Added: Ltd., or Otsuka, submitted a Marketing Authorization Application, or MAA, for vadadustat for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients to the European Medicines Agency, or EMA, in October 2021.
+Added: As vadadustat did not meet the PRO 2 TECT program's primary safety endpoint, we are remaining cautious in our outlook for potential approval of vadadustat in NDD-CKD adult patients in the United States and Europe.
In June of 2020, we announced the first regulatory approval of vadadustat for the treatment of anemia due to CKD in DD-CKD and NDD-CKD adult patients in Japan.
−Removed: Our collaboration partner in Japan, Mitsubishi
−Removed: Tanabe Pharma Corporation, or MTPC, commenced commercial sales of vadadustat in Japan under the trade name, Vafseo TM , in August 2020.
+Added: Our collaboration partner in Japan, Mitsubishi Tanabe Pharma Corporation, or MTPC, commenced commercial sales of vadadustat in Japan under the trade name, Vafseo TM , in August 2020.
+Added: In addition, MTPC filed a new drug application for vadadustat for the treatment of anemia due to CKD in adult patients in Taiwan in January of 2022.
In addition to anemia due to CKD, we believe that vadadustat has the potential to treat other serious or life-threatening conditions, including preventing and lessening the severity of acute respiratory distress syndrome, or ARDS, a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19, infection.
−Removed: More specifically, in July of 2020, we announced an investigator-sponsored clinical study by The University of Texas Health Science Center at Houston, or UTHealth, in Houston, Texas, evaluating the use of vadadustat as a potential therapy to prevent and lessen the severity of ARDS in up to 400 adult patients who have been hospitalized due to COVID-19.
+Added: More specifically, in July of 2020, we announced an investigator-sponsored clinical study by The University of Texas Health Science Center at Houston, or UTHealth, in Houston, Texas, evaluating the use of vadadustat as a potential therapy to prevent and lessen the severity of ARDS adult patients who have been hospitalized due to COVID-19.
+Added: With the support of its data monitoring committee, UTHealth decided to expand the study beyond the initial 400 patients, an enrollment target they have now surpassed.
Within this randomized, double-blind, placebo-controlled study, pa tients will be dosed with vadadustat or a placebo starting within 24 hours of hospital admission and continuing for up to 14 days.
−Removed: This study is being conducted under a U.S.
−Removed: Food and Drug Administration, or FDA, Investigational New Drug application, or IND, with UTHealth as the study sponsor and is currently enrolling patients.
+Added: This study is being conducted under an Investigational New Drug application, or IND, with UTHealth as the study sponsor and is currently enrolling patients.
In January of 2021, UTHealth announced that it had been awarded $5.1 million in funding from the U.S.
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(1) the control of serum phosphorus levels in adult patients with DD-CKD, or the Hyperphosphatemia Indication, and (2) the treatment of iron deficiency anemia, or IDA, in adult patients with NDD-CKD, or the IDA Indication.
−Removed: Ferric citrate is also approved and marketed in Japan as an oral treatment for the improvement of hyperphosphatemia in patients with CKD, including DD-CKD and NDD-CKD, under the trade name Riona (ferric citrate hydrate).
−Removed: We plan to commercialize vadadustat, subject to FDA approval, in the United States with our existing nephrology-focused commercial organization, while also leveraging our collaboration with Otsuka Pharmaceutical Co.
−Removed: Ltd., or Otsuka, and its U.S.
−Removed: commercial organization.
−Removed: We granted Otsuka exclusive rights to commercialize vadadustat in Europe, China and certain other markets, subject to marketing approvals.
−Removed: We granted MTPC exclusive rights to commercialize vadadustat in Japan, where MTPC is currently commercializing vadadustat under the trade name, Vafseo TM , and in certain other countries in Asia, subject to marketing approvals.
−Removed: We also granted Vifor (International) Ltd., or Vifor Pharma, an exclusive license to sell vadadustat solely to Fresenius Kidney Care Group LLC, or FKC, which manages approximately 40% of the dialysis patients in the United States, at its U.S.
−Removed: dialysis clinics, and to certain third party dialysis organizations in the United States, approved by us, or Third Party Dialysis Organizations, which account for up to an additional 20% of the dialysis market in the United States.
−Removed: The license granted to Vifor Pharma would be effective upon FDA approval of vadadustat in the DD-CKD indication, the earlier of a determination by the Centers for Medicare & Medicaid Services, or CMS, that vadadustat will be included in Medicare’s bundled reimbursement model or that vadadustat will be reimbursed using the Transitional Drug Add-On Payment Adjustment, or TDAPA, and a milestone payment by Vifor Pharma.
+Added: Ferric citrate is also approved and marketed in Japan as an oral treatment for the improvement of hyperphosphatemia in patients with CKD, including DD-CKD and NDD-CKD, and for the treatment of patients with IDA, under the trade name Riona (ferric citrate hydrate).
+Added: Since 2018, Auryxia product revenue has grown at a compounded annual growth rate of 14% due to market share gains and improved net price per pill, while total prescriptions for phosphate binders in the United States have declined 8%.
+Added: We believe this growth is due to the benefits of the product perceived by the prescribing nephrologists as communicated by our nephrology-focused commercial and medical organizations.
+Added: If we obtain FDA approval of vadadustat, we plan to commercialize vadadustat in the United States with our well-established, nephrology-focused commercial organization, while also leveraging our collaboration with Otsuka and its U.S.
+Added: nephrology commercial organization.
+Added: In addition, in February 2022, we entered into a Second Amended and Restated License Agreement, or the Vifor Second Amended Agreement with Vifor (International) Ltd., or Vifor Pharma, which amended and restated the Amended and Restated License Agreement, dated April 8, 2019, or the Vifor First Amended Agreement.
+Added: Pursuant to the Vifor Second Amended Agreement, we granted Vifor Pharma an exclusive license to sell vadadustat to Fresenius Medical Care North America and its affiliates, including Fresenius Kidney Care Group LLC, to certain third-party dialysis organizations approved by us, to independent dialysis organizations that are members of group purchase organizations, and to certain non-retail specialty pharmacies in the United States, or the Territory .
+Added: We refer to Fresenius Medical Care North America and its affiliates, these organizations and specialty pharmacies collectively as the “Supply Group" .
+Added: We currently retain rights to commercialize vadadustat for use in the non-dialysis dependent CKD market and to sell to dialysis organizations outside of the Supply Group.
+Added: During the term of the Vifor Second Amended Agreement, Vifor Pharma is not permitted to sell any HIF product that competes with vadadustat in the Territory to the Supply Group.
We market Auryxia in the United States with our well-established, nephrology-focused commercial organization.
Our Japanese sublicensee, Japan Tobacco, Inc., or JT, and its subsidiary, Torii Pharmaceutical Co., Ltd., or Torii, commercialize Riona in Japan.
−Removed: On December 12, 2018, we completed a merger, or the Merger, with Keryx Biopharmaceuticals, Inc., or Keryx, combining a nephrology-focused commercial organization with our robust development organization.
−Removed: Following the Merger, Keryx is our wholly owned subsidiary.
+Added: In addition, we continue to explore additional development opportunities to expand our pipeline and portfolio of novel therapeutics through both internal research and external innovation.
+Added: Our development pipeline includes several earlier stage opportunities, including praliciguat, an investigational oral soluble guanylate cyclase, or sGC, stimulator, that we licensed from Cyclerion Therapeutics, Inc., or Cyclerion, in June 2021.
+Added: Praliciguat is in development for the treatment of focal segmental glomerulosclerosis, which is highly complementary to our strategy to identify and develop novel therapeutics for people impacted by kidney diseases.
+Added: Further, our internal innovation efforts include several preclinical opportunities, both in the HIF pathway, leveraging our learnings from the research and development of vadadustat, as well as new areas of focus we are currently exploring.
Our mission and our culture are centered around the goal of improving the lives of people impacted by kidney disease through the discovery, development and commercialization of innovative therapeutics.
Our strategy is to execute on the following initiatives, which we believe will create significant market opportunities for us:
−Removed: • Prepare for the potential commercialization of vadadustat for the treatment of anemia due to CKD in the United States and Europe.
−Removed: We believe vadadustat has the potential to address limitations of injectable ESAs, and set a new oral standard of care for the treatment of anemia due to CKD, subject to regulatory approval.
−Removed: We plan to submit an NDA for vadadustat to the FDA by the middle of the second quarter of 2021.
−Removed: In addition, we and Otsuka are working in close collaboration to prepare an MAA for vadadustat for submission to the EMA in 2021 .
−Removed: We believe we are well positioned to commercialize vadadustat in the United States with our nephrology-focused commercial team, our partnership with Otsuka, and our agreement with Vifor Pharma, subject to FDA approval.
−Removed: We plan to support Otsuka’s commercialization of vadadustat in Europe
−Removed: and certain other markets, subject to regulatory approvals.
+Added: • Prepare for the potential commercialization of vadadustat for the treatment of anemia due to CKD in the United States.
+Added: We believe vadadustat has the potential to address limitations of injectable ESAs, and become the new oral standard of care for the treatment of anemia due to CKD, if approved.
+Added: We submitted an NDA to the FDA for vadadustat in March of 2021, which was accepted by the FDA in May of 2021.
+Added: The FDA assigned the application standard review and a PDUFA target action date of March 29, 2022.
+Added: We believe we are well positioned to commercialize vadadustat in the United States with our nephrology-focused commercial team, our partnership with Otsuka, and the Vifor Second Amended Agreement, if vadadustat receives FDA approval.
+Added: • Support vadadustat adoption and growth outside of the United States.
+Added: We plan to continue to support MTPC’s commercialization and growth of Vafseo in Japan.
+Added: In addition, Otsuka submitted a MAA for vadadustat to the EMA in October 2021, and MTPC filed a new drug application for vadadustat for the treatment of anemia due to CKD in adult patients in Taiwan in January 2022.
+Added: We also plan to support MTPC's and Otsuka’s commercialization efforts for vadadustat in Japan and Europe and certain other markets for which MTPC and Otsuka have commercialization rights, subject to the applicable regulatory approvals.
We retain full commercial rights to vadadustat in Latin America, allowing us maximum flexibility in the region.
−Removed: • Support vadadustat (Vafseo) adoption and growth in Japan.
−Removed: We plan to continue to support MTPC’s commercialization of Vafseo in Japan.
−Removed: We also plan to support MTPC's commercialization efforts for vadadustat in certain other markets in Asia for which MTPC has commercialization rights, subject to regulatory approvals.
• Maximize the value of Auryxia, and leverage the product as a commercial foundation for vadadustat, in CKD.
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In addition to our CKD program and the ARDS study, we plan to identify and initiate development planning for other programs where vadadustat may have therapeutic benefits.
−Removed: • Expand our pipeline and portfolio of novel therapeutics .
−Removed: We aim to add to our pipeline and portfolio of novel therapeutics through internal discovery and development, and through strategic transactions, such as in-licenses, collaborations and acquisitions.
+Added: • Continue to expand our pipeline and portfolio of novel therapeutics .
+Added: We aim to continue to add to our pipeline and portfolio of novel therapeutics through internal research, discovery and development, and through external innovation and strategic transactions, such as in-licenses, collaborations and acquisitions.
+Added: In June 2021, we entered into the Cyclerion Agreement with Cyclerion, pursuant to which Cyclerion granted us an exclusive global license under certain intellectual property rights to research, develop and commercialize praliciguat, an investigational oral sGC stimulator, which is highly complementary to our strategy to identify and develop novel therapeutics for people impacted by kidney disease.
+Added: We plan to continue to develop praliciguat and explore similar opportunities that align with our strategic vision in the future.
In addition, given our expertise in research and development, we believe there may be opportunities to leverage these assets and establish mutually beneficial relationships with other companies that are looking to enter the renal market or attempting to develop renal therapeutics.
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eventually many patients will progress to a stage where they are dependent on dialysis, with high morbidity and a significant increase in mortality rate.
−Removed: Kidney disease can be caused by a number of distinct and concomitant factors, including cardiometabolic disorders (primarily diabetes and hypertension), genetic kidney diseases, autoimmune disorders, and aging.
+Added: Kidney disease can be caused by a number of distinct and concomitant factors, including cardiometabolic disorders (primarily diabetes and hypertension), genetic diseases, autoimmune disorders, and aging.
Given the prevalence and growth rates of these various underlying conditions, kidney disease prevalence is expected to continue to increase globally.
In the United States, CKD significantly impacts the U.S.
−Removed: healthcare system, affecting about 37 million patients and costing Medicare over $120 billion annually in 2017 for treating Medicare beneficiaries with CKD of end-stage renal disease or end-stage kidney disease, or ESRD or ESKD.
−Removed: Department of Health and Human Services has recognized this national pandemic and partnered with ASN to found the KidneyX Innovation Accelerator, a public-private partnership to improve the lives of the 850 million people worldwide currently affected by kidney diseases by accelerating innovation in the prevention, diagnosis and treatment of kidney diseases.
−Removed: Most of the conditions covered by the term “kidney disease” may lead to dependence on dialysis or kidney transplant for survival, causing renal failure, directly or indirectly, by accelerating the onset of CKD.
+Added: healthcare system, potentially affecting about 37 million patients and costing Medicare nearly $120 billion annually for treating Medicare beneficiaries with CKD of end-stage renal disease or end-stage kidney disease, or ESRD or ESKD, according to the Centers for Disease Control and Prevention.
+Added: Department of Health and
+Added: Human Services has recognized this national pandemic and partnered with ASN to found the KidneyX Innovation Accelerator, a public-private partnership to improve the lives of the 850 million people worldwide currently affected by kidney diseases by accelerating innovation in the prevention, diagnosis and treatment of kidney diseases.
+Added: Most of the conditions covered by the term “kidney disease” may lead to renal failure and dependence on dialysis or kidney transplant for survival.
Dependence on dialysis is associated with a significant increase in mortality and hospitalizations, and a significant reduction in quality of life for patients.
There is a clear need to improve the clinical and quality of life outcomes for people living with kidney disease.
−Removed: It is our vision, in time, to provide or contribute to better alternatives that improve the lives of people impacted by kidney disease.
+Added: We are driven by our purpose, to provide or contribute to better alternatives that improve the lives of people impacted by kidney disease.
CKD is a condition in which the kidneys are progressively damaged to the point that they cannot properly filter the blood circulating in the body.
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Stages and Prevalence of CKD in the United States
−Removed: Stage Description GFR (mL/min/1.73m2)a
−Removed: Prevalence Ratesb, c
−Removed: Estimated Number of U.S.
+Added: Stage Description GFR (mL/min/1.73m2) a U.S.
+Added: Prevalence Rates b, c Estimated Number of U.S.
Patients (millions) d, e
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GFR categories defined in the August 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Anemia in Chronic Kidney Disease, p.
−Removed: Prevalence Rates for Stages 1-4 based on averages of data from 2011-2012, 2013-2014, and 2015-2016, CDC CKD Surveillance System, National Health and Nutrition Examination Survey, or NHANES.
+Added: Prevalence Rates for Stages 1-4 based on averages of data from 2011-2012, 2013-2014, and 2015-2016, CDC CKD Surveillance System, National Health and Nutrition Examination Survey.
Prevalence Rate for Stage 5 is based on a calculation using estimated number of U.S.
patients with ESRD from 2018 U.S.
−Removed: Renal Data System Annual Report, as set forth in this table, and U.S.
+Added: Renal Data System Annual Report, February 21, 2019, as set forth in this table, and U.S.
population data for people 20 years and older from www.census.gov.
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End-Stage Renal Disease Patients from 2018 U.S.
−Removed: Renal Data System Annual Report.
+Added: Renal Data System Annual Report, February 21, 2019.
The prevalence and incidence of CKD is increasing in all segments of the United States population.
Risk factors for the development of CKD include concomitant diseases such as hypertension, diabetes mellitus and cardiovascular disease, lifestyle factors such as tobacco use and inactivity, family history, aging and prenatal factors such as maternal diabetes mellitus, low birth weight and small-for-gestational-age status.
−Removed: According to an article in The Lancet published in May 2013, projected worldwide population changes suggest that the potential number of cases of CKD, specifically end-stage, will increase disproportionately in countries such as Japan, China and India where the number of elderly people is increasing.
−Removed: This effect will be accelerated further if the growth in the prevalence of hypertension and diabetes persists, along with the associated increased risk of stroke and cardiovascular disease, and access to treatment does not improve.
The progression of CKD towards renal failure is complicated by multiple conditions which further deteriorate kidney function and the general health of patients if left untreated.
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Anemia due to CKD:
−Removed: results from inadequate levels of EPO, a protein hormone synthesized by specialized cells in the kidney that stimulates production of red blood cells in the bone marrow.
+Added: results from inadequate levels of EPO, a protein hormone synthesized by specialized cells in the kidney that stimulates RBC production in the bone marrow.
As renal function declines, the body progressively loses the ability to produce endogenous EPO;
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The global Phase 3 clinical development program for vadadustat evaluated the efficacy and safety of vadadustat for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients.
+Added: We submitted an NDA to the FDA, for vadadustat in March of 2021 for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients.
IDA in adult patients with NDD-CKD is an FDA-approved indication for Auryxia.
Hyperphosphatemia in DD-CKD patients is also an FDA-approved indication for Auryxia.
−Removed: Hyperphosphatemia is another condition associated with CKD that is characterized by elevated serum phosphorus levels and is also typically associated with a worsening of health including increased cardiovascular risk and increased mortality.
+Added: Hyperphosphatemia is another condition associated with CKD that is characterized by elevated serum phosphorus levels and is also typically associated with a worsening of health including increased cardiovascular risk and mortality.
Market Opportunity for Vadadustat
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Left untreated, anemia accelerates overall deterioration of patient health with increased morbidity and mortality.
