Dr. Reddy's is urging FDA to start now to define a policy that assures that restricted distribution programs and other types of Risk Evaluation and Mitigation Strategies won't be used to block generic drug approvals.

The petition, filed June 10, asks FDA to put some teeth behind a provision in the FDA Amendments of Act of 2007, which states that "no holder of an approved covered application shall use any element to assure safe use" imposed under the new REMS authority "to block or delay approval" of an ANDA.

At issue: Dr. Reddy's plan to develop a generic equivalent to Celgene's anticancer agent Revlimid (lenalidomide), which is marketed under a restricted distribution program.

In the context of that product, the petition is best viewed as a pre-emptive strike by Dr. Reddy's - one that will only be a preliminary skirmish in a much longer campaign. Revlimid has new chemical entity exclusivity through 2010, orphan drug exclusivity until 2012, and Celgene lists 12 separate patents for the product in FDA's ¹ Orange Book.'

For other sponsors, however, the petition could help bring clarity in what is certain to become an important area: the interaction between the new post-marketing safety provisions enacted in FDAAA and the generic drug approval process.

That issue has already been raised in the context of Celgene's first product, Thalomid (thalidomide), which pioneered the REMS model adopted by FDAAA. Celgene has filed a series of citizen petitions asserting that the risks of Thalomid make a conventional generic approval impossible (² Also see "Can A REMS Block A Generic? Thalomid Could Be Early Test" - Pink Sheet, 22 September, 2008., p. 14). Celgene has also filed patent litigation against Barr over its thalidomide ANDA (³ Also see "Celgene Commences Thalomid Patent Litigation Against Barr" - Pink Sheet, 24 January, 2007.).

It is also an issue in the background of FDA's development of a massive, class-wide REMS for opioids (⁴ Also see "REMS For Opioids Still Has A Long Road Ahead; Advisory Committee Is Likely" - Pink Sheet, 8 June, 2009., p. 18).

"The number of drug products subject to REMS is growing," Dr. Reddy's notes in its petition. "Unless FDA takes swift action now by exercising the authority that Congress granted the agency [in FDAAA] to prevent REMS gaming, consumers will be prevented from having timely access to generic versions of an increasing number of important drugs."

You Can't Study What You Can't Buy

In its petition, Dr. Reddy's describes what sounds like a classic "Catch 22." Given the tightly controlled access to Revlimid, the company can't simply obtain the brand through commercial channels to conduct bioequivalence studies. But Celgene, not surprisingly, doesn't see any reason to sell any samples to the generic company directly.

According to Dr. Reddy's, its attempt to purchase Revlimid for use in bioequivalence trials ended with a one-sentence brush off: "Celgene has no obligation to supply Dr. Reddy's with Revlimid and declines to do so."

As for finding creative ways to obtain Revlimid without Celgene's participation, Dr. Reddy's notes that would provide an opening for Celgene to claim it "unlawfully procured" the product. The concern is not strictly hypothetical: Dr. Reddy's quotes Celgene's patent case against Barr in which it makes that assertion regarding Barr's bioequivalence testing of thalidomide.

Dr. Reddy's describes this as an "abuse of REMS as a lifecycle management tool." That is precisely why Congress included the clause on access to generics in FDAAA, Dr. Reddy's says.

Technically, neither Thalomid nor Revlimid is yet covered by a REMS; both are in the process of conversions from the pre-FDAAA "voluntary" programs into formal REMS.

Even without that technicality, however, it is far from a black-and-white issue. Given that FDAAA sets penalties for sponsors who fail to live up to their REMS obligations, it is certainly easy to understand why sponsors who provide drug for bioequivalence studies would worry about potential liabilities.

Dr. Reddy's asks FDA to take four specific steps to implement the FDAAA provision on REMS and generics:

1) Issue guidance defining a procedure to allow generic applicants to obtain a formal finding from FDA that its request to obtain drug for bioequivalence trials is in compliance with a REMS;

2) Incorporate into REMS that include restricted distribution programs a specific provision stating that the sponsor will not use the REMS to delay generics;

3) Take action against sponsors who refuse to make drug available for study when requested by a generic applicant who has followed the process for certifications; and

4) Refer all complaints about potential use of REMS to block competition to the Federal Trade Commission.

Dr. Reddy's isn't taking any chances on the last point: the petition was also submitted to FTC.

- Michael McCaughan (m.mccaughan@elsevier.com)

Will REMS Delay Generics? Revlimid Petition May Help Determine The Answer

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