FDAAA Fading? REMS Use Continues To Decline As Drug Safety Law Matures

FDA’s use of REMS continues to fall to almost undetectable levels, with the agency using the safety tools just a handful of times in the sixth full year of the program. REMS are now very much the exception and not the rule for new products – but still a very important exception.

Six years into the REMS era, it is still an open question what (if any) impact Risk Evaluation & Mitigation Strategies have on reducing the risk of adverse events from prescription drugs.

However, there is one key risk that has declined sharply in the past few years: the risk that a sponsor will be required to comply with a REMS in the first place.

FDA was given the ability to impose post-marketing risk management plans under the FDA Amendments Act of 2007, with the relevant portions taking effect in March 2008. The RPM Report has tracked use of the new tools since then, looking at the agency’s use of the REMS authorities and mandatory post-marketing study authorities.

The sixth full year of the REMS era ended in March 2014, and for the fourth consecutive year, the percentage of new drug approvals that included a REMS declined. In the most recent 12 months, FDA used the REMS just three times for new molecular entity approvals, or about 11% of the 26 NMEs cleared during that time. Looking at the broader universe of all original NDA approvals, FDA required a REMS for 8 of the 85 products approved during the 12 months, or about a 9% rate.

Just four years ago, nearly half (48%) of all new molecular entities were approved with a REMS, and just over 40% of all original NDAs. At that time, it looked like the REMS were on their way to becoming a routine part of the drug approval process. Talk about a dramatic change.

Still, there are some patterns amid the overall downward trend that are important to consider:

• The use of REMS may still be declining, but a countervailing trend is also continuing: when FDA does impose a REMS it is highly likely to be the most restrictive “Elements-to-Assure-Safe-Use” version, rather than the softer touch “communication plan” approach.
• REMS can also still “save” a troubled NDA – or stave off a post-market product withdrawal;
• And, last but not least, the use of REMS in some recent cases of rare disease products may point the way to a new model for limited use approvals.

So, what once looked like the rule now looks like the exception. But REMS remain a very important exception.

Overall De-Emphasis of “Drug Safety” Tools?

The declining use of REMS began after the second full year of the new FDAAA authority, at about the time health care stakeholders across the country began to register their concerns about the impact that the new programs had on delivery of care. (Also see "FDAAA Impact Analysis (Year 5): The REMS Paradox" - Pink Sheet, 8 May, 2013.)

However, another element may be starting to have a role too: the overall emphasis on accelerating development and approval of “breakthrough” therapies in the current climate supplanting the post-market safety focus that dominated the 2007 era legislation.

Exhibit 1

Source: Prevision Policy LLC

FDASIA and the related Prescription Drug User Fee Act reauthorization agreement did include targets related to REMS, focused primarily on initiatives to standardize and integrate REMS into the health care system (which offered opportunities to reinforce the feedback to FDA about the disruptive impact REMS have on health care delivery).

However, amid the many deadlines imposed by FDASIA/PDUFA V, the agency has missed some of the ones related to REMS, suggesting a decision to focus on other goals as a higher priority. In particular, the agency missed a September 30, 2013 goal date for issuing a guidance on the elements that trigger a REMS in the first place. FDA now says that draft guidance has a goal date of June 14, 2014.

Exhibit 2

Source: Prevision Policy LLC

FDA is also a late on issuing a report on integration of REMS into the health care system based on the July 2013 workshop on the same topic. That report was due by December 31, but FDA now has a “target date” of June 30. The agency has one other upcoming REMS-related deliverable from PDUFA V: a guidance specifically focused on methodologies for assessing REMS and especially on the ETASU REMS. That is due by the end of fiscal 2014 (September 30).

One of the recently imposed REMS – for Bayer AG’s pulmonary hypertension therapy Adempas—shows both the need for and the challenges inherent in drafting a guidance on what triggers REMS. The review was notable for how smooth and straightforward the overall risk/benefit discussion was, including one of the least contentious Cardiovascular & Renal Drugs Advisory Committee reviews in recent years.

Cardio-Renal Division Director Norman Stockbridge even began his summary review memo on the approval of the application by declaring that “there is no disagreement among the review team or the Advisory Committee on the appropriate regulatory action.”