−Removed: Based on third party prevalence data and company estimates, approximately 37 million people in the United States have CKD and approximately 5.7 million of these individuals suffer from anemia.
−Removed: The current standard of care for anemia due to CKD is treatment by injectable recombinant human ESAs, such as EPOGEN ® (epoetin alfa) and Aranesp ® (darbepoetin alfa), or blood transfusion.
+Added: Based on third party prevalence data and company estimates, potentially 37 million people in the United States have CKD and approximately 5.7 million of these individuals suffer from anemia.
+Added: The current standard of care for anemia due to CKD is treatment by injectable recombinant human ESAs, such as Epogen ® (epoetin alfa), Aranesp ® (darbepoetin alfa) and Mircera ® (methoxy polyethylene glycol-epoetin beta) , or blood transfusion.
Based on publicly available information on ESA sales and market data compiled by a third-party vendor, global sales of injectable ESAs for all uses were estimated to be approximately $6.1 billion in 2018.
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Also, several randomized clinical trials have demonstrated that higher hemoglobin targets
−Removed: (≥13.0 to 14.0 g/dL) with ESA use are associated with increased cardiovascular risk, leading to changes in regulatory and clinical practice guidance.
−Removed: While these safety concerns, which became evident starting in 2006, have led to a significant reduction in the use of injectable ESAs, injectable ESAs remain the current standard of care for both DD-CKD and NDD-CKD patients with anemia.
+Added: (≥13.0 g/dL) with ESA use are associated with increased cardiovascular risk, leading to changes in regulatory and clinical practice guidance.
+Added: While these safety concerns, which became evident starting in 2006, have led to a significant reduction in the use of injectable ESAs, and an increase in the use of injectable iron, injectable ESAs remain the current standard of care for both DD-CKD and NDD-CKD patients with anemia.
DD-CKD Market
−Removed: We believe there is a significant opportunity for vadadustat to address limitations of injectable ESAs and set a new oral standard of care for the treatment of anemia due to CKD in DD-CKD adult patients, subject to approval.
+Added: We believe there is a significant opportunity for vadadustat to address limitations of injectable ESAs and become the new oral standard of care for the treatment of anemia due to CKD in DD-CKD adult patients, if approved.
In addition to clinical data from our Phase 3 INNO 2 VATE program that showed vadadustat was non-inferior to darbepoetin alfa with respect to hematological efficacy (change in hemoglobin concentration) and cardiovascular safety (MACE) in DD-CKD adult patients, we believe the potential opportunity for vadadustat within the DD-CKD market is supported by a number of factors including vadadustat's convenient oral dosing and unique U.S.
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We believe as an oral therapeutic, vadadustat has potential to be a convenient treatment alternative to injectable ESAs not only for in-center dialysis patients, but also for the growing number of home dialysis patients and patients transitioning to home dialysis.
−Removed: Given the concentration of dialysis clinics in large networks, with DaVita, Inc., or DaVita, and FKC accounting for a vast majority of the dialysis population in the United States, treatment is usually driven by medical protocols that are rolled out across the entire network of clinics.
−Removed: These protocols are informed by very large data sets and when updated, result in rapid change applicable to large segments of the patient population.
+Added: Given the concentration of dialysis clinics in large networks, with DaVita, Inc., or DaVita, and Fresenius Kidney Care Group accounting for a vast majority of the dialysis population in the United States, treatment is usually driven by medical protocols that are implemented across the entire network of clinics.
+Added: These protocols are informed by very large data sets and when
+Added: updated, result in rapid change applicable to large segments of the patient population.
This is particularly true of medications covered under the End Stage Renal Disease, or ESRD, Prospective Payment System, or PPS, in Medicare, or the ESRD Bundle, a payment structure with a flat base rate per dialysis session adjusted for individual patient and facility characteristics.
Dialysis-related drugs are included in the ESRD Bundle if they fall into functional categories such as anemia management and bone and mineral metabolism, except that oral-only drugs are exempted from inclusion until 2025.
−Removed: In a final ESRD PPS rule published in November 2018, CMS confirmed that it will expand TDAPA to all new dialysis drugs approved by the FDA after January 1, 2020.
+Added: In a final ESRD PPS rule published in November 2018, CMS confirmed that it will expand the Transitional Drug Add-on Payment Adjustment, or TDAPA, to all new dialysis drugs approved by the FDA after January 1, 2020.
The TDAPA will provide separate payment for new drugs for two years based on the drug’s Average Sales Price, or ASP, that will be in addition to the base rate in order to facilitate the adoption of innovative therapies.
−Removed: Although there are several details that need further clarification, including the process and timing associated with applying for and receiving codes to allow for reimbursement under TDAPA, which codes are assigned on a quarterly basis, the rule provides support for our assumption that new anemia treatments, including those in the HIF-PHI class, will be included in the ESRD Bundle and will be eligible for separate payment initially under TDAPA.
−Removed: We believe these and other factors will help position vadadustat as a potential new oral standard of care for the treatment of anemia due to CKD in adult DD-CKD patients, upon approval.
+Added: Although there are several details that need further clarification, and the precise timing of when we could receive codes to allow for reimbursement under TDAPA is not known, the codes are assigned on a quarterly basis, and the rule provides support for our assumption that new anemia treatments, including those in the HIF-PH inhibitor class, will be included in the ESRD Bundle and will be eligible for separate payment initially under TDAPA.
NDD-CKD Market
−Removed: Data from the USRDS 2015 Annual Data Report indicate that the collective injectable ESA treatment rate in NDD-CKD patients in the United States decreased by approximately half from 2009 to 2013.
−Removed: As a result of the safety concerns associated with ESAs, today, a high proportion of NDD-CKD patients with anemia are either not treated or inadequately treated despite having low hemoglobin levels.
−Removed: In contrast to treatment with ESAs, we believe vadadustat, subject to regulatory approval, has the potential to expand the number of NDD-CKD patients receiving treatment by offering an alternative oral treatment for anemia due to CKD.
+Added: Data from the USRDS 2015 Annual Data Report indicate that the collective injectable ESA treatment rate in NDD-CKD patients in the United States decreased by approximately half from 2009 to 2013 as a result of the safety concerns associated with ESAs.
+Added: Today, a high proportion of NDD-CKD patients with anemia are either not treated or inadequately treated despite having low hemoglobin levels.
+Added: In contrast to treatment with ESAs, we believe vadadustat, if approved for use in NDD-CKD patients, has the potential to expand the number of NDD-CKD patients receiving treatment by offering an alternative oral treatment for anemia due to CKD.
Results from our Phase 3 PRO 2 TECT program showed vadadustat was non-inferior to darbepoetin alfa with respect to hematological efficacy in treating anemia due to CKD in NDD-CKD adult patients, meeting both the primary and key secondary hematological efficacy endpoints.
However, it did not meet the program's primary cardiovascular safety (MACE) endpoint.
−Removed: We plan to pursue regulatory approval for vadadustat for the treatment of anemia due to CKD in NDD-CKD adult patients;
−Removed: however , as PRO 2 TECT did not meet the program's primary safety endpoint , we are remaining cautious in our outlook for potential approval of vadadustat as a treatment for anemia due to CKD in NDD-CKD adult patients.
−Removed: Vadadustat Has the Potential to Set a New Oral Standard of Care
−Removed: Below is a summary of the key clinical findings;
−Removed: further details are included below.
+Added: We are pursuing regulatory approval for vadadustat for the treatment of anemia due to CKD in NDD-CKD adult patients;
+Added: however , as PRO 2 TECT did not meet the program's primary safety endpoint , we remain cautious in our outlook for potential approval of vadadustat as a treatment for anemia due to CKD in NDD-CKD adult patients.
+Added: Vadadustat Has the Potential to Become the New Oral Standard of Care
+Added: We believe vadadustat has the potential to become the new oral standard of care for the treatment of anemia due to CKD, if approved.
+Added: Below is a summary of certain of the key clinical findings;
+Added: further details are included in the discussion below.
• Vadadustat stimulated endogenous EPO production.
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Our global Phase 3 program and Phase 2 studies in CKD patients with anemia demonstrated that vadadustat significantly increased and/or maintained hemoglobin levels.
−Removed: In addition, our partner, MTPC’s, Phase 3 studies in Japanese NDD-CKD and DD-CKD patients with anemia due to CKD further demonstrated the durability of vadadustat with data that showed that vadadustat’s effect on hemoglobin was sustained through to 52 weeks comparable to the control arm, darbepoetin alfa.
• Vadadustat was dosed orally once daily and three times weekly.
Our Phase 2 studies showed that vadadustat can be orally dosed once daily in NDD-CKD patients with up to 20 weeks of dosing.
−Removed: In addition, our Phase 2 clinical study in DD-CKD patients demonstrated that in patients who remained on therapy, once daily oral dosing of vadadustat maintained stable hemoglobin levels in patients converting from injectable ESA therapy over 16 weeks.
−Removed: This study also showed the potential for three-times weekly dosing of vadadustat in DD-CKD.
−Removed: We are conducting and plan to conduct additional larger studies of vadadustat evaluating a modified approach to once-daily and three-times weekly dosing.
−Removed: • Vadadustat resulted in favorable changes in iron parameters.
−Removed: In three Phase 2 clinical studies, treatment with vadadustat was associated with decreases in ferritin and hepcidin and increases in total iron binding capacity.
−Removed: These changes are consistent with improved iron mobilization and utilization for erythropoiesis in NDD-CKD and DD-CKD patients.
−Removed: Based on this and other data, we believe vadadustat has the potential to be a treatment for anemia due to CKD by:
+Added: This study also showed the potential for three-times weekly dosing of vadadustat in DD-CKD patients.
+Added: We are conducting additional larger studies of vadadustat evaluating three-times weekly dosing and a modified approach to once-daily dosing.
+Added: Based on this and other data, we believe vadadustat has the potential to be a treatment for anemia due to CKD and become the new oral standard of care by:
• stimulating erythropoiesis and avoiding supraphysiologic EPO levels;
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Vadadustat Clinical Development Program
−Removed: We believe vadadustat has the potential to set a new oral standard of care for the treatment of anemia due to CKD, subject to regulatory approval.
Below is a summary of the clinical development work undertaken for vadadustat.
−Removed: Recently Completed Vadadustat Global Phase 3 Clinical Program in Anemia Due To CKD
+Added: Vadadustat Global Phase 3 Clinical Program in Anemia Due To CKD
We conducted a global Phase 3 clinical development program for vadadustat, which included two programs, INNO 2 VATE and PRO 2 TECT.
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The mean (SD) Hb level at week 40 to week 52 was 10.51 (1.19) g/dL for vadadustat treated-patients compared to 10.55 (1.14) g/dL for darbepoetin alfa-treated patients.
−Removed: In INNO 2 VATE’s Conversion study of dialysis patients (n=3,554):
+Added: In INNO 2 VATE’s Conversion study of prevalent dialysis patients (n=3,554):
• Primary Efficacy Endpoint Result :
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Vadadustat achieved the INNO 2 VATE program’s primary safety endpoint of non-inferiority for MACE.
−Removed: In the primary analysis of time to first MACE event, vadadustat demonstrated non-inferiority to darbepoetin alfa using a non-inferiority margin of 1.25 prospectively agreed to by FDA and a non-inferiority margin of 1.3 prospectively agreed to by EMA.
+Added: In the primary analysis of time to first MACE event, vadadustat demonstrated non-inferiority to darbepoetin alfa using a non-inferiority margin of 1.25 based on discussion with the FDA and a non-inferiority margin of 1.3 based on discussion with the EMA.
The INNO 2 VATE program ( Correction/Conversion and Conversion studies) of dialysis patients (n=3,902):
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Serious treatment emergent adverse events were slightly lower for vadadustat treated patients at 55.0% and 58.3% for darbepoetin alfa-treated patients.
+Added: Patients with DD-CKD experienced an increased risk of thromboembolic events compared to darbepoetin alfa with a time to first event HR of 1.20 (95% CI 0.96 - 1.50) driven by thrombosis of vascular access.
INNO 2 VATE results on key secondary safety endpoints showed that vadadustat also demonstrated non-inferiority to darbepoetin alfa in analyses of expanded MACE, cardiovascular MACE, cardiovascular mortality, and all-cause mortality.
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patients were treated to a target Hb range of 10 to 12 g/dL.
−Removed: In October of 2020, we presented a pre-specified regional analysis using age as a dichotomous variable, that showed vadadustat was not associated with a clinically meaningful increase in cardiovascular risk compared to darbepoetin alfa in U.S.
+Added: In October of 2020, we presented a pre-specified regional analysis that showed vadadustat was not associated with a clinically meaningful increase in cardiovascular risk compared to darbepoetin alfa in U.S.
patients treated to a target Hb range of 10 to 11 g/dL, in an analysis of MACE (HR 1.06, 95% CI:
−Removed: In October 2020, we announced that based on these analyses and the totality of the data from our Phase 3 program, we plan to pursue regulatory approval in the United States for vadadustat for the treatment of anemia in adult NDD-CKD patients.
−Removed: However, a s vadadustat did not meet the PRO 2 TECT program's primary safety endpoint, we are remaining cautious in our outlook for potential approval of vadadustat in adult NDD-CKD patients and we look forward to working with the FDA in their review of these data.
+Added: In March 2021, based on these analyses and the totality of the data from our Phase 3 program, we submitted an NDA to the FDA for vadadustat for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients .
+Added: However, a s vadadustat did not meet the PRO 2 TECT program's primary safety en dpoint, we remain cautious in our outlook for potential approval of vadadustat in adult NDD-CKD patients.
The incidence of treatment emergent adverse events during the Correction study in the vadadustat-treated patients was 90.9%, and 91.6% in darbepoetin alfa-treated patients.
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Serious treatment emergent adverse events were 58.5% for vadadustat-treated patients and 56.6% for darbepoetin alfa-treated patients.
−Removed: We are also conducting and plan to conduct additional studies of vadadustat evaluating a modified approach to once-daily and three-times weekly dosing, including assessment of a vadadustat starting dose based on an individual’s pre-conversion ESA dose prior to study entry and higher titration doses of vadadustat (600 mg and 900 mg).
−Removed: We believe data from these and other studies could support registration of the modified approach to once daily dosing and supplemental registration of three times weekly dosing, and further strengthen our potential commercial position if vadadustat is approved for marketing.
+Added: We are also conducting additional studies of vadadustat evaluating a modified approach to once-daily and three-times weekly dosing, including assessment of a vadadustat starting dose based on an individual’s pre-conversion ESA dose prior to study entry and higher titration doses of vadadustat (up to 1200 mg).
+Added: We believe data from these and other studies could support registration of the modified approach to once daily dosing and three times weekly dosing, and further strengthen our potential commercial position if vadadusta t is approved for marketing.
Hepatic Safety Profile of Vadadustat in Clinical Studies
−Removed: Following the completion of our global Phase 3 clinical program for vadadustat, there was a review of hepatic safety across the vadadustat clinical program, which includes 8 completed Phase 2 and 3 studies in NDD-CKD patients, 10 completed Phase 1, 2, and 3 studies, and 1 ongoing Phase 3b study in subjects with DD-CKD patients, and 18 completed studies in healthy subjects (17 Phase 1 and one Phase 3).
−Removed: The review of hepatic safety included a blinded assessment of all hepatic events in the studies by a panel of hepatic experts and analysis by an independent hepatic expert and our team.
−Removed: Based on this review, we concluded that the data across the clinical program showed that the overall hepatic safety profiles of vadadustat and darbepoetin alfa appear to be similar.
−Removed: In addition, we concluded that there were no events across the clinical program that met the biochemical criteria for Hy’s Law.
−Removed: More specifically, we concluded that the case of drug induced liver injury from our Phase 2b study of vadadustat in non-dialysis patients with anemia due to CKD that we previously reported as Hy’s Law did not, in fact, meet the biochemical criteria of Hy’s Law.
−Removed: Our conclusion on this case will be reflected in our NDA for vadadustat .
−Removed: Other Studies of Vadadustat
−Removed: We completed a series of clinical drug-drug interaction studies largely focusing on transporter pathways evaluating vadadustat as a victim (using probe inhibitors) or perpetrator (using probe substrates) of drug interactions.
−Removed: No meaningful drug interactions were observed with atorvastatin (P-gp/OATP1B1 substrate), pravastatin (OATP1B1/1B3 substrate), digoxin (P-gp substrate), furosemide (OAT1/OAT3 substrate), adefovir (OAT1 substrate), cyclosporine (P-gp/BCRP/OATP inhibitor), probenecid
−Removed: (OAT3 and UGT inhibitor), or rabeprazole (gastric acid-reducing agent).
−Removed: With concomitant administration of vadadustat, a mild-to-moderate interaction was observed with simvastatin (OATP1B1/B3 substrate), and moderate drug interactions were observed with rosuvastatin (BCRP/OATP1B1/1B3 substrate), ferrous sulfate, and sulfasalazine (BCRP substrate).
−Removed: In addition, in vitro drug-drug interaction studies demonstrated a very low risk of vadadustat for drug interactions due to alteration of metabolic enzyme activities, i.e.
−Removed: cytochrome P450 or UDP-glucuronosyltransferase isoforms.
−Removed: No clinical drug-interaction was observed with celecoxib (CYP2C9).
+Added: Following the completion of our global Phase 3 clinical program for vadadustat, there was a review of hepatic safety across the vadadustat clinical program, which includes 8 completed Phase 2 and 3 studies in NDD-CKD patients, 10 completed Phase 1, 2, and 3 studies, and one ongoing Phase 3b study in patients with DD-CKD, and 18 completed studies in healthy subjects (17 Phase 1 and one Phase 3).
+Added: This review included a blinded assessment of all hepatic events in the studies by a panel of hepatic experts and analysis by an independent hepatic expert and our team.
