ANDA sponsors may increasingly face a new roadblock to FDA approval: a Risk Evaluation and Mitigation Strategy (REMS) that restricts access to samples of the brand name product.

Celgene Corp. was the first company to use its REMS precursor for Thalomid (thalidomide) and Revlimid (lenalidomide) to refuse to sell the two drugs for use in bioequivalence testing. But other companies are apparently following Celgene’s lead.

“It is, from my perspective, a growing problem,” Kurt Karst, of Hyman, Phelps & McNamara, stated at the American Conference Institute’s “Maximizing Pharmaceutical Patent Life Cycles” meeting, held in New York City Oct. 4-5.

As REMS with “elements to assure safe use” become more prevalent they are “going to set up these de facto exclusivity periods” for the holder of the reference listed drug, he stated.

Karst said FDA has been receiving complaints from ANDA sponsors and forwarding them to the Federal Trade Commission. At ACI’s meeting last year, FTC’s Markus Meier noted that the agency was concerned about this potential use of REMS and was looking into it. At that time FTC had just launched an investigation of Celgene (Also see "Playing It Too Safe?: FTC Investigating Use Of REMS To Block Generics" - Pink Sheet, 18 October, 2010.).

FDA Says Constitution Ties Its Hands

Karst said FDA contends that it cannot order a manufacturer to sell its product to another company since it would violate the takings clause of the Fifth Amendment, which prohibits private property from being taken for public use without just compensation.

The FDA Amendments Act of 2007, which gave FDA the authority to require a REMS, specifies that these strategies cannot be used to block or delay generic competition. But Karst said this is “squishy language” that does not clarify what would constitute delaying or blocking competition. If someone on the brand side is not satisfied with the information provided or not provided by the ANDA sponsor and denies the request for the product, is the brand using a REMS to block competition, he asked.

Karst said brand companies have legitimate concerns since they may be on the hook for a product liability lawsuit and thus they want reasonable assurances that the ANDA sponsor has procedures in place so patients will not be hurt.

Members of the audience expressed frustration with FDA’s stance. One attendee noted that the takings argument was raised during initial enactment of the Hatch-Waxman Act but did not go anywhere. “This seems like yet another way in which the FDA is taking sides by not taking sides,” he said.

A Question For PDUFA – Or The Courts

Dr. Reddy’s Laboratories Inc. filed a citizen petition with FDA in June 2009 requesting that the agency establish a procedure to prevent “REMS gaming.” The company asked FDA to issue a letter to a generic applicant stating that the applicant has agreed to restrictions on the listed drug. Dr. Reddy’s said it had sought to purchase study samples from Celgene and was refused. FDA has not yet responded to the petition.

The Generic Pharmaceutical Association has also advocated that FDA adopt this procedure (Also see "Generics Should Get REMS Exemption For Sample Collection, GPhA Says" - Pink Sheet, 18 January, 2010.).

Karst said the issue could be addressed when the Prescription Drug User Fee Act is reauthorized. He suggested that an amendment could be made to require companies to sell drug samples for testing as long as specific steps are taken to assure safe distribution.

If the FDA, FTC and Congress do not take action on the issue it is likely to be resolved in the courts. In response to a question as to whether third party payers might file an antitrust suit, Karst said he could envision such a suit alleging a company was using REMS to block generic access.

Celgene’s Conditions For Thalomid Sale

Lannett Company Inc. has sued Celgene for denying it a sample of Thalomid for bioequivalence testing. Thalomid and Revlimid are both associated with teratogenicity. The REMS for each requires elements to assure safe use, including patient and prescriber registration and controlled distribution.

Lannett filed an initial antitrust complaint in January 2008, which was dismissed on the basis that Lannett had not yet received a response from FDA on its proposed bioequivalence study. After Lannett received a response from the agency it filed a new complaint in August 2008 seeking a preliminary injunction.

In March the U.S. District Court for the Eastern District of Pennsylvania denied Celgene’s motion to dismiss the case. It issued a separate order denying Lannett’s motion to enforce a purported settlement agreement. The court found that the parties had engaged in negotiations to settle their differences but never reached a point where all issues had been resolved.

The opinion gives a sense of the battle over the terms Lannett must meet to get Celgene to provide the Thalomid sample.

Lannett contends that Celgene has demanded more each time Lannett has agreed upon Celgene’s conditions. The court noted that as a condition of Celgene’s selling a quantity of Thalomid, Lannet was to provide Celgene with an indemnification agreement, liability insurance covering Celgene, a study protocol for the bioequivalence testing in a form approved by FDA, and Lannett’s adverse drug event reporting history for the previous five years.

“Celgene contends that the insurance policy has inadequate limits of liability and does not cover human clinical trials,” the court stated. “It also questions the efficacy of the study protocol’s safety.”

By Brenda Sandburg

Brand/Generic Battles Over REMS Raise Constitutional Questions For FDA

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