However, when it came to the decision to impose a REMS to prevent pregnancy in women using the drug, Stockbridge himself sounded unconvinced: “The sponsor and the review team conclude that the teratogenicity findings are a sufficient basis for a REMS. I suppose it is, but the case seems pretty weak.”

Fewer PMRs

The most recent 12 months showed not just a decline in the use of the REMS authorities, but also the first potential indication of a decline in the imposition of mandatory post-marketing studies at the time of approval as well.

For new molecular entity approvals, the decline was not dramatic: FDA imposed PMRs for just under 70% of the 26 NMEs. That is down from the high of 80% two years earlier, but still in the range of the overall average of about three-quarters of NME approvals coming with mandatory post-marketing studies.

Still, coupled with the sparing use of the REMS authorities, the proportion of NMEs that were approved without mandatory post-market studies or controls was 27%, the second year in a row of an increase.

The change was more pronounced looking at all original NDA approvals, where FDA imposed PMRs on just 29% of the new products, the lowest percentage for any year since the authorities took effect – and steep drop off from the 46% rate of mandatory study requirements imposed in the fifth year of the program.

Exhibit 3

Source: Prevision Policy LLC

Coupled with the continued decline in the use of the REMS authorities, that means that two-thirds of original NDA approvals were free of FDAAA safety mandates, compared to a 50% rate for the first five years of the program.

A one-year decline in use of the mandatory trials authority is certainly not as pronounced a trend as the longer term, steady decline in REMS. But there is at least one case study suggesting that the agency may be starting to move away from defaulting to the PMR requirement as readily as it did in the first five years after FDAAA.

In December, FDA approved GlaxoSmithKline PLC’s long-acting muscarinic antagonist combo product Anoro Ellipta, and decided not to require any post-marketing follow-up on CV outcomes. That was a significant decision for at least three reasons:

• First, it came after FDA has seemingly adopted a de facto outcomes standard for the LAMA class, with outcomes studies required for several prior sponsors;
• Second, GSK did not ask to be exempt from an outcomes requirement, but only sought to be allowed to do an observational study rather than a clinical trial; and
• Third, FDA highlighted the decision during an Institute of Medicine forum on “uncertainty” in risk/benefit analysis hosted by the agency at its White Oak headquarters. In other words, FDA didn’t just decide to back away from using a drug safety tool in this case, it essentially bragged about the decision in the context of a meeting on shaping future policy. (Also see "FDA/IoM “Uncertainty” Conference Adds Uncertainty to Biogen Growth Plans For Tysabri" - Pink Sheet, 20 Feb, 2014.)

Still, the decline in use of PMRs has a long way to go before it is as obvious a trend as the decline in use of REMS.

Unwinding Communication Plans

In addition to using REMS less, FDA also continues to release some of the first wave of programs it imposed on sponsors. FDA released six REMS during the 12 month period between April 2013 and March 2014.

As was the case in the prior year, most of the “released” REMS were “communication plan” programs, with FDA determining that the sponsor had fulfilled its obligations to craft appropriate messages around the launch of a new brand. That was the case with five of the six released REMS: Acorda Therapeutics Inc.’s Ampyra for MS, Dyax Corp.’s Kalbitor for hereditary angioedema,Novartis AG’s Tasigna for leukemia, and two anti-clotting therapies:AstraZeneca PLC’s Brilinta, and Johnson & Johnson/Bayer AG’s Xarelto.

Each of those sponsors received a boilerplate response to a request to be released from their REMS obligations, following up on several prior letters from FDA essentially declaring success in a communication plan based primarily on metrics tied to delivery of the appropriate messages – not any measures tied to prescribing behavior in response. (Also see "Declaring Victory: How FDA Releases REMS" - Pink Sheet, 7 May, 2013.)

The sixth product released from a REMS during the period was J&J’s Nucynta, which was one of few remaining “MedGuide-only” REMS. When FDA initially interpreted the new REMS authority, it decided that any case where it intended to mandate a consumer Medication Guide would trigger a REMS. However, the agency decided at the end of 2010 that a mandatory MedGuide does not inevitably mean invoking the REMS authority, and the agency released dozen of products from those early REMS obligations as a result.