+Added: Hepatocellular injury attributed to vadadustat was reported in less than 1% of patients;
+Added: there was one case of severe hepatocellular injury with jaundice.
+Added: All events were asymptomatic and resolved after discontinuation of vadadustat.
Commercialization
−Removed: We are in the process of supporting MTPC's commercial launch of vadadustat in Japan, preparing for a potential commercial launch of vadadustat in the United States and supporting potential commercial launches of vadadustat in certain other markets.
−Removed: Our ability to launch vadadustat in the United States is dependent on the successful filing and defense of an NDA, and approval by the FDA.
−Removed: We plan to commercialize vadadustat, subject to FDA approval, in the United States with our well-established, nephrology-focused commercial organization, while leveraging our collaboration with Otsuka and its U.S.
+Added: We are supporting MTPC's commercialization of vadadustat in Japan, preparing for a potential commercial launch of vadadustat in the United States and supporting potential commercial launches of vadadustat in certain other markets.
+Added: Our ability to launch vadadustat in the United States is dependent on the successful review of the NDA, and approval by the FDA.
+Added: If we obtain FDA approval of vadadustat, we plan to commercialize vadadustat in the United States with our well-established, nephrology-focused commercial organization, while leveraging our collaboration with Otsuka and its U.S.
nephrology commercial organization.
We granted Otsuka exclusive rights to commercialize vadadustat in Europe, China and certain other markets, subject to marketing approvals.
+Added: Otsuka submitted a MAA for vadadustat for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients to the EMA in October 2021.
We granted MTPC exclusive rights to commercialize vadadustat in Japan, where MTPC commenced commercial sales of vadadustat under the trade name, Vafseo TM , in August 2020, and in certain other countries in Asia, subject to marketing approvals.
−Removed: In addition, we granted Vifor Pharma an exclusive license to sell vadadustat to FKC and Third Party Dialysis Organizations, which combined manage up to approximately 60% of the dialysis patients in the United States, which would be effective upon FDA approval of vadadustat, the earlier of vadadustat’s reimbursement under a bundled reimbursement model or using the TDAPA, and a milestone payment by Vifor Pharma.
−Removed: During the term of the license agreement, Vifor Pharma is not permitted to sell any HIF product that competes with vadadustat in the United States to FKC or its affiliates or to any Third Party Dialysis Organization, and we may not directly supply vadadustat to FKC or any other affiliate of Fresenius Medical Care North America, or FMCNA, or any Third Party Dialysis Organization.
+Added: In addition, MTPC filed a new drug application for vadadustat for the treatment of anemia due to CKD in adult patients in Taiwan.
+Added: In addition, in February 2022, we entered into the Vifor Second Amended Agreement with Vifor Pharma, which amended and restated the Vifor First Amended Agreement.
+Added: Pursuant to the Vifor Second Amended Agreement, we granted Vifor Pharma an exclusive license to sell vadadustat to the Supply Group in the Territory.
+Added: We currently retain rights to commercialize vadadustat for use in the non-dialysis dependent CKD market and to sell to dialysis organizations outside of the Supply Group.
+Added: During the term of the Vifor Second Amended Agreement, Vifor Pharma is not permitted to sell any HIF product that competes with vadadustat in the Territory to the Supply Group.
For more information about our license, collaboration and strategic agreements relating to vadadustat, see Part I, Item 1.
Business – License, Collaboration and Other Strategic Agreements – Vadadustat.
−Removed: We entered into a letter agreement on February 14, 2020, or the Letter Agreement, with Vifor Pharma, relating to Vifor Pharma’s agreement with a third party to purchase a Priority Review Voucher, or the PRV, issued by the FDA subject to satisfaction of customary closing conditions, or the PRV Purchase.
+Added: In February 2020, the Company entered into a letter agreement, or the Letter Agreement, with Vifor Pharma relating to Vifor Pharma’s agreement with a third party to purchase a Priority Review Voucher, or the PRV, issued by the FDA, or the PRV Purchase.
A PRV entitles the holder to priority review of an NDA, or a Biologics License Application for a new drug, which reduces the target FDA review time to six months after official acceptance of the submission, and could lead to expedited approval.
Pursuant to the Letter Agreement, we paid Vifor Pharma $10.0 million in connection with the closing of the PRV Purchase.
−Removed: Vifor Pharma is obligated to retain all rights to, and maintain the validity of, the PRV until we and Vifor Pharma (a) enter into a definitive agreement setting forth the financial and other terms by which Vifor Pharma will assign the PRV to us for use with our planned NDA for vadadustat for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients, or (b) make a mutual decision to sell the PRV and share the proceeds based on certain terms.
+Added: In March of 2021, we submitted an NDA for the treatment of anemia due to CKD in both DD-CKD and NDD-CKD adult patients.
+Added: Our NDA submission did not include a PRV.
+Added: In August 2021, we entered into an amendment to the Letter Agreement with Vifor Pharma whereby the parties agreed that Vifor Pharma would sell the PRV to a third party, and we and Vifor Pharma will share the proceeds from the sale based on certain terms.
+Added: In the fourth quarter of 2021, Vifor Pharma sold the PRV to a third party, and Vifor Pharma paid us $8.6 million in proceeds from the sale.
+Added: These proceeds were subsequently paid to Otsuka as reimbursement for their contribution to the purchase of the PRV, as required under a separate Letter Agreement executed with Otsuka.
Our Commercial Product:
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In July 2019, JT, and its subsidiary, Torii, reported positive top-line results from a pivotal Phase 3 comparative study evaluating Riona for the treatment of IDA in adult patients in Japan.
−Removed: In May 2020, JT and Torii filed an application for approval of IDA as an additional indication for Riona in Japan .
+Added: In May 2020, JT and Torii filed an application for approval of IDA as an additional indication for Riona in Japan, which was approved in March 2021 .
In September 2015, we received approval to market ferric citrate in the European Union under the tradename Fexeric.
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Business - License, Collaboration and Other Strategic Agreements – License Agreement with Panion & BF Biotech, Inc.
−Removed: We have received Paragraph IV certification notice letters regarding Abbreviated New Drug Applications, or ANDAs, submitted to the FDA requesting approval for generic versions of Auryxia tablets (210 mg iron per tablet), with the first having been received on October 31, 2018.
−Removed: We have filed certain complaints for patent infringement relating to such ANDAs, and have entered into settlement and license agreements with three such ANDA filers.
+Added: We received Paragraph IV certification notice letters regarding Abbreviated New Drug Applications, or ANDAs, submitted to the FDA requesting approval for generic versions of Auryxia tablets (210 mg iron per tablet), with the first received on October 31, 2018.
+Added: We filed certain complaints for
+Added: patent infringement relating to such ANDAs, and have entered into settlement and license agreements with each of the ANDA filers.
See Part I, Item 3.
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Auryxia, as an oral drug, is covered by Medicare only under Part D.
−Removed: We have gained broad access for Auryxia in the United States in both Medicare Part D and commercial channels.
−Removed: Auryxia is currently covered for the Hyperphosphatemia Indication in nine of the ten largest Medicare Part D plans, which provide coverage for approximately 35.8 million people, and the ten largest commercial plans and pharmacy benefit managers in the United States, which provide coverage for approximately 131.0 million people.
+Added: We have gained access for Auryxia in the United States in both Medicare Part D and commercial channels.
+Added: Auryxia is currently covered for the Hyperphosphatemia Indication in nine of the ten largest Medicare Part D plans, which provide coverage for approximately 35.8 million people, and the ten largest
+Added: commercial plans and pharmacy benefit managers in the United States, which provide coverage for approximately 131.0 million people.
In September 2018, the Centers for Medicare & Medicaid Services, or CMS, decided that Auryxia would no longer be covered by Medicare for the IDA Indication.
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Department of Health and Human Services challenging CMS’s decision that Auryxia would no longer be covered by Medicare for the IDA Indication and imposing a prior authorization requirement for Auryxia in the Hyperphosphatemia Indication, or the CMS Decision.
+Added: On October 22, 2021, the parties agreed to dismiss the litigation.
See Part I, Item 3.
2 unchanged sentences
JT, and its subsidiary, Torii, market Riona in Japan.
−Removed: We receive tiered double-digit royalties from JT and Torii based on their sales in Japan.
+Added: We receive tiered double-digit royalties from JT and Torii bas ed on their sales in Japan.
Manufacturing and Supply
1 unchanged sentence
We currently rely on third-party contract manufacturing organizations, or CMOs, to produce all of our preclinical and clinical material and commercial supply and third-party distributors to distribute Auryxia.
−Removed: We expect to continue to rely on either existing or alternative distributors and CMOs to distribute our products and supply our ongoing and planned preclinical and clinical studies and for commercial production.
+Added: We expect to continue to rely on either existing or alternative distributors and CMOs to distribute our products and supply our ongoing and planned preclinical studies and clinical trials and for commercial production.
+Added: Our CMOs have other clients and may have other priorities that could affect their ability to perform the work satisfactorily and/or on a timely basis.
+Added: Both of these occurrences would be beyond our control.
We have established relationships with several CMOs under which the CMOs manufacture preclinical, clinical and commercial supply of vadadustat drug substance and drug product, and clinical and commercial supply of Auryxia drug substance and drug product.
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and STA for the manufacture of vadadustat drug product for commercial use.
−Removed: We plan to mitigate potential commercial supply risks for vadadustat, if any, through inventory management and additional redundant manufacturing arrangements for both drug substance and drug product;
−Removed: however, the timing of such arrangements is uncertain and may occur following the launch of vadadustat, if approved.
+Added: We plan to mitigate potential commercial supply risks for vadadustat, if any, through inventory management and additional redundant manufacturing arrangements for both drug substance and drug product and changes may occur following the launch of vadadustat, if approved.
Vadadustat is a small molecule.
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The drug substance for Auryxia is supplied by Siegfried Evionnaz SA (two approved sites) and BioVectra Inc.
−Removed: (one approved site), pursuant to supply agreements with pricing structured on a per-kilogram basis.
−Removed: Consistent with our previously disclosed plans to lower the cost of goods sold for Auryxia, BioVectra and Keryx entered into an Amended and Restated Product Manufacture and Supply and Facility Construction Agreement on
−Removed: September 4, 2020.
−Removed: Auryxia drug product is supplied by Patheon Manufacturing Services LLC (Thermo Fisher) (three approved sites) pursuant to a Master Manufacturing Service Agreement with per-bottle pricing structured on a tiered basis, with the price reduced as the product volume increases.
+Added: (one approved site), pursuant to supply agreements with pricing structured on a per-kilogram ba sis.
+Added: Consistent with our previously disclosed plans to lower the cost of goods sold for Auryxia, BioVectra and Keryx entered into an Amended and Restated Product Manufacture and Supply and Facility Construction Agreement on September 4, 2020.
+Added: A uryxia drug product is supplied by Patheon Manufacturing Services LLC (Thermo Fisher) (three approved sites) pursuant to a Master Manufacturing Service Agreement with per-bottle pricing structured on a tiered basis, with the price reduced as the product volume increases.
These agreements require that we satisfy certain minimum purchase requirements, but we are not obligated to use them as our sole suppliers.
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Financial Statements and Supplementary Data.
−Removed: Our CMOs have other clients and may have other priorities that could affect their ability to perform the work satisfactorily and/or on a timely basis.
−Removed: Both of these occurrences would be beyond our control.
The active pharmaceutical ingredient of Auryxia, ferric citrate, is a small molecule.
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Agreement, pursuant to which we agreed to co-exclusively collaborate with Otsuka with respect to the development and commercialization of vadadustat in the United States, subject to the approval of vadadustat by the FDA.
−Removed: We continue to lead the ongoing global Phase 3 development program for vadadustat, for which we reported top-line data for INNO 2 VATE and PRO 2 TECT in the second and third quarters of 2020, respectively.
−Removed: We and Otsuka will co-commercialize vadadustat in the United States, subject to the approval of vadadustat by the FDA.
+Added: We are responsible for leading the development of vadadustat, for which we submitted an NDA to the FDA in March of 2021.
+Added: We will co-commercialize vadadustat in the United States with Otsuka, subject to the approval of vadadustat by the FDA.
+Added: We control and retain final decision-making authority with respect to certain matters, including U.S.
+Added: pricing strategy and manufacturing.
Under the terms of the Otsuka U.S.
Agreement, Otsuka paid us an upfront payment of $125.0 million and we expect Otsuka to provide additional funding of $393.9 million or more, depending on the actual costs incurred, toward the vadadustat global Phase 3 development program.
+Added: This amount includes the Additional Funding (as defined below).
Due to the costs incurred in completing the activities under the current global development plan exceeding a certain threshold in the second quarter of 2019, we elected to require Otsuka to increase the aggregate percentage of current global development costs it funds under the Otsuka U.S.
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Under the Otsuka U.S.
−Removed: Agreement, we and Otsuka will jointly conduct all medical affairs and commercialization activities pursuant to plans agreed by the parties.
+Added: Agreement, we and Otsuka will jointly conduct all medical affairs and commercialization activities pursuant to plans agreed to by the parties.
We will remain responsible for manufacturing vadadustat.
Additionally, the parties agreed not to promote, market or sell any competing product in the territory covered by the agreement.
+Added: Unless earlier terminated, the Otsuka U.S.
+Added: Agreement will expire in the United States on a product-by-product basis on the date that one or more generic versions of vadadustat first achieves 90% market penetration.
+Added: Either party may terminate the Otsuka U.S.
+Added: Agreement in its entirety upon an uncured breach or insolvency on the part of the other party.
+Added: Otsuka may terminate the Otsuka U.S.
+Added: Agreement in its entirety upon 12 months’ prior written notice at any time after the release of the first top-line data from the global Phase 3 development program for vadadustat, which release occurred in the second quarter of 2020.
International Collaboration with Otsuka Pharmaceutical Co.
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The territory covered by the Otsuka International Agreement includes the European Union, Russia, China, Australia, Canada, the Middle East and certain other countries, or the Otsuka International Territory, but excludes Latin America and previously licensed jurisdictions.
−Removed: Under the Otsuka International Agreement, Otsuka is responsible
−Removed: for certain development activities and commercializing vadadustat in the Otsuka International Territory, while we lead the ongoing global Phase 3 development program, for which we reported top-line data for INNO 2 VATE and PRO 2 TECT in the second and third quarters of 2020, respectively.
+Added: Under the Otsuka International Agreement, Otsuka is responsible for certain development activities and commercializing vadadustat in the Otsuka International Territory, while we led the global Phase 3 development program of vadadustat, and Otsuka submitted a MAA with the EMA in October 2021.
Otsuka will fund a significant percentage of the costs of such global development program regardless of the total actual costs ultimately incurred.
−Removed: We and Otsuka have final decision-making authority with respect to certain matters.
Additionally, the parties agreed not to promote, market or sell any competing product in the territory covered by the agreement.
Under the terms of the Otsuka International Agreement, we expect Otsuka to pay us at least $317.7 million, comprised of $73.0 million that was paid upon execution of the Otsuka International Agreement and $244.8 million or more, depending on actual costs incurred, of development funding.
−Removed: In addition, we are eligible to receive from Otsuka up to $52.0 million in regulatory milestones and up to $525.0 million in commercial milestones.
+Added: In addition, we are eligible to receive from Otsuka up to $17.0 million in regulatory milestones for the licensed HIF product if we achieve the associated event within 12 to 24 months of the first HIF product approval and up to $525.0 million in commercial milestones.
Otsuka also agreed to make tiered, escalating royalty payments ranging from low double digits up to thirty percent of net sales of vadadustat within the Otsuka International Territory.
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Otsuka will pay a percentage of the costs of any such studies, and we will pay its portion of the costs in the form of a credit against future amounts due to us under the Otsuka International Agreement.
+Added: Unless earlier terminated, the Otsuka International Agreement will expire upon the expiration of the royalty term in the last country in the Otsuka International Territory.
+Added: Either party may terminate the Otsuka International Agreement in its entirety upon an uncured material breach or insolvency on the part of the other party.
+Added: Otsuka may terminate the Otsuka International Agreement in its entirety or for a specific region in the Otsuka International Territory upon 12 months’ prior written notice at any time after the release of the first top-line data from the global Phase 3 development program for vadadustat, which release occurred in the second quarter of 2020.
Collaboration with Mitsubishi Tanabe Pharma Corporation
On December 11, 2015, we entered into a collaboration agreement with MTPC, or the MTPC Agreement, providing MTPC with exclusive development and commercialization rights to vadadustat in Japan and certain other Asian countries, or the MTPC Territory.
−Removed: In addition, we will supply vadadustat for both clinical and commercial use in the MTPC Territory, subject to MTPC’s option to manufacture commercial drug product in the MTPC Territory.
+Added: In addition, we will supply vadadustat to MTPC for both clinical and commercial use in the MTPC Territory, subject to MTPC’s option to manufacture commercial drug product in the MTPC Territory.
On July 15, 2020, we entered into a supply agreement with MTPC for the commercial supply of vadadustat for use in Japan and certain other Asian countries, as contemplated by the MTPC Agreement.
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In June 2020, vadadustat was approved in Japan for the treatment of anemia due to CKD by the Ministry of Health, Labor and Welfare.
−Removed: In August 2020, MTPC launched vadadustat commercially in Japan under the trade name, Vafseo TM , as a treatment of anemia due to CKD for adult patients on dialysis and not on dialysis.
−Removed: Under the terms of the MTPC Agreement, MTPC will make payments to us of up to $225.0 million in the aggregate based on the achievement of certain development, regulatory and sales milestones, as well as tiered royalty payments ranging from 13% to 20% on annual net sales of vadadustat in the MTPC Territory, subject to reduction upon launch of a generic product on a country-by-country basis.
