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FDA is ending one of the landmark drug safety programs from the REMS era, announcing it has released Amgen from its mandatory obligations for the erythropoiesis-stimulating agent (ESA) class. The decision comes just ahead of the likely approval of the first biosimilar application in the class.


FDA’s decision to end the erythropoiesis-stimulating agent (ESA) class REMS is yet another symbolic milestone for the agency in moving beyond the drug safety debates of the 2000s – and also a timely step to help advance the emerging era of biosimilars.


FDA announced April 13 that it is releasing Amgen from its formal Risk-Evaluation and Mitigation Strategy obligations for the anti-anemia therapies darbepoetin (Amgen Inc.’s Aranesp) and epoetin (Amgen’s Epogen, but marketed by Johnson & Johnson as Procrit for the oncology market).


The ESA REMS – which applied to oncologic indications for the anti-anemia agents – was one of the largest programs put in place by FDA in the period following the enactment of the 2007 FDA Amendments Act. It also almost immediately became a touchstone for the pushback from providers that has helped define the more recent and very restrained use of the FDAAA authorities.


The formal termination of the REMS is in line with a number of recent agency actions that close the books on high-profile drug safety controversies from a decade ago. But it is also timely in clearing out a potential obstacle for the launch of the new era of biosimilars.


Hospira Inc.’s pending biosimilar application for epoetin appears headed towards a near term FDA approval on its second go-around at the agency: FDA announced April 17 that it will be reviewed by the agency’s Oncologic Drugs Advisory Committee on May 25. In general, FDA makes a policy of taking “first biosimilar” applications to committee prior to approval, as a public confidence-building exercise. That likely means that the application from the Pfizer Inc. unit would be approved by the agency ahead of its user fee goal date in June. (Also see "Biosimilars In 2017: Crowded US FDA Review Queue, Key Legal Decisions" - Pink Sheet, 24 Jan, 2017.)


Like the other approved biosimilars, there will still be a number of legal challenges ahead before the epoetin product can be launched in the US. However, by removing the ESA REMS obligation, FDA has eliminated any administrative headaches associated with trying to build a shared program for the biosimilar.


FDA’s approval letter for the release of the REMS obligations indicates that the decision was originally made by FDA, and then the formal regulatory action came as an amendment to a pending supplement to revise the warnings on Amgen’s ESA products.


“As communicated in the March 7, 2017 REMS Modification Notification Letter, we determined that the elements to assure safe use are no longer necessary to ensure the benefits of Aranesp (darbepoetin alfa) outweigh the risks and that the approved REMS for Aranesp (darbepoetin alfa) had to be modified to minimize the burden on the healthcare delivery system of complying with the REMS,” FDA wrote. Amgen then amended its pending sBLA filings on March 17 to include elimination of the REMS, and the supplement was formally approved April 13.


There is a much larger symbolism in the removal of the REMS that should not be overlooked in the context of the end of the product’s exclusivity.


The reasons given for the REMS withdrawal by FDA come close to an acknowledgment that the program was unnecessary in the first place given changes in reimbursement policy that preceded the REMS. That in turn is likely to be a theme of FDA’s approach to drug safety issues during the tenure of FDA Commissioner-nominee Scott Gottlieb.



A Landmark Of The REMS Era

FDA decision to impose the ESA REMS was a milestone event in 2008, when the class became the first major product group to have a risk management program mandated under FDAAA provisions that went into effect in March of that year. It also quickly became a case study in the complexity of implementing REMS.


First, from a regulatory process standpoint, it took two years from FDA’s decision to order the REMS in April 2008 before the program was actually approved by the agency, and then another year before it was implemented in 2011. Almost immediately, the agency began to get pushback from providers concerned about the certification and registration process: despite the long run-up, there was very little prior appreciation in the oncology community of the burdens of complying with the program.


FDA’s use of REMS has declined markedly over the years, and now the unwinding of the ESA REMS fits with a broader pattern of the agency revisiting and largely undoing some of the key actions of the “drug safety” era a decade ago. For instance, FDA formally released the Avandia REMS at the end of 2015. (Also see "'Orphans' Hit Historic High At US FDA; More 'Me-Too' Drugs Urged" - Pink Sheet, 16 Dec, 2015.)


The ESA REMS was imposed based on studies suggesting that routine use of ESAs in conjunction with myelosuppressive chemotherapy may actually be having a negative impact on treatment outcomes – perhaps due to a tumor-promoting effect of the ESAs.


However, the REMS itself came only after a prolonged period of safety scrutiny, including a formal relabeling by FDA intended to reinforce the agency’s view that there was no data to support routine use of ESAs to reduce fatigue or for any other “quality of life” benefit, and that instead the indication was focused solely on reducing the risk of a blood transfusion. In addition, the Centers for Medicare and Medicaid Services instituted a new coverage policy to limit reimbursement for the therapies to patients where the risk of transfusion would be greatest. (Also see "Living in a Bipolar World: Implications of the EPO Safety Debate (Part 1) " - Pink Sheet, 1 Jul, 2007.)