However, FDA is still going to impose “MedGuide-only” REMS in cases where it believes the enhanced assessment and monitoring are appropriate.

Exhibit 4

Source: Prevision Policy LLC

The release of the Nucynta (tapentadol) REMS took a bit longer than many of the other “MedGuide-only” sponsors’ requests. J&J filed a supplemental NDA seeking the release in November 2011, but FDA waited nearly two years (July 2013) before agreeing. That may reflect an understandable extra degree of caution in reviewing opioid ingredients’ post-marketing obligations.

Here is how FDA Anesthesia, Analgesia & Addiction Products Division Director Bob Rappaport explained the decision to release the REMS in the approval letter:

“The requirement of a REMS for Nucynta IR tablets was, at the time of its approval, consistent with the Agency’s policies concerning drug products with Medication Guides to address serious and significant public health concerns under the standard in 21 CFR 208.1. However, during the four years of marketing history of Nucynta IR tablets, the concerns about this product having distinctive properties indicating a high potential for abuse did not manifest as serious adverse events of abuse/misuse any different or worse than other immediate-release oral opioids which do not have Medication Guides. We agree with your proposal that the Medication Guide be eliminated as part of the approved labeling for Nucynta IR tablets. We agree also that the REMS for Nucynta IR tablets can now be eliminated.”

J&J also markets an extended release version of tapentadol that is still covered by the long-acting opioid REMS. That remains arguably the most important use of the new FDAAA tools in terms of impact, both because long-acting opioids are so commonly prescribed and because of the political and medical importance of curbing prescription drug abuse.

ER/LA REMS Adds One Sponsor – But Not Two

The one new product added to that REMS during the year is by far the most controversial, Zogenix Inc.’s Zohydro. The agency’s ability to weather the pushback to that decision may be the most important test of the REMS to date: much of the agency’s argument in allowing the launch of the first long-acting hydrocodone formulation without abuse deterrent properties hinges on the ability of the REMS, traditional labeling, and mandatory studies to work more effectively to curb abuse. (Also see "Zogenix Zohydro Launch Will Test FDA’s Balanced Approach On Opioid Pain Reviews" - Pink Sheet, 10 Mar, 2014.)

Interestingly, FDA opted to approve another novel opioid formulation without adding it to the shared REMS: Mallinckrodt AG’s Xartemis (oxycodone/acetaminophen). That product is a long acting formulation, but includes features intended to deter abuse. But, unlike other long-acting opioids, it is indicated for acute—not chronic—use.

FDA initially focused on the “long-acting” features of the formulation and told the company it would need to join the ER/LA Opioid REMS. However, upon reflection, the agency ended up deciding that a REMS would not be necessary.

DAARP Deputy Director Sharon Herz explained the change of thinking in her summary review of the application.

“Based on review of the proposed REMS in conjunction with OSE’s Division of Risk Management, it became apparent that inclusion of a Xartemis XR with an acute pain indication in the ER/LA REMS would undermine the two key educational messages of the ER/LA REMS, that ER/LA products are indicated for chronic use and are not intended for acute pain that could be managed with other products, and that ER/LA products for chronic pain are not for use on an intermittent basis. An additional complication was that the postmarketing requirement (PMR) for the ER/LA opioids for chronic pain negotiated under the safety labeling changes provisions of FDAAA would not apply to Xartemis XR as the epidemiologic studies require data from chronic use of the medications.”

Deciding to exempt the product from the ER/LA REMS did not necessarily mean that no REMS would be necessary at all. FDA, however, decided to look at others in the acute pain class, and maintain a level playing field:

“Although the formulation has extended-release characteristics, the amount of oxycodone in each tablet is 7.5 mg, the same as available in immediate-release combination oxycodone and acetaminophen products. As a result, even if individuals were to mistakenly or intentionally attempt to defeat the extended-release characteristics of Xartemis, the amount of oxycodone would not exceed the amount available in an immediate-release product. Furthermore, the total daily dose of oxycodone from Xartemis XR has the same limitations as immediate-release combination oxycodone and acetaminophen products in order to avoid exceeding the safe daily limit of acetaminophen. The overall risks associated with Xartemis XR are more comparable to immediate-release combination oxycodone and acetaminophen products than to the products included in the ER/LA opioid REMS. Therefore, it was concluded that there was no need for a REMS for this product.”