−Removed: MTPC is responsible for the costs of the Phase 3 program for vadadustat in Japan and other studies required in Japan and made no funding payments for our global Phase 3 program.
+Added: In August 2020, MTPC launched vadadustat commercially in Jap an under the trade name, Vafseo TM , as a treatment of anemia due to CKD for adult patients on dialysis and not on dialysis.
+Added: In January 2022, MTPC filed a new drug application for vadadustat for the treatment of anemia due to CKD in adult patients in Taiwan .
+Added: Unless earlier terminated, the MTPC Agreement will continue in effect on a country-by-country basis until the later of the following:
+Added: expiration of the last-to-expire patent covering vadadustat in such country in the MTPC Territory;
+Added: expiration of marketing or regulatory exclusivity in such country in the MTPC Territory;
+Added: or ten years after the first commercial sale of vadadustat in such country in the MTPC Territory.
+Added: MTPC may terminate the MTPC Agreement upon twelve months’ notice at any time after the second anniversary of the effective date of the MTPC Agreement.
+Added: Either party may terminate the MTPC Agreement upon the material breach of the other party that is not cured within a specified time period or upon the insolvency of the other party.
+Added: Under the terms of the MTPC Agreement, MTPC will make payments to us of up to approximately $225.0 million in the aggregate based on the achievement of certain development, regulatory and sales milestones, as well as tiered royalty payments ranging from 13% to 20% on annual net sales of vadadustat in the MTPC Territory, subject to reduction upon launch of a generic product on a country-by-country basis.
+Added: MTPC was responsible for the costs of the Phase 3 program for vadadustat in Japan and other studies required in Japan and made no funding payments for our global Phase 3 program.
Additionally, the development costs of approximately $20.5 million for our Phase 2 studies in Japan were reimbursed to us by MTPC.
−Removed: For information on our royalty interest acquisition agreement with HealthCare Royalty Partners IV, L.P.
−Removed: with respect to royalties and sales milestones under the MTPC Agreement, see Part II, Item 9B.
−Removed: Other Information.
+Added: In February 2021, we entered into a royalty interest acquisition agreement with HealthCare Royalty Partners IV, L.P., or HCR, whereby we sold our right to receive royalties and sales milestones for vadadustat in Japan and certain other Asian countries in the MTPC territory under the MTPC Agreement.
+Added: For more information on our royalty interest acquisition agreement with HCR, see Note 5 to our consolidated financial statements in Part II, Item 8.
+Added: Financial Statements and Supplementary Data of this Annual Report on Form 10-K.
Vifor Pharma License Agreement
−Removed: On May 12, 2017, we entered into a License Agreement with Vifor Pharma, or the Vifor Agreement.
−Removed: On April 8, 2019, we entered into an Amended and Restated License Agreement with Vifor Pharma, or the Vifor Amended Agreement, which amends and restates in full the Vifor Agreement, pursuant to which we granted Vifor Pharma an exclusive license to sell vadadustat to FKC, an affiliate of Fresenius Medical Care North America, and to Third Party Dialysis Organizations, in the United States, which would be effective upon the approval of vadadustat for DD-CKD patients by the FDA, inclusion of vadadustat in a bundled reimbursement model or that vadadustat will be reimbursed using the TDAPA, and payment by Vifor Pharma of a $25.0 million milestone upon the occurrence of these two events.
−Removed: The Vifor Agreement is structured as a profit share arrangement between us and Vifor Pharma in which we will receive a majority of the profit from Vifor Pharma’s sales of vadadustat to FKC and to Third Party Dialysis Organizations in the United States.
−Removed: We will share the milestone payment and the revenue from the profit share with Otsuka pursuant to the Otsuka U.S.
−Removed: We retain all rights to commercialize vadadustat for use in the NDD-CKD market and in other dialysis organizations in the United States, which will be done in collaboration with Otsuka if vadadustat is approved by the FDA.
−Removed: Prior and subject to FDA approval of vadadustat, we and Vifor Pharma plan to enter into a commercial supply agreement for vadadustat pursuant to which we would supply all of Vifor Pharma’s commercial requirements for vadadustat in the United States.
−Removed: In addition, pursuant to the Vifor Agreement, Vifor Pharma will enter into supply agreements that govern the terms pursuant to which Vifor Pharma would supply vadadustat to FKC and Third Party Dialysis Organizations for use in patients at its dialysis centers, subject to FDA approval;
−Removed: however, FKC and the Third Party Dialysis Organizations are not obligated to utilize vadadustat in its clinics.
−Removed: During the term of the Vifor Agreement, Vifor Pharma will not sell to FKC, its affiliates, or Third Party Dialysis Organizations any HIF product that competes with vadadustat in the United States, and we may not directly supply vadadustat to FKC or any other affiliate of FMCNA or any Third Party Dialysis Organization.
+Added: On February 18, 2022, we entered into the Vifor Second Amended Agreement with Vifor Pharma, which amended and restated the Vifor First Amended Agreement.
+Added: Pursuant to the Vifor Second Amended Agreement, we granted Vifor Pharma an exclusive license to sell vadadustat to the Supply Group in the Territory.
+Added: We currently retain rights to commercialize vadadustat for use in the non-dialysis dependent CKD market and to sell to dialysis organizations outside of the Supply Group.
+Added: During the term of the Vifor Second Amended Agreement, Vifor Pharma is not permitted to sell any HIF product that competes with vadadustat in the Territory to the Supply Group.
+Added: Like the Vifor First Amended Agreement, the Vifor Second Amended Agreement is structured as a profit share arrangement between us and Vifor Pharma in which we will receive approximately 66% of the profit, net of certain pre-specified costs.
+Added: Under the Vifor First Amended Agreement, Vifor Pharma will make an upfront payment to us of $25 million in lieu of the previously disclosed milestone payment of $25 million that Vifor Pharma was to pay to us following approval of vadadustat by the FDA.
+Added: In addition, Vifor Pharma made an equity investment in us, as further described below.
+Added: We currently retain rights to commercialize vadadustat for use in the non-dialysis dependent CKD market and to sell to dialysis organizations outside of the Supply Group.
+Added: As under the Vifor First Amended Agreement, during the term of the Vifor Second Amended Agreement, Vifor Pharma is not permitted to sell any HIF product that competes with vadadustat in the Territory to the Supply Group.
+Added: As under the Vifor First Amended Agreement, the Vifor Second Amended Agreement provides that Akebia and Vifor Pharma will enter into a commercial supply agreement for vadadustat pursuant to which we will supply all of Vifor Pharma’s requirements for vadadustat in the Territory.
+Added: Under the Vifor Second Amended Agreement, Vifor Pharma will contribute $40 million to a working capital facility established to partially fund our costs of purchasing vadadustat from our contract manufacturers, which amount of funding will fluctuate, and which funding we will repay to Vifor Pharma over time.
+Added: Unless earlier terminated, the Vifor Second Amended Agreement will expire upon the later of the expiration of all patents that claim or cover vadadustat or the expiration of marketing or regulatory exclusivity for vadadustat in the Territory.
+Added: Vifor Pharma may terminate the Vifor Second Amended Agreement in its entirety upon 30 months’ prior written notice after the first anniversary of the receipt of regulatory approval, if approved, from the FDA for vadadustat for dialysis-dependent CKD patients.
+Added: We may terminate the Vifor Second Amended Agreement in its entirety for convenience, following the earlier of a certain period of time elapsing or following certain specified regulatory events, and upon six months’ prior written notice.
+Added: If we so terminate for convenience, subject to a specified exception, we will pay a termination fee to Vifor Pharma.
+Added: In addition, either party may, subject to a cure period, terminate the Vifor Second Amended Agreement in the event of the other party’s uncured material breach or bankruptcy.
+Added: We may also terminate the Vifor Second Amended Agreement upon the occurrence of certain other events.
+Added: The Vifor Second Amended Agreement also continues to include a standstill provision and customary representations and warranties.
+Added: Also in connection with entering into the Vifor Second Amended Agreement, on February 18, 2022, we and Vifor Pharma entered into an Investment Agreement, or the Investment Agreement, pursuant to which we sold an aggregate of 4,000,000 shares of our common stock to Vifor Pharma for a total of $20.0 million dollars.
+Added: For more information on the Vifor Second Amended Agreement and Investment Agreement with Vifor Pharma, see Note 18 to our consolidated financial statements in Part II, Item 8.
+Added: Financial Statements and Supplementary Data of this Annual Report on Form 10-K.
Janssen Pharmaceutica NV Research and License Agreement
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Once a compound was designated for development and commercialization, we were to be solely responsible for the development and commercialization of the compound worldwide at our own cost and expense.
−Removed: Under the terms of the Janssen Agreement, we paid an upfront payment of $1.0 million in cash to Janssen and issued a warrant to purchase 509,611 shares of our common stock.
+Added: Under the terms of the Janssen Agreement, we paid an upfront payment of $1.0 million in cash to Janssen and issued a warrant to purchase 509,611 shares of our common stock, which expired on February 9, 2022.
In addition, Janssen could be eligible to receive up to an aggregate of $16.5 million from us in specified development milestone payments on a product-by-product basis.
Janssen will also be eligible to receive up to $215.0 million from us in specified commercial milestones as well as tiered, escalating royalties ranging from a low to mid-single digit percentage of net sales, on a product-by-product basis, and subject to reduction upon expiration of patent rights or the launch of a generic product in the territory.
−Removed: Unless earlier terminated, the Janssen Agreement will expire on a product-by-product and country-by-country basis upon the expiration of the last royalty term, which ends upon the longer of the expiration of the patents licensed under the Janssen Agreement, the expiration of regulatory exclusivity for such product, or 10 years from first commercial sale of such product.
+Added: Unless earlier terminated, the Janssen Agreement will expire on a product-by-product and country-by-country basis upon the expiration of the last royalty term, which ends upon the longer of the expiration of the patents licensed under the Janssen
+Added: Agreement, the expiration of regulatory exclusivity for such product, or 10 years from first commercial sale of such product.
We may terminate the Janssen Agreement in its entirety or only with respect to a particular licensed compound or product upon 180 days’ prior written notice to Janssen.
1 unchanged sentence
As discussed above, we issued a Common Stock Purchase Warrant, or the Warrant, to Johnson & Johnson Innovation – JJDC, Inc., or JJDC, an affiliate of Janssen, for 509,611 shares of our common stock at an exercise price of $9.81 per share.
−Removed: The Warrant is exercisable by JJDC, in whole or in part, at any time prior to February 9, 2022.
−Removed: The Warrant and the shares issuable upon exercise of the Warrant will be sold and issued without registration under the Securities Act of 1933, as amended, or the Securities Act.
+Added: The Warrant was issued without registration under the Securities Act of 1933, as amended, or the Securities Act.
+Added: The Warrant was exercisable by JJDC, in whole or in part, at any time prior to February 9, 2022.
We recorded the fair value of the Warrant in the amount of $3.4 million to additional paid-in capital and research and development expense in March 2017.
+Added: Cyclerion Therapeutics License Agreement
+Added: On June 4, 2021, we entered into the Cyclerion Agreement with Cyclerion, pursuant to which Cyclerion granted us an exclusive global license under certain intellectual property rights to research, develop and commercialize praliciguat, an investigational oral sGC stimulator.
+Added: Under the terms of the Cyclerion Agreement, we made an upfront payment of $3.0 million in cash to Cyclerion, which was paid during the second quarter of 2021.
+Added: In addition, Cyclerion is eligible to receive up to an aggregate of $222.0 million from us in specified development and regulatory milestone payments on a product-by-product basis.
+Added: Cyclerion will also be eligible to receive specified commercial milestones as well as tiered royalties ranging from a mid-single-digit to mid-teen percentage of net sales, on a product-by-product basis, and subject to reduction upon expiration of patent rights or the launch of a generic product in the territory.
+Added: We recorded the upfront payment in the amount of $3.0 million to research and development expense in June 2021.
+Added: Unless earlier terminated, the Cyclerion Agreement will expire on a product-by-product and country-by-country basis upon the expiration of the last royalty term, which ends upon the longest of (i) the expiration of the patents licensed under the Cyclerion Agreement, (ii) the expiration of regulatory exclusivity for such product, and (iii) 10 years from first commercial sale of such product.
+Added: We may terminate the Cyclerion Agreement in its entirety or only with respect to a particular licensed compound or product upon 180 days' prior written notice to Cyclerion.
+Added: We and Cyclerion also have customary termination rights, subject to a cure period, in the event of the other party’s material breach of the Cyclerion Agreement or in the event of certain additional circumstances.
License Agreement with Panion & BF Biotech, Inc.
Prior to the Merger, Keryx entered into a license agreement, or the Panion License Agreement, which was amended from time to time, with Panion & BF Biotech, Inc., or Panion, under which Keryx in-licensed the exclusive worldwide rights, excluding certain Asian-Pacific countries, or the Licensor Territory, for the development and commercialization of ferric citrate.
−Removed: On April 17, 2019, we and Panion entered into a second amended and restated license agreement, or the Panion Amended License Agreement, which amends and restates in full the Panion License Agreement, effective as of April 17, 2019.
+Added: On April 17, 2019, we and Panion entered into a second amended and restated license agreement, or the Panion Amended License Agreement, which amends and restates in full the Panion License Agreement.
The Panion Amended License Agreement provides Keryx with an exclusive license under Panion-owned know-how and patents covering the rights to sublicense, develop, make, use, sell, offer for sale, import and export ferric citrate worldwide, excluding the Licensor Territory.
The Panion Amended License Agreement also provides Panion with an exclusive license under Keryx-owned patents covering the rights to sublicense (with our written consent), develop, make, use, sell, offer for sale, import and export ferric citrate in certain countries in the Licensor Territory.
−Removed: Consistent with the Panion License Agreement, under the Panion Amended License Agreement, Panion is eligible to receive from us or any sublicensee royalty payments based on a mid-
−Removed: single digit percentage of sales of ferric citrate in our licensed territories.
+Added: Consistent with the Panion License Agreement, under the Panion Amended License Agreement, Panion is eligible to receive from us or any sublicensee royalty payments based on a mid-single digit percentage of sales of ferric citrate in our licensed territories.
We are eligible to receive from Panion or any sublicensee royalty payments based on a mid-single digit percentage of net sales of ferric citrate in Panion’s licensed territories.
2 unchanged sentences
We and Panion also each have the right to terminate the Panion Amended License Agreement upon the occurrence of a material breach of the Panion Amended License Agreement by the other party, subject to certain cure provisions, or certain insolvency events.
−Removed: The Panion Amended License Agreement also provides that, on a country-by-country basis, until the second anniversary of the expiration of our or Panion’s obligation, as applicable, to pay royalties in a country in which such party has ferric citrate for sale on the date of such expiration, neither the other party nor its affiliates will, directly or indirectly, sell, distribute or otherwise commercialize or supply or cause to supply ferric citrate to a third party for sale or distribution in such country.
−Removed: In addition, the Panion Amended License Agreement provides that each of us and Panion has the right, but not the obligation, to conduct litigation against any infringer of certain patent rights under the Panion Amended License Agreement in certain territories.
−Removed: During the year-ended December 31, 2020, Panion earned $11.2 million in royalty payments relating to the sales of Auryxia in the United States and JT and Torii net sales of Riona in Japan, as we are required to pay a mid-single digit percent of sublicense income to Panion under the terms of the license agreement, excluding any income under the JT and Torii sublicense.
+Added: The Panion Amended License Agreement also provides that, on a country-by-country basis, during the term and until the second anniversary of the expiration of our or Panion’s obligation, as applicable, to pay royalties in a country in which such party has ferric citrate for sale on the date of such expiration, neither the other party nor its affiliates will, directly or indirectly, sell, distribute or otherwise commercialize or supply or cause to supply ferric citrate to a third party for sale or distribution in such country.
+Added: In addition, the
+Added: Panion Amended License Agreement provides that each of us and Panion has the right, but not the obligation, to conduct litigation against any infringer of certain patent rights under the Panion Amended License Agreement in certain territories.
+Added: During the year-ended December 31, 2021, Panion earned $11.8 million in royalty payments relating to the sales of Auryxia in the United States and JT and Torii net sales of Riona in Japan, as we are required to pay a mid-single digit percent of JT and Torii’s net sales of Riona in Japan to Panion under the terms of the Panion Amended License Agreement.
Sublicense Agreement with Japan Tobacco Inc.
4 unchanged sentences
Ferric citrate hydrate, which launched in May 2014 and is being marketed in Japan by Torii under the brand name Riona, is indicated as an oral treatment for the improvement of hyperphosphatemia in patients with CKD, including NDD-CKD and DD-CKD.
−Removed: In July 2019, JT and Torii, reported positive top-line results from a pivotal Phase 3 comparative study evaluating Riona for the treatment of IDA in adult patients in Japan.
+Added: In July 2019, JT and Torii, reported positive top-line results from a pivotal Phase 3 comparative study evaluating Riona for the treatment of IDA in adult patients in Japan, which was approved in March 2021.
In May 2020, JT and Torii filed an application for approval of IDA as an additional indication for Riona in Japan.
−Removed: Under the terms of the Revised Agreement with JT and Torii, we are eligible to receive royalty payments based on a tiered double-digit percentage of net sales of Riona in Japan escalating up to the mid-teens, subject to certain reductions upon expiration or termination of the Panion Amended License Agreement, and may also receive up to an additional $55.0 million upon the achievement of certain annual net sales milestones.
−Removed: In accordance with our revenue recognition policy, royalty revenues are recognized in the quarter that JT and Torii provide their written report and related information to us regarding sales of Riona, which generally will be one quarter following the quarter in which the underlying sales by JT and Torii occurred.
