REMS Abuse Website: Has It Changed The Behavior Of Innovators?
Executive Summary
Updated numbers from the US FDA's REMS abuse website show that Celgene has received two additional safety determination letters, raising question's about whether the public list has changed the practices of brand companies hindering generic company access to samples.
The Association for Accessible Medicines (AAM) has contended that the US FDA's public list of drug companies suspected of using risk evaluation and mitigation strategies (REMS) to stonewall generic developer access to branded samples has done little to change the behavior of innovators. Based to the most recent data posted by the agency, the generic drug trade association may have a point.
Since the list was published in May 2018, there have been 10 additional inquiries into brand drugs and three new safety determination letters sent to innovators. Inquiries consist of generic sponsors informing FDA that they are having trouble accessing a certain branded drug and questioning if there is a REMS causing the delay, while safety determination letters are sent by the agency to brand sponsors at the request of generic manufacturers to inform the innovators that the generic company's protocol meets all the requirements of the REMS.
Notably, two of the three new safety determination letters went to Celgene Corp. Celgene was among the most prominent innovators featured in the list when it was first published, as it led the pack in inquiries into its products and received the second most safety determination letters from FDA behind Johnson & Johnson subsidiary Actelion Pharmaceuticals Ltd. (Also see "REMS Abuse Website: Celgene, Actelion Top List Of Suspected 'Gamers'" - Pink Sheet, 18 May, 2018.)
One of the two most recent letters sent to Celgene was a fourth letter for Revlimid (lenalidomide). The other was for Pomalyst (pomalidomide). Although it was the first safety determination letter sent to Celgene regarding Pomalyst, the thalidomide analogue has previously been the subject of eight different inquiries by generic manufacturers. (See table at end of story.)
The third new safety determination letter went to Jazz Pharmaceuticals PLC's schizophrenia treatment Fazaclo ODT (clozapine). Fazaclo ODT was on the original list for having received one inquiry from a generic manufacturer.
With the updates to the webpage, generic companies have now sent 173 inquiries to FDA about 54 innovator drugs, with the agency sending out 24 safety determination letters.
Daraprim Gets An Inquiry
One of the most notable additions to the list in the Feb. 7 update was Vyera Pharmaceuticals' Daraprim (pyrimethamine). Daraprim had become a poster child of high drug prices in 2015, when the company, formerly known as Turing Pharmaceuticals AG under the tenure of then-CEO Martin Shkreli, boosted the list price of the antiparasitic by 5,000% overnight. (Also see "At Drug Pricing Hearing, Innovator Companies Mainly Escape Congressional Wrath" - Pink Sheet, 4 Feb, 2016.)
There has been one inquiry into Daraprim since the list was first released, although the drug does not have a REMS with elements to assure safe use (ETASU).
Also making in onto the list for the first time was Mission Pharmacal Co.'s Thiola (tiopronin) with two inquiries, and Otsuka Holdings Co. Ltd.'s Jynarque (tolvaptan) with one. Thiola does not have a REMS with ETASU, although Jynarque does.
The following drugs were already on the webpage, and each had one additional inquiry added to their tally following the update:
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Ranbaxy Laboratories Ltd.'s Absorica (isotretinoin);
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Corcept Therapeutics Inc.'s Korlym (mifepristone);
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Danco Laboratories' Mifeprex (mifepristone);
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Swedish Orphan Biovitrum AB's Orfadin (nitisinone); and
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Lundbeck Inc.'s Sabril (vigabatrin for solution).
When the initial list was published, FDA Commissioner Scott Gottlieb noted in a statement that there are "many cases" where brand companies claim that their products have a REMS with ETASU when they actually do not.
Is The List Working?
AAM President and CEO Chip Davis contended at the trade group's generics and biosimilars conference in September 2018 that the webpage has not changed the behavior of the branded companies it identified. Anna Abram, FDA’s deputy commissioner for policy, planning, legislation and analysis, also said that the agency has continued to receive complaints from generic drug developers about not being able to secure the necessary samples of a brand product for generic testing. (Also see "REMS Abuse Website: All Sizzle, No Steak?" - Pink Sheet, 5 Sep, 2018.)
The updated data do provide some evidence that the innovators on the list have not changed their practices. The recent letters to Celgene appear to suggest that generic manufacturers are still having issues accessing samples from the company, and the growing tally of inquiries could also be evidence of the problem more broadly.