FDA did not impose a REMS for the products in the dialysis setting, in part because the outcomes data in those patients appear to show clear benefits for routine use of ESAs. In addition, the dialysis payment system operates in a very different manner than the Part B physician payment system, and so there is less concern about potential incentives for overuse. (Also see "FDA And ESA Safety: A Conversation With Bob Temple And Ellis Unger" - Pink Sheet, 31 May, 2010.)



Was The REMS Necessary In The First Place?

FDA said it made the determination to release the REMS “based on an evaluation of the results of the REMS Assessments submitted by Amgen, Inc., and additional FDA analyses to understand the impact of the various regulatory and other actions on the use of ESAs.” Under terms of the REMS agreement, Amgen submitted annual assessments every February; the most recent submission reviewed by FDA was the February 2016 assessment.


Based on the sponsor’s assessment, FDA concluded that “surveyed prescribers demonstrate acceptable knowledge of the product risks,” and that “drug utilization data indicates appropriate prescribing of ESAs consistent with the intended use as a treatment alternative to RBC transfusion for anemia associated with myelosuppressive chemotherapy.”


FDA’s separate review of the utilization trends for ESAs from 2006-2014 essentially concluded that the market had already shifted to more appropriate use before the REMS was implemented in 2011.


“The FDA conducted an evaluation of the impact of multiple actions, including the ESA REMS, on the utilization of the ESAs using sponsor-submitted data from outpatient oncology practices between 2006 and 2014,” FDA said. “During 2004-2009, the FDA took multiple regulatory actions, including labeling changes. In 2007, the Center for Medicare and Medicaid Services (CMS) made a National Coverage Determination (NCD) to limit coverage of ESAs for non-renal disease indications,” the agency noted.


Collectively, those changes led to a decrease in use of ESAs overall, and an increase in the proportion of patients who appeared to be appropriate candidates for therapy (hemoglobin levels below 10g/dL) and who received doses “consistent with product prescribing information.”


“Full implementation of the ESA REMS in 2011 had minimal impact on trends in these three ESA utilization metrics beyond the changes observed after the CMS coverage determination and multiple other FDA regulatory actions,” FDA found. “This information led the FDA to conclude it is no longer necessary to require the certification of prescribers and hospitals that prescribe and/or dispense ESAs to patients with cancer in order to ensure the benefits outweigh the risks.”


FDA goes on to note that the release of the REMS does not mean a change in view of the safety issue: “the serious risks of shortened overall survival and/or increased risk of tumor progression or recurrence associated with these drugs remain.”


However, “the risks can be communicated by the current product prescribing information,” FDA says. Moreover, “The appropriate use of ESAs is supported by the CMS NCD, the American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) clinical guidelines which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology.”



Themes To Continue Under Gottlieb

The decision to withdraw the REMS – and, more importantly, the justifications for doing so – are likely to resonate with the incoming Trump/Gottlieb FDA team. (Also see "Gottlieb's Confirmation: He's Willing To Disagree With Trump, Sec. Price" - Pink Sheet, 5 Apr, 2017.)


Gottlieb was a deputy commissioner at FDA when the ESA safety issues first arose, but left FDA before the FDAAA authorities took effect. After leaving the agency, he was critical of the early implementation of the REMS authority as infringing on the practice of medicine.


Gottlieb was asked about those views during his confirmation hearing in the Senate Health, Education, Labor & Pension Committee April 5. In an exchange about the agency’s response to opioid abuse, Sen. Maggie Hassan (D-N.H.) cited an article published by Gottlieb in which he expressed concerns about the use of REMS. She wondered whether he would seek to roll-back FDA’s program for prescription opioids.


Gottlieb first reassured Hassan that he supports the opioid REMS. In fact, in the article Hassan cited, “I affirmed…the use of trying to prevent diversion and abuse of opioid drugs” as consistent with FDA’s mission and past practices, Gottlieb said. “I do fully support the use of that tool in this context,” he added.


The commissioner nominee, however, also offered a broader message of support for FDA’s recent, more-restrained use of REMS overall. The article, he told Hassan, “spoke to a different issue” that he sees as unrelated to the opioid crisis: the use of REMS “to attenuate the off-label prescribing” of drugs. “In fact, I support the use of the tool across a lot of contexts” beyond opioids, Gottlieb said. “The agency has gone on to use the program in ways that are more judicious than I was worried about when I wrote that article.”


Gottlieb’s past interest in FDA/CMS coordination – including his prior tenure at both agencies – is another theme underscored by the agency’s rationale for dropping the REMS requirement. As commissioner, Gottlieb is likely to support the view that FDA can take a lighter touch on regulatory controls and defer to other entities – payers and medical societies/clinical practice standards – as better situated to optimize real world use of therapies. (Also see "Drug Pricing Pundit Gottlieb Likely To Stay In His Lane At FDA" - Pink Sheet, 14 Apr, 2017.)

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