+Added: Under the terms of the Revised Agreement with JT and Torii, we are eligible to receive royalty payments based on a tiered low double-digit percentage of net sales of Riona in Japan inclusive of amounts that we must pay to Panion on JT and Torii’s net sales of Riona under the Panion Amended License Agreement, subject to certain reductions upon expiration or termination of the Panion Amended License Agreement, and may also receive up to an additional $55.0 million upon the achievement of certain annual net sales milestones.
We recorded $5.8 million in license revenue related to royalties earned on net sales of Riona in Japan during the twelve months ended December 31, 2021.
−Removed: We record the associated mid-single digit percentage of net sales royalty expense due to Panion, the licensor of ferric citrate, in the same period as the royalty revenue from JT and Torii is recorded.
The sublicense under the Revised Agreement terminates upon the expiration of all underlying patent rights.
7 unchanged sentences
See “—Regulatory Matters.”
−Removed: Our commercial success will depend in part on obtaining and maintaining patent protection of our current products as well as current and future product candidates, methods of their use and the methods used to develop and manufacture them, as well as
−Removed: successfully defending these patents against third-party challenges.
+Added: Our commercial success will depend in part on obtaining and maintaining patent protection of our current products as well as current and future product candidates, methods of their use and the methods used to develop and manufacture them, as well as successfully defending these patents against third-party challenges.
Our ability to stop third parties from making, using, selling, offering to sell or importing our products depends on the extent to which we have rights under valid and enforceable patents that cover these activities.
4 unchanged sentences
Generally, patents issued from applications filed in the United States are effective for 20 years from the earliest filing date of a United States non-provisional application or an international application filed under the Patent Cooperation Treaty.
−Removed: In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period, however, the restoration period cannot be longer than five years and the total patent term including the restoration period must not exceed 14 years following FDA approval.
+Added: In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period,
+Added: however, the restoration period cannot be longer than five years and the total patent term including the restoration period must not exceed 14 years following FDA approval.
The duration of foreign patents varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest international filing date.
9 unchanged sentences
Because of the extensive time required for clinical development and regulatory review of a drug we may develop, it is possible that, before any of our drugs can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.
−Removed: The patent positions for Auryxia and vadadustat are summarized below.
+Added: The patent positions for vadadustat and Auryxia are summarized below.
Vadadustat Patent Portfolio
6 unchanged sentences
Auryxia Patent Portfolio
−Removed: Pursuant to Keryx’s license with Panion & BF Biotech, Inc., or Panion, we have the exclusive rights under a series of patents and patent applications to commercialize Auryxia worldwide, excluding certain Asian-Pacific countries.
+Added: Pursuant to Keryx’s license with Panion, we have the exclusive rights under a series of patents and patent applications to commercialize Auryxia worldwide, excluding certain Asian-Pacific countries.
These patents and patent applications include claims directed to compositions of matter, pharmaceutical compositions, methods of treatment, as well as methods for the manufacture of Auryxia.
7 unchanged sentences
To date, to our knowledge, no contested proceedings or third-party claims have been lodged against any of these Japanese patents.
−Removed: We have received Paragraph IV certification notice letters regarding ANDAs submitted to the FDA requesting approval for generic versions of Auryxia tablets (210 mg ferric iron per tablet), have filed certain complaints for patent infringement relating to such ANDAs, and have entered into settlement and license agreements with three ANDA filers.
+Added: We received Paragraph IV certification notice letters regarding ANDAs submitted to the FDA requesting approval for generic versions of Auryxia tablets (210 mg ferric iron per tablet), filed certain complaints for patent infringement relating to such
+Added: ANDAs, and have entered into settlement and license agreements with each of the ANDA filers.
See Part II, Item 3.
9 unchanged sentences
We may also seek to utilize market exclusivities in other territories.
−Removed: We cannot assure that our drug products or any drug candidates we may acquire or in-license, will obtain such orphan drug designation, pediatric exclusivity, new chemical entity exclusivity or any other market exclusivity in the United States, European Union or any other territory, or that we will be the first to receive the respective regulatory approval for such drugs so as to be eligible for any market exclusivity protection.
+Added: We cannot assure you that our drug products or any drug candidates we may acquire or in-license, will obtain such orphan drug designation, pediatric exclusivity, new chemical entity exclusivity or any other market exclusivity in the United States, European Union or any other territory, or that we will be the first to receive the respective regulatory approval for such drugs so as to be eligible for any market exclusivity protection.
In addition to patents, we rely upon unpatented know-how and continuing technological innovation to develop and maintain our competitive position.
9 unchanged sentences
An ANDA provides for marketing of a drug product that has the same active ingredients in the same strengths and dosage form as the listed drug and has been shown through bioequivalence testing to be therapeutically equivalent to the listed drug.
−Removed: Other than the
−Removed: requirement for bioequivalence testing, ANDA applicants are usually not required to conduct, or submit results of, nonclinical or clinical tests to prove the safety or effectiveness of their drug product.
+Added: Other than the requirement for bioequivalence testing, ANDA applicants are usually not required to conduct, or submit results of, nonclinical or clinical tests to prove the safety or effectiveness of their drug product.
Drugs approved in this way are commonly referred to as “generic equivalents” to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.
13 unchanged sentences
If there is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA may be filed before the expiration of the exclusivity period.
−Removed: On August 23, 2018, Keryx submitted a Citizen Petition requesting, inter alia, that FDA recognize that Auryxia is eligible for five years of NCE exclusivity based on its novel active ingredient and for three years exclusivity for the IDA Indication.
−Removed: On January 19, 2019, FDA responded that Auryxia is eligible for a three-year exclusivity period for the IDA Indication, which expires on November 6, 2020.
−Removed: FDA, however, denied the NCE exclusivity based on its determination that Auryxia contains a previously-approved active moiety (ferric cation).
−Removed: FDA’s decision on the Citizen Petition is subject to further review both within FDA and in the courts.
−Removed: On February 21, 2019, Akebia filed a Petition for Reconsideration of FDA’s decision on the NCE determination for Auryxia.
Patent Term Extension
2 unchanged sentences
The time can be shortened if the FDA determines that the applicant did not pursue approval with due diligence.
−Removed: The total patent term after the extension may not exceed 14 years.
+Added: The total patent term after the extension may not exceed 14 years from the date of approval by virtue of the patent term extension.
We have filed applications under the patent term extension provisions of 35 U.S.C.
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The director of the USPTO must determine that approval of the drug covered by the patent for which a patent extension is being sought is likely.
−Removed: We have filed for and received interim patent term extension in accordance with 35 U.S.C.
+Added: We previously filed for and received interim patent term extension in accordance with 35 U.S.C.
§ 156(e)(2) for U.S.
−Removed: 5,753,706, which currently has an expiration date of February 3, 2022.
+Added: 5,753,706 until February 3, 2022.
In addition, certain jurisdictions outside of the U.S., including Japan, have provisions that provide for patent term extension.
3 unchanged sentences
4964585 and 4173553 will expire in November 2025 and November 2022, respectively.
+Added: In the future, if and when our product candidates, including vadadustat, receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those drugs, depending upon the length of the clinical trials for each product candidate and other factors.
+Added: There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.
The pharmaceutical and biotechnology industries are highly competitive.
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To compete successfully in this industry, we must identify novel and unique drugs or methods of treatment and then complete the development of those drugs as treatments in advance of our competitors.
−Removed: If vadadustat is approved and launched commercially, competing branded drugs may include EPOGEN ® (epoetin alfa) and Aranesp ® (darbepoetin alfa), both commercialized by Amgen, Procrit ® (epoetin alfa) and Eprex ® (epoetin alfa), commercialized by Johnson & Johnson in the United States and Europe, respectively, and Mircera ® (methoxy PEG-epoetin beta), commercialized by Vifor Pharma in the United States and Roche Holding Ltd.
−Removed: outside the United States.
−Removed: We may also face competition from potential new anemia therapies.
−Removed: There are several other HIF-PHI product candidates in various stages of active development for anemia indications that may be in direct competition with vadadustat if and when they are approved and launched commercially.
−Removed: These candidates are being developed by such companies as FibroGen, Inc., or FibroGen, Japan Tobacco International, GlaxoSmithKline plc and Bayer HealthCare AG.
−Removed: FibroGen, together with its collaboration partners, Astellas Pharma Inc.
−Removed: and AstraZeneca PLC, is currently in global Phase 3 clinical development of its HIF-PHI product candidate, roxadustat.
−Removed: In Japan, roxadustat has launched for the treatment of anemia due to CKD in patients on dialysis, or DD-CKD.
−Removed: In November 2020, Astellas and Fibrogen announced the approval of roxadustat for NDD-CKD patients in Japan.
−Removed: In China, roxadustat has launched for the treatment of anemia of DD-CKD and for the treatment of anemia due to CKD in patients not on dialysis, or NDD-CKD .
−Removed: FibroGen announced that the FDA has set a Prescription Drug User Fee Act, or PDUFA, date of March 20, 2021 for its NDA for roxadustat for both DD-CKD and NDD-CKD.
−Removed: In Japan, roxadustat, daprodustat and enarodustat are approved for treatment of anemia due to CKD.
−Removed: In addition, Bayer HealthCare AG has submitted an NDA for its product candidate for the treatment of renal anemia in Japan.
+Added: Drugs that may compete with vadadustat, if approved, include Epogen® (epoetin alfa) and Aranesp® (darbepoetin alfa), both commercialized by Amgen, Procrit® (epoetin alfa) and Eprex® (epoetin alfa), commercialized by Johnson & Johnson in the United States and Europe, respectively, and Mircera® (methoxy PEG-epoetin beta), commercialized by Vifor Pharma in the United States and Roche Holding Ltd.
+Added: outside of the United States.
+Added: We and our partners may also face competition from potential new anemia therapies.
+Added: There are several other HIF-PH inhibitor product candidates in various stages of development for anemia indications that may be in direct competition with vadadustat if and when they are approved and launched commercially.
+Added: These candidates are being developed by companies such as FibroGen Inc., or FibroGen, together with its collaboration partners, Astellas Pharma Inc.
+Added: and AstraZeneca PLC, Japan Tobacco International, or JT, GlaxoSmithKline plc, or GSK, and Bayer HealthCare AG, or Bayer.
Furthermore, certain companies are developing potential new therapies for renal-related diseases that could potentially reduce injectable ESA utilization and thus limit the market potential for vadadustat if they are approved and launched commercially.
+Added: Other new therapies are in development for the treatment of conditions inclusive of renal anemia that may impact the market for anemia-targeted treatment.
+Added: In addition, in the United States, FibroGen filed an NDA for its product candidate, roxadustat, with the FDA, but the FDA issued a complete response letter indicating the FDA will not approve the NDA in its present form.
+Added: In Europe however, roxadustat is approved for the treatment of anemia in patients with CKD.
+Added: In Japan, Vafseo, which is approved for patients with CKD, including both DD-CKD and NDD-CKD, competes with roxadustat, daprodustat and enarodustat.
+Added: Roxadustat is approved for the treatment of anemia due to CKD, including DD-CKD and NDD-CKD patients.
+Added: In addition, daprodustat, GSK’s product candidate, and enarodustat, JT’s product candidate, are approved in Japan for the treatment of anemia due to CKD.
+Added: In addition, Bayer HealthCare AG has submitted a new drug application for its product candidate for the treatment of renal anemia in Japan.
+Added: In China, FibroGen launched roxadustat for the treatment of anemia of DD-CKD and for the treatment of anemia due to CKD in NDD-CKD patients.
A biosimilar is a biologic product that is approved based on demonstrating that it is highly similar to an existing, FDA-approved branded biologic product.
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In addition, an application for a biosimilar product cannot be approved by the FDA until 12 years after the existing, branded product was approved under a Biologics License Application, or BLA.
−Removed: The patents for epoetin alfa, an injectable ESA, expired in 2004 in the European Union, and the remaining patents expired between 2012 and 2016 in the United States.
−Removed: Because injectable ESAs are biologic products, the introduction of biosimilars into the injectable ESA market in the United States will constitute additional competition for vadadustat if we are able to obtain approval for and commercially launch our product.
−Removed: Several biosimilar versions of injectable ESAs are available for sale in the European Union.
−Removed: In the United States, Pfizer’s biosimilar version of injectable ESAs, Retacrit ® (epoetin alfa-epbx), was approved by the FDA in May 2018 and launched in November 2018 by Vifor Pharma.
+Added: The patents for epoetin alfa, an injectable ESA, expired in 2004 in the EU, and the remaining patents expired between 2012 and 2016 in the United States.
+Added: Because injectable ESAs are biologic products, the introduction of biosimilars into the injectable ESA market in the United States will constitute additional competition for vadadustat if we are able to obtain approval for and commercially launch vadadustat.
+Added: In the United States, Pfizer’s biosimilar version of injectable ESAs, Retacrit® (epoetin alfa-epbx), was approved by the FDA in May 2018 and launched in November 2018 and several biosimilar versions of injectable ESAs are available for sale in the EU.
+Added: Furthermore, vadadustat’s commercial opportunities, if approved, may be reduced or eliminated if our competitors develop and market products that are less expensive, more effective, safer or offer greater patient convenience than vadadustat.
Hyperphosphatemia Competition
−Removed: Auryxia competes in the Hyperphosphatemia Indication in the United States with other FDA-approved phosphate binders such as Renagel ® (sevelamer hydrochloride) and Renvela ® (sevelamer carbonate), both marketed by Genzyme Corporation (a wholly-owned subsidiary of Sanofi), PhosLo ® and Phoslyra ® (calcium acetate), marketed by Fresenius Medical Care North America, Fosrenol ® (lanthanum carbonate), marketed by Shire Pharmaceuticals Group plc, and Velphoro ® (sucroferric oxyhydroxide), marketed by Fresenius Medical Care North America, as well as over-the-counter calcium carbonate products such as TUMS ® and metal-based options such as aluminum, lanthanum and magnesium.
−Removed: Many of the phosphate binders listed above are now also available in generic forms.
−Removed: In addition, other phosphate binders are in various phases of development, including OPKO Health Inc.’s Alpharen™ Tablets (fermagate tablets) and Ardelyx, Inc’s tenapanor, that may impact the market for Auryxia.
+Added: Auryxia is competing in the hyperphosphatemia market in the United States with other FDA-approved phosphate binders such as Renagel® (sevelamer hydrochloride) and Renvela® (sevelamer carbonate), both marketed by Sanofi, PhosLo® and Phoslyra® (calcium acetate), marketed by Fresenius Medical Care North America, Fosrenol® (lanthanum carbonate), marketed
+Added: by Shire Pharmaceuticals Group plc, and Velphoro® (sucroferric oxyhydroxide), marketed by Fresenius Medical Care North America, as well as over-the-counter calcium carbonate products such as TUMS® and metal-based options such as aluminum, lanthanum and magnesium.
+Added: Most of the phosphate binders listed above are now also available in generic forms.
+Added: In addition, other agents are in development, including OPKO Health Inc.’s Alpharen™ Tablets (fermagate tablets) or could otherwise enter the market, including Ardelyx, Inc.’s tenapanor (which is approved in the U.S.
+Added: for the treatment of adults with irritable bowel syndrome with constipation, but for which the FDA issued a complete response letter with respect to the control of serum phosphorus in adult patients with CKD on dialysis) , that may impact the market for Auryxia.
Iron Deficiency Anemia Competition
−Removed: Auryxia competes in the IDA Indication in the United States with over-the-counter oral iron, other prescription oral iron formulations, including ferrous sulfate, ferrous gluconate, ferrous fumerate, and polysaccharide iron complex, and IV iron formulations, including Feraheme ® (ferumoxytol injection), Venofer ® (iron sucrose injection), Ferrlicit ® (sodium ferric gluconate complex in sucrose injection), Injectafer ® (ferric carboxymaltose injection), and Triferic ® (ferric pyrophosphate citrate).
−Removed: In addition, other new therapies are available for the treatment of IDA that may impact the market for Auryxia, such as Shield Therapeutics’ ferric maltol, which is currently approved in Europe as Ferracru ® for IDA and more recently in the United States as Accrufer ® .
+Added: Auryxia is competing in the IDA market in the United States with over-the-counter oral iron, ferrous sulfate, other prescription oral iron formulations, including ferrous gluconate, ferrous fumerate, and polysaccharide iron complex, and intravenous iron formulations, including Feraheme® (ferumoxytol injection), Venofer® (iron sucrose injection), Ferrlicit® (sodium ferric gluconate complex in sucrose injection), Injectafer® (ferric carboxymaltose injection), and Triferic® (ferric pyrophosphate citrate).
+Added: In addition, other new therapies for the treatment of IDA may impact the market for Auryxia, such as Shield Therapeutic’ plc's Feraccru® (ferric maltol), which is available in Europe for the treatment of IDA, and Accrufer® (ferric maltol), which was launched in the United States for the treatment of IDA in July 2021.
+Added: Furthermore, Auryxia’s commercial opportunities may be reduced or eliminated if our competitors develop and market products that are less expensive, more effective, safer or offer greater patient convenience than Auryxia.
+Added: Other companies have product candidates in various stages of preclinical or clinical development to treat diseases and complications of the diseases for which we are marketing Auryxia.
+Added: In addition, we entered into settlement agreements with each of our ANDA filers pursuant to which we granted licenses to market a generic version of Auryxia in the United States beginning in March 2025 (subject to FDA approval), or earlier under certain circumstances customary for settlement agreements of this nature, which may impact our business and results of operation.
Government Regulation and Product Approvals
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The failure to comply with applicable requirements under the FDCA and other applicable laws at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.
+Added: Our product candidates must be approved by the FDA for therapeutic indications before we or our partners are able to market them in the United States.
An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following:
• completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations and consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, or ICH, requirements;
−Removed: • submission to the FDA of an IND, which must be reviewed and active by the FDA before human clinical trials may begin;
+Added: • design of a clinical protocol and submission to the FDA of an IND, which must be reviewed and active by the FDA before human clinical trials may begin;
• approval by an independent local or central institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;
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Preclinical Studies
−Removed: Before an applicant begins testing a compound with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.