Interestingly, Herz’ analysis does not give any “credit” to the sponsor for the abuse-deterrent properties of the formulation in the context of the REMS discussion. The formulation was approved without any specific claim related to the formulation, though the sponsor hopes to build a case post-approval.

Does REMS Now Mean ETASU?

The release of five “communication plan” REMS is significant beyond the impact on those sponsors, as it appears that FDA is backing away from using those programs with new products.

Just as the decision that a MedGuide does not mandate use of the REMS authorities led to a significant step down in the imposition of REMS at the time of approval, the agency’s early experience with communication plans seems to have led to a reluctance to use that tool to deliver launch messages for new drugs.

Instead, when FDA does impose a REMS at the time of approval, it increasingly means that it is using the most restrictive ETASU REMS. Indeed, all three of the REMS for new molecular entities in the sixth year of the program were ETASU REMS. (The products covered by the REMS are AstraZeneca PLC’s Myalept for leptin deficiency, Actelion Pharmaceuticals Ltd.’s Optsumit for PAH and Bayer’s Adempas.)

In addition to tracking the number of REMS over time, The RPM Report also tracks the intensity of REMS when the tools are used, using a four-point scale. That metric has been trending higher as FDA moved away from MedGuide-only REMS and communication plan programs – and in the sixth year the average intensity was the highest possible (4).

The RPM Report also tracks the average number of mandatory trials imposed on new molecular entities as an admittedly crude measure of the burden of that aspect of FDA’s post-market authorities. By that measure, FDA has been fairly consistent, asking for an average of 3.6 PMRs when it invokes that authority for a new molecular entity.

Among the other REMS imposed by FDA during the year, three were ETASU REMS, including a new program for Endo Pharmaceuticals Inc.’s Aveed testosterone gel, and the addition of two new products to existing “shared” REMS, Zogenix Inc.’s Zohydro to the long-acting opioid REMS and Orexo AB’s Zubsolv to the buprenorphine shared REMS.

FDA did affirm two existing communication plan REMS in approving new formulations of Innoviva Inc.’s Vibativ antibiotic and J&J’s Simponi anti-arthritic therapy.

However, the agency only approved one new communication plan REMS during the 12-month period: a program tied to the reintroduction of Ariad Pharmaceuticals Inc.’s Iclusig after a temporary withdrawal due to high rates of cardiovascular adverse events. (Also see "The Impact of Iclusig: Access Program May Have Important Implications For Personalized Medicine" - Pink Sheet, 14 Nov, 2013.)

REMS Still Can Save A Product

The Iclusig experience does suggest that a REMS can still be a powerful tool for sponsors and the agency in the context of a post-marketing safety signal, serving as an option short of outright withdrawal.

However, it also shows how tenuous that role is at a time when FDA is backing away from the use of REMS overall. Ariad, in fact, immediately proposed a REMS (including elements to assure safe use) as an alternative to suspending the product in the first place. FDA, instead, opted to pull the product and, at least initially, seemed to hope that it could be limited to some form of expanded access for existing patients only.

Exhibit 5

Source: Prevision Policy LLC

The agency, however, heard loud and clear from providers and patients that the expanded access model wasn’t viable, and ended up re-approving the drug without the kind of sharp restrictions inherent in an ETASU program.

Oncology, however, has always been something of an outlier in the REMS model, both because significant toxicity is such a common feature for chemotherapy drugs and because the delivery model for oncology care typically makes “restricted distribution” programs somewhat redundant. (Also see "Carving REMS Out of Oncology? FDA, ASCO Plan Follow-Up Workshop " - Pink Sheet, 1 Dec, 2010.)

Still, the Iclusig experience suggests that a REMS can still play a role in helping FDA be more comfortable in allowing continued access to a product with unexpected post-marketing safety issues.