Celgene has asserted in the past that all of its drugs that appear on the list – Revlimid, Pomalyst and Thalomid (thalidomide) – all come with the risk of significant side effects. A Jazz spokesperson acknowledged the letter for Fazalco – for which there are several marketed generics – in a statement to the Pink Sheet, commenting that "once the requestor identified a qualified U.S. distributor, we facilitated providing supply of Fazaclo for the overseas manufacturer through the Clozapine REMS."
"Jazz worked collaboratively with multiple sponsors and the FDA to develop the Clozapine REMS, which is the single shared system for clozapine products, including brand and generic products," the spokesperson added.
FDA did not offer much of an assessment when asked whether the agency believes the webpage is helping to change the behavior of brand companies.
"Our hope is that increased transparency about the [reference listed drug] access issue will help to reduce the abuse of limited distribution systems (whether imposed in connection with a REMS program or voluntarily imposed by a brand company) to block or delay generic development," an FDA spokesperson told the Pink Sheet. "However, FDA is generally not informed about whether brand companies ultimately provide samples after issuance of a safety determination letter from the Agency (or after other efforts by interested generic applicants to negotiate access)."
The CREATES Act Is Back (Again)
In a statement to the Pink Sheet about the webpage, AAM said that, "We applaud the FDA’s ongoing efforts, which highlight why legislative fixes, like the newly introduced and bipartisan-supported CREATES Act, must be passed by Congress to provide patients with relief."
The Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act would allow drug companies to a sue an innovator that refuses to make samples of a product available for generic drug or biosimilar testing. (Also see "Brands Push Back Against REMS Reform, Call Problem Small With Burdensome Fixes" - Pink Sheet, 18 Jul, 2017.)
Sen. Patrick Leahy, D-VT, reintroduced legislation Feb. 5. The bill currently has 27 co-sponsors, including an even split of 13 Democrats and 13 Republicans. Sen. Angus King, I-ME, who caucuses with the Democrats, is also a cosponsor. The measure is likely to be a topic of discussion at a Feb. 26 Senate Finance Committee hearing on drug pricing. (Also see "Invitation Accepted: Biopharma Leaders Will Testify At Senate Hearing On Pricing" - Pink Sheet, 7 Feb, 2019.)
The CREATES Act has gained bipartisan traction in Congress over the past few years, although it has not yet been able to cross the finish line. (Also see "CREATES Act To Face Major Reshaping By Innovator-Friendly Amendments On Senate Floor" - Pink Sheet, 14 Jun, 2018.) But the bill could be in a stronger position this year with support from Sen. Chuck Grassley, R-IA, who now chairs the Finance Committee.
A Spike In Citizen Petitions
Another area that has been targeted for reform to allow for a more robust generic marketplace is the citizen petition process.
On Feb. 7, FDA published its tenth annual report to Congress on delays in approvals of applications related to citizen petitions for fiscal year 2017. According to the report, the agency made 28 determinations on 505(q) citizen petitions during the fiscal year, nearly twice the total from fiscal year 2016 when there were 15. (See chart below.)
However, FDA's conclusion remains nearly identical to that of the previous fiscal year's report.
"The Agency continues to be concerned that section 505(q) does not discourage the submission of petitions that are intended primarily to delay the approval of competing drug products and do not raise valid scientific issues," the report states. "The FD&C Act requires FDA to prioritize these petitions above other matters, such as safety petitions, that may raise important public health concerns.
"FDA remains concerned about the resources required to respond to 505(q) petitions within the 150-day deadline at the expense of completing the other work of the Agency. Accordingly, as part of the Drug Competition Action Plan, FDA is reviewing what actions can be taken to address these issues."
FDA notes that no approvals of 351(k) applications or abbreviated new drug applications (ANDAs) were delayed by a 505(q) citizen petition, although there was one delay in the approval of a 505(b)(2) application. The report says that the approval was pushed back by 28 days to assess the petition.
"FDA's decision to delay the approval of one 505(b)(2) application during this reporting period was based on the Agency's assessment that further review of the issues raised in the 505(q) petition was required to fully assess the petitioner's arguments against approval," the report states. "FDA was concerned that if it approved the 505(b)(2) application before resolving the issues raised in the petition and later concluded that one or more of the arguments against approval were meritorious, then the presence on the market drug product that did not meet the requirements for approval could negatively affect public health."
AAM has proposed that FDA conduct a 30-day pre-filing citizen petition assessment to determine whether a 505(q) citizen petition is sufficiently complete to warrant a full review. (Also see "AAM, PhRMA Renew Rivalry In Hatch-Waxman Public Comments" - Pink Sheet, 21 Nov, 2017.)