−Removed: Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug product, as well as in vitro and animal studies to assess the safety and activity of the product candidate for initial testing in humans and to establish a rationale for therapeutic use.
−Removed: The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations.
+Added: Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.
+Added: Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as other studies to evaluate, among other things, the toxicity of the product candidate.
+Added: The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards and the United States Department of Agriculture’s Animal Welfare Act, if applicable .
+Added: The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND.
+Added: Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and long-term toxicity studies, may continue after the IND is submitted.
The IND and IRB Processes
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An IRB must operate in compliance with FDA regulations.
−Removed: An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.
−Removed: Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on its website.
+Added: An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if
+Added: the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.
+Added: A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND.
+Added: When a foreign clinical study is conducted under an IND, all IND requirements must be met unless waived by the FDA.
+Added: When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval.
+Added: Specifically, the studies must be conducted in accordance with GCP, including undergoing review and receiving approval by an independent ethics committee, or IEC, and seeking and receiving informed consent from subjects.
+Added: GCP requirements encompass both ethical and data integrity standards for clinical trials.
+Added: The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as well as the quality and integrity of the resulting data.
+Added: Reporting Clinical Trial Results
+Added: Under the Public Health Service Act, or PHSA, sponsors of clinical trials of certain FDA-regulated products, including prescription drugs and biologics, are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S.
+Added: National Institutes of Health, or NIH.
+Added: In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial.
+Added: Although sponsors are also obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for up to two years after the date of completion of the trial.
+Added: The NIH’s Final Rule on registration and reporting requirements for clinical trials became effective in 2017, and both NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.
+Added: Specifically, the PHSA grants the Secretary of the U.S.
+Added: Department of Health and Human Services, or HHS, the authority to issue a notice of noncompliance to a responsible party for failure to submit clinical trial information as required.
+Added: The responsible party, however, is allowed 30 days to correct the noncompliance and submit the required information.
+Added: The failure to submit clinical trial information to clinicaltrials.gov, as required, is also a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.
+Added: In addition to civil monetary penalties, violations may also result in other regulatory action, such as injunction and/or criminal prosecution or disqualification from federal grants.
+Added: Although the FDA has historically not enforced these reporting requirements due to HHS’s long delay in issuing final implementing regulations, those regulations have now been issued and the FDA did issue its first Notice of Noncompliance to a manufacturer in April 2021.
Expanded Access to an Investigational Drug for Treatment Use
−Removed: Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or
−Removed: satisfactory alternative treatment options.
+Added: Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.
The rules and regulations related to expanded access are intended to improve access to investigational drugs for patients who may benefit from investigational therapies.
3 unchanged sentences
and larger populations for use of the drug under a treatment protocol or Treatment IND Application.
+Added: There is no obligation for a sponsor to make its investigational products available for expanded access;
+Added: however, as required by amendments to the FDCA included in the 21st Century Cures Act, or the Cures Act, passed in 2016, if a sponsor has a policy regarding how it responds to expanded access requests with respect to product candidates in development to treat serious diseases or conditions, it must make that policy publicly available.
+Added: Sponsors are required to make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 study for a covered investigational product;
+Added: or 15 days after the investigational product receives designation from the FDA as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.
On May 30, 2018, the Right to Try Act was signed into law.
1 unchanged sentence
Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.
−Removed: There is no obligation for a drug manufacturer to make its product candidates available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.
+Added: There is no obligation for a
+Added: drug manufacturer to make its product candidates available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.
Human Clinical Trials in Support of an NDA
8 unchanged sentences
These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
+Added: A clinical trial may combine the elements of more than one phase and the FDA often requires more than one Phase 3 trial to support marketing approval of a product candidate.
+Added: A company’s designation of a clinical trial as being of a particular phase is not necessarily indicative that the study will be sufficient to satisfy the FDA requirements of that phase because this determination cannot be made until the protocol and data have been submitted to and reviewed by the FDA.
+Added: Moreover, as noted above, a pivotal trial is a clinical trial that is believed to satisfy FDA requirements for the evaluation of a product candidate’s safety and efficacy such that it can be used, alone or with other pivotal or non-pivotal trials, to support regulatory approval.
+Added: Generally, pivotal trials are Phase 3 trials, but they may be Phase 2 trials if the design provides a well-controlled and reliable assessment of clinical benefit, particularly in an area of unmet medical need.
Progress reports detailing the results of the clinical trials conducted under the IND must be submitted at least annually to the FDA and, more frequently, if serious adverse events occur.
5 unchanged sentences
The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.
−Removed: Under the Pediatric Research Equity Act of 2003, or PREA, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
−Removed: With enactment of the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012, sponsors must also submit pediatric study plans prior to the assessment data.
−Removed: Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation.
−Removed: The legislation requires the FDA to meet with drug sponsors by no later than the end-of-Phase 1 meeting for serious or life-threatening diseases and by no later than ninety days after the FDA’s receipt of the study plan.
−Removed: FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
−Removed: Submission of an NDA to the FDA
+Added: In response to the COVID-19 pandemic, the FDA issued guidance on March 18, 2020, and has updated it periodically since that time to address the conduct of clinical trials during the pandemic.
+Added: The guidance sets out a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical study report (or as a separate document) contingency measures implemented to manage the study, and any disruption of the study as a result of COVID-19;
+Added: a list of all study participants affected by COVID-19-related study disruptions by a unique subject identifier and by investigational site, and a description of how the individual’s participation was altered;
+Added: and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study, among other things.
+Added: The FDA has indicated that it will continue to provide any necessary guidance to sponsors, clinical investigators, and research institutions as the public health emergency evolves.
+Added: Pediatric Studies
+Added: Under the Pediatric Research Equity Act, or PREA, applications and certain types of supplements to applications must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
+Added: The sponsor must submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-phase 2 meeting or as may be agreed between the sponsor and the FDA.
+Added: Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.
+Added: The sponsor and the FDA must reach agreement on a final plan.
+Added: A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from nonclinical trials, early phase clinical trials, and/or other clinical development programs.
+Added: For investigational products intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of an applicant, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.
+Added: In addition, the FDA will meet early in the development process to discuss pediatric study plans with sponsors, and the FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than ninety days after the FDA’s receipt of the study plan.
+Added: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
+Added: A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.
+Added: Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although FDA has recently taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.
+Added: The FDA also maintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric population.
+Added: Acceptance and Review of an NDA
Assuming successful completion of required clinical testing and other requirements, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things are submitted to the FDA as part of an NDA requesting approval to market the product candidate for one or more indications.
−Removed: Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2020 is $2,875,842 for an application requiring clinical data.
−Removed: The sponsor of an approved NDA is also subject to an annual program fee, which for fiscal year 2021 is $336,432.
−Removed: Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for product candidates with orphan designation and a waiver for certain small businesses.
−Removed: The FDA conducts a preliminary review of an NDA within 60 days of its receipt and strives to inform the sponsor by the 74th day after the FDA’s receipt of the submission to determine whether the application is sufficiently complete to permit substantive review.
+Added: The fee required for the submission and review of an application under the Prescription Drug User Fee Act, or PDUFA, is substantial (for example, for fiscal year 2022 this application fee is approximately $3.1 million), and the sponsor of an approved application is also subject to an annual program fee, currently more than $369,000 per eligible prescription product.
+Added: These fees are typically adjusted annually, and exemptions and waivers may be available under certain circumstances, such as where a waiver is necessary to protect the public health, where the fee would present a significant barrier to innovation, or where the applicant is a small business submitting its first human therapeutic application for review.
+Added: The FDA conducts a preliminary review of all applications within 60 days of receipt and must inform the sponsor at that time or before whether an application is sufficiently complete to permit substantive review.
This is known as the filing decision.
+Added: In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File determination to the applicant.
The FDA may request additional information rather than accept an NDA for filing.
7 unchanged sentences
Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.
−Removed: These pre-approval inspections may cover all facilities associated with an NDA submission, including drug component manufacturing such as active pharmaceutical ingredients, finished drug product manufacturing, control testing laboratories, as well as packaging and labeling facilities.
+Added: These pre-approval inspections may cover all facilities associated with an NDA submission, including drug component
+Added: manufacturing such as active pharmaceutical ingredients, finished drug product manufacturing, control testing laboratories, as well as packaging and labeling facilities.
The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
13 unchanged sentences
Second, in 2012, Congress enacted the Food and Drug Administration Safety and Improvement Act.
−Removed: This law established a new regulatory scheme allowing for expedited review of products designated as “breakthrough therapies.” A product may be
−Removed: designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
+Added: This law established a new regulatory scheme allowing for expedited review of products designated as “breakthrough therapies.” A product may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process;
6 unchanged sentences
A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s review clock goal for taking action on a marketing application from ten months to six months.
−Removed: For new chemical entities, or NCEs, the review clock starts after the NDA is filed with a total clock of twelve and eight months, respectively.
Priority Review Vouchers
A PRV is a voucher that the FDA issues to a sponsor of a rare pediatric disease or tropical disease product application at the time of the marketing application approval.
−Removed: Vouchers are transferrable to other sponsors that may apply it to their NDAs or BLAs.
+Added: Vouchers are transferable to other sponsors that may apply it to their NDAs or BLAs.
A PRV entitles the holder to designate a single human drug application submitted under Section 505(b)(1) of the U.S.
2 unchanged sentences
Applying the PRV to a marketing application does not ensure the FDA’s approval of the marketing application and all requirements supporting the safety and efficacy of the product must be met.
+Added: Our NDA submission for vadadustat did not include a PRV.
The FDA’s Decision on an NDA
−Removed: On the basis of the FDA’s evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.
−Removed: An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.
−Removed: A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing, analyses, or information in order for the FDA to reconsider the application.
−Removed: This may include the requirement to conduct another clinical study or studies.
−Removed: If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.
−Removed: The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.
−Removed: Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
−Removed: If the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and profitability of the product.
−Removed: The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.
−Removed: After approval, many types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
+Added: The FDA reviews an application to determine, among other things, whether the product is safe and whether it is effective for its intended use(s), with the latter determination being made on the basis of substantial evidence.
+Added: The term “substantial evidence” is defined under the FDCA as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the product involved, on the basis of which it could fairly and responsibly be concluded by such experts that the product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”
+Added: The FDA has interpreted this evidentiary standard to require at least two adequate and well-controlled clinical investigations to establish effectiveness of a new product.
+Added: Under certain circumstances, however, FDA has indicated that a single trial with certain characteristics and additional information may satisfy this standard.
+Added: This approach was subsequently endorsed by Congress in 1998 with legislation providing, in pertinent part, that “If [FDA] determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, FDA may consider such data and evidence to constitute substantial evidence.” This modification to the law recognized the potential for FDA to find that one adequate and well controlled clinical investigation with confirmatory evidence, including supportive data outside of a controlled trial, is sufficient to establish effectiveness.
+Added: In December 2019, FDA issued draft guidance further explaining the studies that are needed to establish substantial evidence of effectiveness.
+Added: It has not yet finalized that guidance.
+Added: After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue either a Complete Response Letter, or CRL, or an approval letter.
+Added: To reach this determination, the FDA must determine that the drug is effective and that its expected benefits outweigh its potential risks to patients.
+Added: This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the NDA or BLA.
+Added: This assessment is also informed by other factors, including:
+Added: the severity of the underlying condition and how well patients’ medical needs are addressed by currently available therapies;
+Added: uncertainty about how the premarket clinical trial evidence will extrapolate to real-world use of the product in the post-market setting;
+Added: and whether risk management tools are necessary to manage specific risks.
+Added: In connection with this assessment, the FDA review team will assemble all individual reviews and other documents into an “action package,” which becomes the record for FDA review.
+Added: The review team then issues a recommendation, and a senior FDA official makes a decision.
+Added: A CRL indicates that the review cycle of the application is complete, and the application will not be approved in its present form.
+Added: A CRL generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.
+Added: The CRL may require additional clinical or other data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time- consuming requirements related to clinical trials, preclinical studies or manufacturing.
+Added: If a CRL is issued, the applicant will have one year to respond to the deficiencies identified by the FDA, at which time the FDA can deem the application withdrawn or, in its discretion, grant the applicant an additional six month extension to respond.
+Added: The FDA has committed to reviewing resubmissions in response to an issued CRL in either two or six months depending on the type of information included.
+Added: Even with the submission of this additional information, however, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
+Added: The FDA has taken the position that a CRL is not final agency action making the determination subject to judicial review.
+Added: An approval letter, on the other hand, authorizes commercial marketing of the product with specific prescribing information for specific indications.
+Added: That is, the approval will be limited to the conditions of use (e.g., patient population, indication) described in the FDA-approved labeling.
+Added: Further, depending on the specific risk(s) to be addressed, the FDA may require that contraindications, warnings or precautions be included in the product labeling, require that post-approval trials, including Phase 4 clinical trials, be conducted to further assess a product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS which can materially affect the potential market and profitability of the product.
+Added: The FDA may prevent or limit further marketing of a product based on the results of post-marketing trials or surveillance programs.
+Added: After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
+Added: Under the Ensuring Innovation Act, which was signed into law in April 2021, the FDA must publish action packages summarizing its decisions to approve new drugs and biologics within 30 days of approval of such products.
+Added: To date, CRLs are not publicly available documents.
Post-Approval Requirements and Commitments
4 unchanged sentences
Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.
−Removed: After approval, most changes to the approved
−Removed: product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.
+Added: After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.
There also are continuing, annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
17 unchanged sentences
After approval, a drug product generally may not be promoted for uses that are not approved by the FDA or in a manner that is inconsistent with the product’s prescribing information.
+Added: In September 2021, the FDA published final regulations which describe the types of evidence that the agency will consider in determining the intended use of a drug product.
In the United States, healthcare professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as off-label uses, because the FDA does not regulate the practice of medicine.
3 unchanged sentences
However, if a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.
−Removed: This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products.
+Added: This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the
+Added: manner in which a company promotes or distributes drug products.
The federal government has levied large civil and criminal fines against companies for alleged improper promotion and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
−Removed: In addition, the distribution of prescription pharmaceutical products and drug samples are subject to the Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or DSCA, which regulate the distribution and tracing of prescription drugs and prescription drug samples at the federal level and set minimum standards for the regulation of drug distributors by the states.
−Removed: The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.
+Added: In addition, the distribution of prescription pharmaceutical products is subject to a variety of federal and state laws, the most recent of which is still in the process of being phased into the U.S.
+Added: supply chain and regulatory framework.
+Added: The Prescription Drug Marketing Act, or PDMA, was the first federal law to set minimum standards for the registration and regulation of drug distributors by the states and to regulate the distribution of drug samples.
+Added: Today, both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.
+Added: Congress more recently enacted the Drug Supply Chain Security Act, or DSCSA, which made significant amendments to the FDCA, including by replacing certain provisions from the PDMA pertaining to wholesale distribution of prescription drugs with a more comprehensive statutory scheme.
+Added: The DSCSA now requires uniform national standards for wholesale distribution and, for the first time, for third-party logistics providers;
+Added: it also provides for preemption of certain state laws in the areas of licensure and prescription drug traceability.
+Added: Section 505(b)(2) NDAs
+Added: NDAs for most new drug products are based on two full clinical trials which must contain substantial evidence of the safety and efficacy of the proposed new product for the proposed use.
+Added: These applications are submitted under Section 505(b)(1) of the FDCA.
+Added: The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA.
+Added: This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature.
+Added: Specifically, Section 505(b)(2) applies to NDAs for a drug for which the investigations made to show whether or not the drug is safe for use and effective in use and relied upon by the applicant for approval of the application “were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”
+Added: Section 505(b)(2) authorizes the FDA to approve an NDA based on safety and effectiveness data that were not developed by the applicant.
+Added: NDAs filed under Section 505(b)(2) may provide an alternate and potentially more expeditious pathway to FDA approval for new or improved formulations or new uses of previously approved products.
+Added: If the 505(b)(2) applicant can establish that reliance on the FDA’s previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical studies or clinical trials of the new product.
+Added: The FDA may also require companies to perform additional studies or measurements to support the change from the approved product.
+Added: The FDA may then approve the new drug candidate for all or some of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.
+Added: Products approved under Section 505(b)(2) are often referred to as follow-on products.
Abbreviated New Drug Applications for Generic Drugs
4 unchanged sentences
Instead, in support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.
−Removed: Under the Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of non-patent exclusivity for the RLD has expired.
−Removed: The FDCA provides a period of five years of non-patent data exclusivity for a new drug containing a new chemical entity.
−Removed: For the purposes of this provision, a new chemical entity, or NCE, is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA.
+Added: Under the Hatch-Waxman Act, the FDA may not approve an ANDA or 505(b)(2) application until any applicable period of non-patent exclusivity for the RLD has expired.
+Added: The FDCA provides a period of five years of non-patent data exclusivity for a new drug containing a NCE.
+Added: For the purposes of this provision, the FDA has consistently taken the position that an NCE is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA.
+Added: This interpretation was confirmed with enactment of the Ensuring Innovation Act in April 2021.
An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance.
−Removed: In cases where such NCE exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.
+Added: In cases where such NCE exclusivity has been granted, a generic or follow-on drug application may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.
The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to the approval of the application.
1 unchanged sentence
Three-year exclusivity would be available for a drug product that contains a previously approved active moiety, provided the statutory requirement for a new clinical investigation is satisfied.
−Removed: Unlike five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs seeking approval for generic versions of the drug as of the date of approval of the original drug product.
+Added: Unlike five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs or 505(b)(2) applications seeking approval for generic versions of the drug as of the date of approval of the original drug product.