Endo’s experience with the long-acting testosterone formualtion Aveed, on the other hand, offers a less equivocal demonstration that a REMS can indeed still serve as a way to salvage an NDA that otherwise appears doomed – provided the REMS is vetted on FDA’s terms, and not the sponsor’s.

Based on problems associated with the Aveed formulation overseas and new concerns about the overall safety profile of testosterone replacement therapy in general, Endo had a tough road to approval with Aveed. The sponsor attempted to use a REMS as a fallback to win an advisory committee recommendation in 2012 – but FDA carefully managed the meeting to make sure that the committee focused on the core questions of risks vs. benefits without a REMS. (Also see "Endo’s Aveed and the State of REMS After Five Years" - Pink Sheet, 7 May, 2013.)

The panel overwhelmingly rejected the application, and FDA followed up with a Complete Response that included a request for a more formal REMS submission and review. That ended with the product clearing the agency in 2013.

Rare Disease REMS a Model to Watch

Among the few REMS imposed in the past year, there is nevertheless at least one sign of a theme that could yet mean that the REMS become a transformative regulatory tool.

The REMS for AstraZeneca’s Myalept (metreleptin) is the third recent case of FDA using the drug safety tool to, in effect, assure that a drug is used only for the limited rare disease population where FDA deems the risk/benefit ratio appropriate – and not for a much vaster potential patient population.

Metreleptin was first developed for obesity, but failed to deliver anything close to the efficacy profile in humans that researchers initially saw in animal models. Two decades later, it was finally approved for an extremely rare population of patients with lipodystrophy. (Also see "Repurposing Leptin (Part 2): It Really Is A One-In-A-Million Drug" - Pink Sheet, 20 Dec, 2013.)

Exhibit 6

Source: Prevision Policy LLC

FDA’s decision to impose a REMS directly reflected the prior development history, and what FDA saw as a potential ongoing interest in the therapy for obesity.

“The review team’s primary concern is the potential for metreleptin’s off-label use as a weight loss product,” the agency’s risk management reviewer (Suzanne Robottom) noted in a November 26 review. Use of the product in patients who are not leptin-deficient poses a significant risk given the potential development of neutralizing antibodies. “Even if the incidence of neutralizing anti-leptin antibody development is very low, use in a broader population such as the obesity population could result in a substantial number of people developing a worse metabolic state than before metreleptin treatment.”

“Given that in 2009-2010, 35.7% of US adults were obese and the resulting public interest in weight loss therapies, without any restrictions, use of metreleptin could quickly exceed its intended use, although we acknowledge this may be impacted by the drug’s cost and/or insurance coverage requirements.”

In invoking the REMS, the review team specifically compared it to two programs required last year in conjunction with the approval of two new drugs for homozygous familial hypercholesterolemia: Aegerion Pharmaceuticals Inc.’s Juxtapid and Sanofi/Ionis Pharmaceuticals Inc.’s Kynamro.

The Myalept REMS is “consistent, in principle, with the REMS approved for Juxtapid (lomitapide; approved December 21, 2012) and Kynamro (mipomersen; approved January 29, 2013),” FDA noted. “Juxtapid and Kynamro are approved for use in an orphan population (homozygous familial hypercholesterolemia), a condition where, similar to metreleptin, a specific blood test or genetic test cannot be relied upon to make the diagnosis; rather, it is a clinical diagnosis. Also similar to metreleptin, the clinical development programs for Juxtapid and Kynamro were very small, and in the case of Juxtapid, were uncontrolled.”

“The off-label population for Juxtapid and Kynamro include the much broader dyslipidemic population, similar to the broader off-label obesity population for metreleptin,” the agency reviewers added. “All three of these programs had concerning safety signals despite small exposures – hepatotoxicity for Juxtapid and Kynamro, and lymphoma and immunogenicity for metreleptin.”

That suggests a potentially broader role for REMS (or REMS-like programs) to put barriers around initially approved indications pending further research to expand patient populations – a model being pushed under various acronyms in the context of anti-infective drug approvals (LPAD), obesity treatments (SMU) or as a general approval standard (“Progressive Approval”). (Also see "Antibiotic Incentive Legislation: Can Reimbursement Horn In?" - Pink Sheet, 25 Apr, 2014.)