The FDA typically makes decisions about awards of data exclusivity shortly before a product is approved.
−Removed: The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug application within eight months for a drug that has three or fewer approved drugs listed in the Orange Book and is no longer protected by any patent or regulatory exclusivities, or is on the FDA’s drug shortage list.
+Added: The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug application within eight months for a drug that has three or fewer appr oved drugs listed in the Orange Book and is no longer protected by any patent or regulatory exclusivities, or is on the FDA’s drug shortage list.
The new legislation also authorizes FDA to expedite review of ‘‘competitor generic therapies’’ or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.
Hatch-Waxman Patent Certification and the 30-Month Stay
−Removed: Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or an approved method of using the product.
−Removed: Each of the patents listed by the NDA sponsor is published in the Orange Book.
−Removed: When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval.
−Removed: To the extent that the Section 505(b)(2) applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.
−Removed: A description of the information that the applicant must specifically certify to with respect to each patent, and the certification process as it relates to patent infringement lawsuits, is described further in Part I, Item 1.
−Removed: Business – Intellectual Property – The Hatch-Waxman Act.
−Removed: A certification that the new product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.
−Removed: If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders once the ANDA has been accepted for filing by the FDA.
−Removed: The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.
−Removed: The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically
−Removed: prevents the FDA from approving the ANDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.
+Added: As part of the submission of an NDA or certain supplemental applications, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or an approved method of using the product.
+Added: Upon approval of a new drug, each of the patents listed in the application for the drug is then published in the Orange Book.
+Added: The FDA’s regulations governing patent listings were largely codified into law with enactment of the Orange Book Modernization Act in January 2021.
+Added: When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book.
+Added: Specifically, the ANDA applicant must certify that:
+Added: (i) the required patent information has not been filed;
+Added: (ii) the listed patent has expired;
+Added: (iii) the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration;
+Added: or (iv) the listed patent is invalid or will not be infringed by the new product.
+Added: Moreover, to the extent that the Section 505(b)(2) NDA applicant is relying on studies conducted for an already approved product, the applicant also is required to certify to the FDA concerning any patents listed for the NDA-approved product in the Orange Book to the same extent that an ANDA applicant would.
+Added: If the generic drug or follow-on drug applicant does not challenge the innovator’s listed patents, FDA will not approve the ANDA or 505(b)(2) application until all the listed patents claiming the referenced product have expired.
+Added: A certification that the new generic product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.
+Added: If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA owner and patent holders once the ANDA has been accepted for filing by the FDA.
+Added: The NDA owner and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.
+Added: The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earliest of 30 months after the receipt of the Paragraph IV notice, expiration of the patent or a decision in the infringement case that is favorable to the ANDA or 505(b)(2) NDA application.
Pediatric Studies and Exclusivity
−Removed: Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the non-patent and orphan exclusivity.
+Added: Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing patent or regulatory exclusivity, including the non-patent and orphan exclusivity.
This six-month exclusivity may be granted if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.
10 unchanged sentences
Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.
+Added: Federal and State Data Privacy Laws
+Added: There are multiple privacy and data security laws that may impact our business activities, in the United States and in other countries where we conduct trials or where we may do business in the future.
+Added: These laws are evolving and may increase both our obligations and our regulatory risks in the future.
+Added: In the health care industry generally, under the federal Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act, or HIPAA, the HHS has issued regulations to protect the privacy and security of protected health information, or PHI, used or disclosed by covered entities including certain healthcare providers, health plans and healthcare clearinghouses.
+Added: HIPAA also regulates standardization of data content, codes and formats used in healthcare transactions and standardization of identifiers for health plans and providers.
+Added: HIPAA also imposes certain obligations on the business associates of covered entities that obtain protected health information in providing services to or on behalf of covered entities.
+Added: While we are not a covered entity and thus HIPAA does not directly apply to us, we could be subject to penalties, including criminal penalties, if we knowingly obtain or further disclose PHI from a covered entity, such as a health care provider or clinical research site, and therefore we must ensure the proper authorizations are in place before we, or our vendors or business partners, obtain access to any PHI.
+Added: In addition to federal privacy regulations, there are a number of state laws governing confidentiality and security of health information that may be applicable to our business.
+Added: In addition to possible federal civil and criminal penalties for HIPAA violations, state attorneys general are authorized to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.
+Added: In addition, state attorneys general (along with private plaintiffs) have brought civil actions seeking injunctions and damages resulting from alleged violations of HIPAA’s privacy and security rules.
+Added: State attorneys general also have authority to enforce state privacy and security laws.
+Added: New laws and regulations governing privacy and security may be adopted in the future as well.
+Added: At the state level, California recently enacted legislation that has been dubbed the first “GDPR-like” law in the United States.
+Added: Known as the California Consumer Privacy Act, or CCPA, it creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.
+Added: The CCPA went into effect on January 1, 2020 and requires covered companies to provide new disclosures to California consumers, provide such consumers rights as it relates to their personal information, and allow for a new cause of action for data breaches.
+Added: Additionally, effective starting on January 1, 2023, the California Privacy Rights Act, or CPRA, will significantly modify the CCPA, including by expanding consumers’ rights, particularly with respect to certain sensitive personal information and creating new principles, such as data minimization, purpose limitation, and storage limitation.
+Added: The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA.
+Added: The CCPA and CPRA could impact our business activities depending on how it is interpreted and exemplifies the vulnerability of our business to not only cyber threats but also the evolving regulatory environment related to personal data and individually identifiable health information.
+Added: These provisions may apply to some of our business activities.
+Added: In addition, other states already have passed state privacy laws.
+Added: Other states will be considering these laws in the future.
+Added: These laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products, if and once approved.
+Added: Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available under such laws, it is possible that some of our current or future business activities, including certain clinical research, sales and marketing practices and the provision of certain items and services to our customers, could be subject to challenge under one or more of such privacy and data security laws.
+Added: The heightening compliance environment and the need to build and maintain robust and secure systems to comply with different privacy compliance and/or reporting requirements in multiple jurisdictions could increase the possibility that a healthcare company may fail to comply fully with one or more of these requirements.
+Added: If our operations are found to be in violation of any of the privacy or data security laws or regulations described above that are applicable to us, or any other laws that apply to us, we may be subject to penalties, including potentially significant criminal, civil and administrative penalties, damages, fines, imprisonment, contractual damages, reputational harm, diminished profits and future earnings, additional reporting requirements and/or oversight if we become subject to a consent decree or similar agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any
+Added: of which could adversely affect our ability to operate our business and our results of operations.
+Added: To the extent that any product candidates we may develop, once approved, are sold in a foreign country, we may be subject to similar foreign laws.
Review and Approval of Drug Products Outside the United States
6 unchanged sentences
Requirements for the conduct of clinical trials in the European Union including GCP are set forth in the Clinical Trials Directive 2001/20/EC, or the Clinical Trials Directive, and the GCP Directive 2005/28/EC, or the GCP Directive.
−Removed: Pursuant to the Clinical Trials Directive and the GCP Directive 2005/28/EC, as amended, a system for the approval of clinical trials in the European Union has been implemented through national legislation of the EU member states.
+Added: Pursuant to the Clinical Trials Directive and the GCP Directive, as amended, a system for the approval of clinical trials in the European Union has been implemented through national legislation of the EU member states.
Under this system, approval must be obtained from the competent national authority of each EU member state in which a study is planned to be conducted.
To this end, a clinical trial application, or CTA, is submitted to the local competent authority in each country, or Member State, where the clinical trial is being conducted, which must be supported by an investigational medicinal product dossier, or IMPD, and further supporting information prescribed by Clinical Trials Directive and the GCP Directive and other applicable guidance documents.
−Removed: These documents may be amended and/or updated by the EC at any time.
+Added: These documents may be amended and/or updated by the European Commission at any time.
Furthermore, a clinical trial may only be started after a competent ethics committee has issued a favorable opinion on the clinical trial application in that country.
−Removed: In April 2014, the European Union passed the new Clinical Trials Regulation (EU) No 536/2014, or the new Clinical Trials Regulation, which is set to replace the current Clinical Trials Directive.
−Removed: To ensure that the rules for clinical trials are identical throughout the European Union, the new EU clinical trials legislation was passed as a regulation that is directly applicable in all
−Removed: EU member states.
−Removed: All clinical trials performed in the European Union are required to be conducted in accordance with the Clinical Trials Directive until the new Clinical Trials Regulation becomes applicable.
−Removed: The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trial in the European Union.
+Added: In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014, or the Clinical Trials Regulation, was adopted.
+Added: The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.
The main characteristics of the regulation include:
a streamlined application procedure via a single entry point, the “EU portal”;
−Removed: a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures that will spare sponsors from submitting broadly identical information separately to various bodies and different member states.
−Removed: On January 1, 2020, the website of the European Commission reported that the implementation of the new Clinical Trials Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the European Commission publishes a notice of this confirmation.
−Removed: In late 2020, the EMA indicated that it plans to focus on the findings of a system audit;
−Removed: improving the usability, quality and stability of the clinical trial information system;
−Removed: and knowledge transfer to prepare users and their organizations for the new clinical trial system.
−Removed: The EMA has indicated that the system will go live in December 2021.
−Removed: As in the United States, there are similar requirements in the European Union for posting clinical trial information online, and in other countries as well.
+Added: a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;
+Added: and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.
+Added: Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).
+Added: Part II is assessed separately by each Member State concerned.
+Added: Strict deadlines have been established for the assessment of clinical trial applications.
+Added: The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State.
+Added: However, overall related timelines will be defined by the Clinical Trials Regulation.
+Added: The new Clinical Trials Regulation is scheduled to come into application on January 31, 2022, following confirmation of full functionality of the Clinical Trials Information System through an independent audit by the European Commission in mid-2020.
+Added: The Clinical Trials Regulation will come into application in all the EU Member States, repealing the current Clinical Trials Directive.
+Added: The conduct of all clinical trials performed in the EU will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable at the end of January 2022.
+Added: According to the transitional provisions, if a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes applicable, the Clinical Trials Regulation will at that time begin to apply to the clinical trial.
+Added: Parties conducting certain clinical trials must, as in the United States, post clinical trial information in the European Union at the EudraCT website:
+Added: https://eudract.ema.europa.eu.
PRIME Designation in the European Union
1 unchanged sentence
The PRIME scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure.
−Removed: Products from small- and medium-sized enterprises, or SMEs, may qualify for earlier entry into the PRIME scheme than larger companies.
+Added: Products from small- and medium-sized enterprises, or SMEs,
+Added: may qualify for earlier entry into the PRIME scheme than larger companies.
Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted.
−Removed: Importantly, a dedicated agency contact and rapporteur from the Committee for Human Medicinal Products, or CHMP, or Committee for Advanced Therapies, or CAT, are appointed early in the PRIME scheme, facilitating increased understanding of the product at the EMA’s committee level.
+Added: Importantly, a dedicated agency contact and rapporteur from the Committee for Human Medicinal Products, or CHMP, or Committee for Advanced Therapies are appointed early in the PRIME scheme, facilitating increased understanding of the product at the EMA’s committee level.
A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.
+Added: Pediatric Studies
+Added: Prior to obtaining a marketing authorization in the EU, applicants have to demonstrate compliance with all measures included in an EMA-approved Pediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver or a deferral for one or more of the measures included in the PIP.
+Added: The respective requirements for all marketing authorization procedures are set forth in Regulation (EC) No 1901/2006, which is referred to as the Pediatric Regulation.
+Added: This requirement also applies when a company wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized.
+Added: The Pediatric Committee of the EMA, or PDCO, may grant deferrals for some medicines, allowing a company to delay development of the medicine in children until there is enough information to demonstrate its effectiveness and safety in adults.
+Added: The PDCO may also grant waivers when development of a medicine in children is not needed or is not appropriate because (a) the product is likely to be ineffective or unsafe in part or all of the pediatric population;
+Added: (b) the disease or condition occurs only in adult population;
+Added: or (c) the product does not represent a significant therapeutic benefit over existing treatments for pediatric population.
+Added: Before a marketing authorization application can be filed, or an existing marketing authorization can be amended, the EMA determines that companies actually comply with the agreed studies and measures listed in each relevant PIP.
Marketing Authorization
3 unchanged sentences
For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.
−Removed: Under the centralized procedure, the Committee for Medicinal Products for Human Use, or the CHMP, established at the EMA is responsible for conducting the initial assessment of a product.
+Added: Under the centralized procedure, the CHMP established at the EMA is responsible for conducting the initial assessment of a product.
The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.
4 unchanged sentences
The decentralized procedure provides for approval by one or more other, or concerned, member states of an assessment of an application performed by one member state designated by the applicant, known as the reference member state.
−Removed: Under this procedure, an applicant submits an application based on identical dossiers and related materials, including a draft summary of product characteristics, and draft labeling and
−Removed: package leaflet, to the reference member state and concerned member states.
+Added: Under this procedure, an applicant submits an application based on identical dossiers and related materials, including a draft summary of product characteristics, and draft labeling and package leaflet, to the reference member state and concerned member states.
The reference member state prepares a draft assessment report and drafts of the related materials within 210 days after receipt of a valid application.
2 unchanged sentences
A marketing authorization may be granted only to an applicant established in the European Union.
−Removed: Regulation (EC) No.
−Removed: 1901/2006, or Pediatric Regulation, provides that prior to obtaining a marketing authorization in the European Union, an applicant must demonstrate compliance with all measures included in a Pediatric Investigation Plan, or PIP, approved by the Pediatric Committee of the EMA, or PDCO, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, class waiver, or a deferral for one or more of the measures included in the PIP.
−Removed: The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the drug for which marketing authorization is being sought.
−Removed: The PDCO can grant a deferral of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults.
Once the marketing authorization is obtained in all member states of the European Union and study results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension.
For orphan-designated medicinal products, the 10-year period of market exclusivity is extended to 12 years.
+Added: Conditional Approval
+Added: In particular circumstances, E.U.
+Added: legislation (Article 14–a Regulation (EC) No 726/2004 (as amended by Regulation (EU) 2019/5 and Regulation (EC) No 507/2006 on Conditional Marketing Authorizations for Medicinal Products for Human Use) enables applicants to obtain a conditional marketing authorization prior to obtaining the comprehensive clinical data required for an application for a full marketing authorization.
+Added: Such conditional approvals may be granted for product candidates (including medicines designated as orphan medicinal products) if (1) the product candidate is intended for the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases;
+Added: (2) the product candidate is intended to meet unmet medical needs of patients;
+Added: (3) a marketing authorization may be granted prior to submission of comprehensive clinical data provided that the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required;
+Added: (4) the risk-benefit balance of the product candidate is positive, and (5) it is likely that the applicant will be in a position to provide the required comprehensive clinical trial data.
+Added: A conditional marketing authorization may contain specific obligations to be fulfilled by the marketing authorization holder, including obligations with respect to the completion of ongoing or new studies and with respect to the collection of pharmacovigilance data.
+Added: Conditional marketing authorizations are valid for one year, and may be renewed annually, if the risk-benefit balance remains positive, and after an assessment of the need for additional or modified conditions or specific obligations.
+Added: The timelines for the centralized procedure described above also apply with respect to the review by the CHMP of applications for a conditional marketing authorization.
Periods of Authorization and Renewals in the European Union
6 unchanged sentences
During this period, applicants for authorization of generics of these innovative products cannot rely on data contained in the marketing authorization dossier submitted for the innovative medicinal product.
−Removed: Innovative medicinal products are also entitled to ten years’ market
+Added: Innovative medicinal products are also entitled to a total of ten years’ market exclusivity.
During this ten-year period no generic of this medicinal product can be placed on the EU market.
The overall ten-year period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in comparison with existing therapies.
−Removed: Even if a compound is considered to be a new chemical entity so that the innovator gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.
−Removed: Pediatric Studies and Exclusivity
−Removed: Prior to submitting a marketing authorization application in the European Union, applicants must demonstrate compliance with all measures included in an EMA approved PIP covering all subsets of the pediatric population, unless the EMA has granted a product‑specific waiver, a class waiver, or a deferral for one or more of the measures included in the PIP.
−Removed: The respective requirements for all marketing authorization procedures are set forth in the Pediatric Regulation.
−Removed: This requirement also applies when a company wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized.
−Removed: The Pediatric Committee of the EMA, or PDCO, may grant deferrals for some medicines, allowing a company to
−Removed: delay development of the medicine for children until there is enough information to demonstrate its effectiveness and safety in adults.
−Removed: The PDCO may also grant waivers when development of a medicine for children is not needed or is not appropriate, such as for diseases that only affect the elderly population.
−Removed: Before an MAA can be filed, or an existing marketing authorization can be amended, the EMA determines that companies actually comply with the agreed studies and measures listed in each relevant PIP.
−Removed: If an applicant obtains a marketing authorization in all EU member states, or a marketing authorization granted in the Centralized Procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six month period of qualifying patent protection through extension of the term of the Supplementary Protection Certificate.
+Added: Even if a compound is considered to be a NCE so that the innovator gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.
+Added: Pediatric Exclusivity
+Added: If an applicant obtains a marketing authorization in all EU Member States, or a marketing authorization granted in the centralized procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent
+Added: protection through extension of the term of the Supplementary Protection Certificate, or SPC, or alternatively a one year extension of the regulatory market exclusivity from ten to eleven years, as selected by the marketing authorization holder.
Brexit and the Regulatory Framework in the United Kingdom
−Removed: On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union, commonly referred to as Brexit.
−Removed: Following protracted negotiations, the United Kingdom left the European Union on January 31, 2020.
−Removed: Pursuant to the formal withdrawal arrangements agreed between the United Kingdom and the European Union, the United Kingdom withdrew from the European Union, effective December 31, 2020.
−Removed: On December 24, 2020, the United Kingdom and European Union entered into a Trade and Cooperation Agreement, the Agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction.
−Removed: Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom.
+Added: The U.K.'s withdrawal from the EU took place on January 31, 2020.
+Added: The EU and the U.K.
+Added: reached an agreement on their new partnership in the Trade and Cooperation Agreement, or the Agreement, which was applied provisionally beginning on January 1, 2021 and which entered into force on May 1, 2021.
+Added: The Agreement focuses primarily on free trade by ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products.
+Added: Thereafter, the EU and the U.K.
+Added: will form two separate markets governed by two distinct regulatory and legal regimes.
+Added: As such, the Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the U.K.
+Added: is no longer part of the single market.
+Added: As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol.
+Added: The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines.
+Added: The HMR has incorporated into the domestic law, the body of EU law instruments governing medicinal products that pre-existed prior to the U.K.’s withdrawal from the EU.
General Data Protection Regulation
−Removed: The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the European Union, including personal health data, is subject to the EU General Data Protection Regulation, or GDPR, which became effective on May 25, 2018.
−Removed: The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates when required, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.
−Removed: The GDPR also imposes strict rules on the transfer of personal data to countries outside the European Union, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.
+Added: Many countries outside of the United States maintain rigorous laws governing the privacy and security of personal information.
+Added: The collection, use, disclosure, transfer, or other processing of personal data, including personal health data, regarding individuals who are located in the European Economic Area, or EEA, and the processing of personal data that takes place in the EEA, is subject to the European Union General Data Protection Regulation, or GDPR, which became effective on May 25, 2018.
+Added: The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, and it imposes heightened requirements on companies that process health and other sensitive data, such as requiring in many situations that a company obtain the consent of the individuals to whom the sensitive personal data relate before processing such data.
+Added: Examples of obligations imposed by the GDPR on companies processing personal data that fall within the scope of the GDPR include providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, appointing a data protection officer, providing notification of data breaches and taking certain measures when engaging third-party processors.
+Added: The GDPR also imposes strict rules on the transfer of personal data to countries outside the EEA, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.
The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.
−Removed: Compliance with the evolving landscape of GDPR will continue to be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.
+Added: Compliance with the GDPR is a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.
+Added: There are ongoing concerns about the ability of companies to transfer personal data from the EU to other countries.
+Added: In July 2020, the Court of Justice of the European Union, or the CJEU, invalidated the EU-U.S.
+Added: Privacy Shield framework, one of the mechanisms used to legitimize the transfer of personal data from the EEA to the United States.
+Added: The CJEU decision also drew into question the long-term viability of an alternative means of data transfer, the standard contractual clauses, for transfers of personal data from the EEA to the United States.
+Added: This CJEU decision may lead to increased scrutiny on data transfers from the EU to the U.S.
+Added: generally and increase our costs of compliance with data privacy legislation as well as our costs of negotiating appropriate privacy and security agreements with our vendors and business partners.
+Added: As with other issues related to Brexit, there are open questions about how personal data will be protected in the U.K.
+Added: and whether personal information can transfer from the EU to the U.K.
+Added: Following the withdrawal of the U.K.
+Added: from the EU, the U.K.
+Added: Data Protection Act 2018 applies to the processing of personal data that takes place in the U.K.
+Added: and includes parallel obligations to those set forth by GDPR.
+Added: While the Data Protection Act 2018 in the U.K.
+Added: that “implements” and complements the GDPR has achieved Royal Assent on May 23, 2018 and is now effective in the U.K., it is still unclear whether transfer of data from the EEA to the U.K.
+Added: will remain lawful under GDPR.
+Added: government has already determined that it considers all European Union and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the U.K.
+Added: to the European Union/EEA remain unaffected.
+Added: In addition, a recent decision from the European Commission appears to deem the U.K.
+Added: as being “essentially adequate” for purposes of data transfer from the EU to the U.K., although this decision may be re-evaluated in the future.
+Added: Beyond GDPR, there are privacy and data security laws in a growing number of countries around the world.
+Added: While many loosely follow GDPR as a model, other laws contain different or conflicting provisions.
+Added: These laws will impact our ability to conduct our business activities, including both our clinical trials and any eventual sale and distribution of commercial products.
Pharmaceutical Coverage, Pricing and Reimbursement
5 unchanged sentences
Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a particular indication.
+Added: In addition, third-party payors may impose prior authorization or step edit requirements requiring patients to have tried other therapies prior to our products for coverage.
+Added: Payors may also decline to include our products or product candidates on their formulary, which means that unless healthcare providers seek a medical exception for coverage, the payors will not pay for the product.
In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable marketing approvals.
Nonetheless, product candidates may not be considered medically necessary or cost effective.
−Removed: A decision by a third-party payor not to cover a product candidate could reduce physician utilization once the product is approved and have a material adverse effect on sales, results of
−Removed: operations and financial condition.
+Added: A decision by a third-party payor not to cover a product candidate could reduce physician utilization once the product is approved and have a material adverse effect on sales, results of operations and financial condition.
Additionally, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.
Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor.
+Added: Dialysis-related drugs are included in the ESRD Bundle if they fall into functional categories such as anemia management and bone and mineral metabolism, except that oral-only drugs are exempted from inclusion until 2025.
+Added: In a final ESRD PPS rule published in November 2018, CMS confirmed that it will expand the TDAPA to all new dialysis drugs approved by the FDA after January 1, 2020.
+Added: The TDAPA provides separate payment for new drugs for two years based on the drug’s Average Sales Price, or ASP, that will be in addition to the base rate in order to facilitate the adoption of innovative therapies.
+Added: Although there are several details that need further clarification, including precise timing related to receiving codes to allow for reimbursement under TDAPA, which codes are assigned on a quarterly basis, the rule provides support for our assumption that new anemia treatments, including those in the HIF-PH inhibitor class, will be included in the ESRD Bundle and will be eligible for separate payment initially under TDAPA.
The containment of healthcare costs also has become a priority of federal, state and foreign governments and the prices of drugs have been a focus in this effort.
3 unchanged sentences
Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
−Removed: At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
−Removed: In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.
−Removed: These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
−Removed: It is expected that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.
Outside the United States, ensuring adequate coverage and payment for a product also involves challenges.
14 unchanged sentences
There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.
+Added: Dialysis Organizations Protocols
+Added: Dialysis organizations have their own formularies that list primary or preferred therapeutic options based on contracting status with drug manufacturers.
+Added: While a prescriber may make their own independent decision to prescribe what they determine most appropriate for a given patient, any non-formulary therapeutic options are only available through an exception process based on clinical need.
+Added: Similar to how payor coverage may affect the sales of a product, formulary status within dialysis organizations may affect what products are prescribed within that specific organization.
+Added: Therefore, if a product is not on a formulary, the prescribers within that organization may be less likely to prescribe that product or may have a difficult time prescribing that product, resulting in less sales.
+Added: Further, one dialysis organization’s determination to add a product to their formulary does not assure that other dialysis organizations will also add the product to theirs.
+Added: There is always a risk a dialysis organization will not contract with a drug manufacturer for a specific product, resulting in that product not being on that organization’s formulary.
+Added: Additionally, dialysis organizations typically assess a product’s efficacy before adding it to their formulary.
+Added: Their process for assessing a product may differ among organizations and the timing of such assessment could delay adding such treatment to formulary, further affecting product sales.
Healthcare Law and Regulation
4 unchanged sentences
• the federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false, fictitious or fraudulent or knowingly making, using or causing to be made or used a false record or statement to avoid, decrease or conceal an obligation to pay money to the federal government
−Removed: • the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal laws that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
−Removed: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which impose obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
+Added: • HIPAA, which created additional federal criminal laws that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
+Added: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which
+Added: impose obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
• the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;
1 unchanged sentence
officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment;
−Removed: • the federal transparency requirements, known as the federal Physician Payments Sunshine Act (renamed the Open Payments Act), under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, or ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;
+Added: • the federal transparency requirements, known as the federal Physician Payments Sunshine Act (renamed the Open Payments Act), under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, or ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers and their immediate family members;
• the PDMA and its implementation regulations, as well as the DSCA, which regulate the distribution and tracing of prescription drugs and prescription drug samples at the federal level, and set minimum standards for the regulation of drug distributors by the states;
• analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by third-party payors, including private insurers, and state gift ban and disclosure law requirements that differ from the federal Physician Payments Sunshine Act in terms of the nature and type of transfers of value that are reportable and the types of covered recipients.
+Added: Violations of these laws are punishable by criminal and/or civil sanctions, including, in some instances, exclusion from participation in federal and state health care programs, such as Medicare and Medicaid.
+Added: Ensuring compliance is time consuming and costly.
+Added: Similar healthcare laws and regulations exist in the EU and other jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers and laws governing the privacy and security of personal information.
Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines, such as the Pharmaceutical Research and Manufacturers of America Code on Interactions with Health Care Professionals, known as the PhRMA Code.
15 unchanged sentences
However, the IPAB implementation has not been clearly defined.
−Removed: The Affordable Care Act provided that under certain circumstances, IPAB recommendations will become law unless Congress enacts legislation that will achieve the same or greater Medicare cost savings;
+Added: The ACA provided that under certain circumstances, IPAB recommendations will become law unless Congress enacts legislation that will achieve the same or greater Medicare cost savings;
• established the Center for Medicare and Medicaid Innovation within CMS, to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
Funding has been allocated to support the mission of the Center for Medicare and Medicaid Innovation from 2011 to 2019.
−Removed: Other legislative changes have been proposed and adopted since the Affordable Care Act was enacted.
−Removed: These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions to Medicare payments to providers of 2% per fiscal year that started in 2013 and will stay in effect through 2029 unless additional Congressional action is taken, and the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
−Removed: These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.
−Removed: Further, there have been several recent U.S.
−Removed: congressional inquiries and proposed state and federal legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.
+Added: Other legislative changes have been proposed and adopted since the ACA was enacted.
+Added: In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.
+Added: A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.
+Added: These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 203.
+Added: Pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES Act, and subsequent legislation, these Medicare sequester reductions have been suspended through the end of March 2022.
+Added: From April 2022 through June 2022 a 1% sequester cut will be in effect, with the full 2% cut resuming thereafter.
+Added: Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.
+Added: For example, with enactment of the Tax Cuts and Jobs Act of 2017, or the Tax Act, which was signed by the prior administration on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.
+Added: On December 14, 2018, a U.S.
+Added: District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.
+Added: Supreme Court heard this case on November 10, 2020 and, on June 17, 2021, dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the ACA.
+Added: Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.
+Added: The prior administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.
+Added: On January 28, 2021, however, President Biden rescinded those orders and issued a new executive order that directs federal agencies to reconsider rules and other policies that limit access to healthcare, and consider actions that will protect and strengthen that access.
+Added: Under this order, federal agencies are directed to re-examine:
+Added: policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19;
+Added: demonstrations and waivers under Medicaid and the ACA that may reduce coverage or undermine the programs, including work requirements;
+Added: policies that undermine the Health Insurance Marketplace
+Added: or other markets for health insurance;
+Added: policies that make it more difficult to enroll in Medicaid and under the ACA;
+Added: and policies that reduce affordability of coverage or financial assistance, including for dependents.
+Added: Pharmaceutical Prices
+Added: The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.
+Added: There have been several recent U.S.
+Added: congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid.
+Added: In 2020, the prior administration issued several executive orders intended to lower the costs of prescription products and certain provisions in these orders have been incorporated into regulations.
+Added: These regulations include an interim final rule implementing a most favored nation model for prices that would tie Medicare Part B payments for certain physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021.
+Added: That rule, however, has been subject to a nationwide preliminary injunction and, on December 29, 2021, CMS issued a final rule to rescind it.
+Added: With issuance of this rule, CMS stated that it will explore all options to incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries' access to evidence-based care.
+Added: In addition, in October 2020, HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program, or SIP, to import certain prescription drugs from Canada into the United States.
+Added: The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire) have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA.
+Added: Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
+Added: The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.
+Added: The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.
+Added: On July 9, 2021, President Biden signed Executive Order 14063, which focuses on, among other things, the price of pharmaceuticals.
+Added: The Order directs the Department of Health and Human Services, or HHS, to create a plan within 45 days to combat “excessive pricing of prescription pharmaceuticals and enhance domestic pharmaceutical supply chains, to reduce the prices paid by the federal government for such pharmaceuticals, and to address the recurrent problem of price gouging.” On September 9, 2021, HHS released its plan to reduce pharmaceutical prices.
+Added: The key features of that plan are to:
+Added: (a) make pharmaceutical prices more affordable and equitable for all consumers and throughout the health care system by supporting pharmaceutical price negotiations with manufacturers;
+Added: (b) improve and promote competition throughout the prescription pharmaceutical industry by supporting market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase transparency;
+Added: and (c) foster scientific innovation to promote better healthcare and improve health by supporting public and private research and making sure that market incentives promote discovery of valuable and accessible new treatments.
+Added: At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: A number of states, for example, require drug manufacturers and other entities in the drug supply chain, including health carriers, pharmacy benefit managers, wholesale distributors, to disclose information about pricing of pharmaceuticals.
+Added: In addition, regional healthcare organizations and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription pharmaceutical and other healthcare programs.
+Added: These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
+Added: We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.
Laws Relating to Foreign Trade
11 unchanged sentences
of 2010, or U.K.
−Removed: Bribery Act applies to any company “carrying on business” in the United Kingdom, irrespective of where the offending conduct occurs.
+Added: Bribery Act applies to any company “carrying on business” in the U.K., irrespective of where the offending conduct occurs.
Bribery Act applies to bribery activities both in the public and private sector and prohibits the provision of an “advantage” intended to induce or reward “improper performance” of the recipient’s function.
10 unchanged sentences
Employees and Human Capital Resources
−Removed: As of December 31, 2020, we had 380 employees, 379 of whom were full-time.
−Removed: None of our employees is represented by any collective bargaining unit.
+Added: As of December 31, 2021, we had 426 employees, all of whom were full-time.
+Added: None of our employees are represented by any collective bargaining unit.
We believe that we maintain good relations with our employees.
Retention, growth, training and development of our employees are integral to our success.
−Removed: We believe we offer competitive compensation (including base salary, incentive bonus, and long-term equity awards tied to the value of our stock price) and benefits packages designed to attract and reward talented individuals who possess the skills necessary to support our business objectives, assist in the achievement of our strategic goals and create value for our stockholders.
−Removed: Our compensation is designed to incentivize achievement of corporate goals, individual performance and adherence to our corporate values.
+Added: We offer competitive compensation (including base salary, incentive bonus, and long-term equity awards tied to the value of our stock price) as well as benefits packages designed to attract, motivate and reward talented individuals who possess the skills necessary to support our business objectives, assist in the achievement of our strategic goals and create value for our stockholders.
+Added: Our compensation program is designed to differentiate us from our talent competition and incentivize achievement of corporate goals, individual performance and demonstrate our corporate values.
In addition, we provide development and leadership opportunities to our employees to cultivate talent throughout the Company.
−Removed: We are also focused on diversity, equality and inclusion opportunities.
−Removed: Three members of our Board of Directors, Maxine Gowen, Ph.D., Cynthia Smith and LeAnne M.
+Added: We are committed to our employees’ health, safety and well-being.
+Added: In March 2020, in response to the COVID-19 pandemic, we adjusted our workplace policies to allow employees to work from home and in 2021 we remodeled our work paradigm to one that is flexible and designed to accommodate a range of work profiles from office based, to hybrid to fully remote, to field-based, allowing us to maximize productivity and performance.
+Added: Further, in October 2021, to comply with federal, state and local mandates and guidelines, and in an effort to keep our employees safe, we announced a requirement that all of our employees be fully vaccinated by January 1, 2022, subject to medical and religious exemptions.
+Added: Recognizing the pandemic has had an impact on well-being as well as the availability of support services, we recently launched Modern Health, a platform focused on services to support employees’ and their dependents in areas such as mental, physical, financial, social and professional health, making it easier for them to get personalized care faster.
+Added: We are also committed to diversity, equality and inclusion, and this is reflected in Akebia’s leadership.
+Added: Two members of our Board of Directors, Cynthia Smith and LeAnne M.
Zumwalt, are women, and women comprise approximately 45% of our senior management team.
−Removed: We believe this structure reflects our strong endorsement of and commitment to female leadership.
−Removed: In addition, we have created a committee called IDEA - The Inclusion, Diversity & Equity Alliance - focused on communication and education around dimensions of diversity, such as gender, ethnicity, or other shared attributes, that we believe help build community and enable individual and corporate growth.
−Removed: We continue to focus on building a pipeline for talent to create more opportunities for workplace diversity.
+Added: In addition, in November 2021, we appointed Ron Frieson to our Board of Directors.
+Added: With the goal of ensuring every employee is included, supported, and treated equitably, we developed a team (IDEA – Inclusion, Diversity & Equity Alliance) to support and guide Akebia as a diverse, inclusive, and culturally intelligent workplace.
+Added: Over the past year this team has worked to identify areas for growth and education in order to develop processes, systems and actions that will enable us to continue to build an inclusive workplace and a diverse workforce.
+Added: We also provide access to LinkedIn Learning, an online learning platform that recommends expert-led courses for relevant skill development for all of our employees.
In addition, we support kidney patient communities where we live and work.
7 unchanged sentences
The information on our website or that may be accessed by links on our website is not incorporated by reference into this Form 10-K.
−Removed: We make available, free of charge and through our website,
−Removed: our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and any amendments to any such reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, as soon as reasonably practicable after they are electronically filed with or furnished to the U.S.
+Added: We make available, free of charge and through our website, our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and any amendments to any such reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, as soon as reasonably practicable after they are electronically filed with or furnished to the U.S.
Securities and Exchange Commission.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.