Applicants seeking approval of Abbreviated New Drug Applications (ANDAs) in most cases must perform bioequivalence studies comparing their proposed generic product to the innovator drug listed in the Orange Book, called the “Reference Listed Drug” or “RLD”. Issues have arisen as to whether a RLD sponsor can provide samples for bioequivalence studies when the RLD is subject to a Risk Evaluation and Mitigation Strategy (“REMS”). A REMS is a program design to assure that a drug with a known significant risk or risks can and will be used safely, by a variety of different measures, including, for example, restricted distribution and labeling. The existence of a REMS has been used by RLD sponsors to refuse to sell samples of their RLD drug product to ANDA applicants who are seeking them for use in bioequivalence studies. This has led to litigation over whether it is legal for the RLD sponsor to do so, as will be discussed hereinafter.

To address this problem, FDA issued a Draft Guidance for Industry: “How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD” in December 2014. Under this Draft Guidance, ANDA applicants would be able to obtain a letter from FDA addressed to the RLD sponsor that the bioequivalence protocol of the ANDA applicant contains protections equivalent to the restrictions in the REMS and that FDA will not consider it a violation of the REMS for the RLD sponsor to provide the ANDA applicant with sufficient product to enable it to conduct bioequivalence testing necessary to support its ANDA.

To get FDA to issue such a letter, the ANDA applicant must:

  • Develop a protocol for the bioequivalence study that incorporates elements of the REMS of the RLD sponsor;
  • Submit the draft bioequivalence protocol draft (along with informed consent and informational materials) to FDA;
  • After FDA review, make any recommended changes and resubmit them; and
  • If accepted, the ANDA applicant must submit a disclosure form to FDA requesting them to send the letter to the RLD sponsor. (A form letter is in Appendix A of Draft Guidance).

Submissions are requested to be made electronically to

So, once a RLD sponsor gets such a letter, are they required to provide samples to the ANDA applicant? There has been litigation over this issue and legislation introduced in Congress.

No definitive court opinion on the legal requirements has been reached yet, but it has not been for lack of trying: Actelion filed a suit in September 2012 against two generic-drug makers asking the New Jersey federal district court to confirm that it was not legally required to supply samples of its patented blood pressure drug Tracleer to Apotex Inc. and Roxanne Laboratories Inc., generic companies seeking samples for their ANDA required bioequivalence testing. The case was dismissed in February 2014, after a confidential settlement was reached.

Recently, in December 2014, the New Jersey federal district court dismissed without prejudice, and without an opinion, Mylan Pharmaceuticals Inc.’s claims against Celgene Corp. under Section 1 of the Sherman Antitrust Act and sections of the New Jersey Antitrust Act governing agreements in restraint of trade. Mylan Pharmaceuticals Inc. v. Celgene Corp., Case No. 2:14-cv-02094-ES-MAH, Dkt. No. 54. Mylan filed suit against Celgene in April 2014, after it had obtained FDA approval for its testing safety protocols, claiming that Celgene is using REMS to refuse to sell Mylan samples of Celgene’s brand name drugs, Revlimid® and Thalomid®, and therefore Mylan cannot perform bioequivalence tests necessary for its ANDA. The FTC has submitted an amicus brief in favor of Mylan’s claims. Id. at Dkt. No. 26 and 30. Numerous claims for violation of Section 2 of the Sherman Act, Sections 15 and 26 of the Clayton, and sections of the New Jersey Antitrust Act remain active. Whether the court does eventually have to explain its action and thus become persuasive authority in the Mylan action remains to be seen. Celgene previously defended against a similar suit brought by Lannett Co. in 2008, alleging that Celgene blocked it from launching its generic version of Thalomid. In that case, the parties reached a confidential settlement before trial, and, according to Celgene’s submissions in the pending case, Lannett has now completed its bioequivalence testing for generic thalidomide. See id. at Dkt. No. 17, p. 10.

Congressional attempts to force an RLD sponsor to provide samples have failed twice. In 2012, Congress considered a provision that would forbid REMS from being applied or construed to prohibit the supply of a drug to a developer for the purpose of bioequivalence tests necessary for an ANDA if the FDA approved the generic company’s safety protocols. The provision (S. 3187, section 1131) was not ultimately enacted as part of the FDA Safety and Innovation Act.

Just this past September 2014, Congressmen Steve Stivers (R-OH) and Peter Welch (D-VT), introduced H.R. 5657, the Fair Access for Safe and Timely Generics Act of 2014 (“FAST Generics Act”) to the U.S. House of Representatives. The FAST Generics Act would amend the Federal Food Drug and Cosmetic Act to ensure that eligible product developers have competitive access to drug and biological products covered by restricted distribution programs. The bill was referred to committee, but no action has been taken. Perhaps the new Congress will take up the issue again.

So, for now, while the FDA draft Guidance has clarified how a generic applicant can obtain a letter that a RLD sponsor is not violating a REMS by supplying samples to an ANDA applicant, it is unclear whether the RLD sponsor can be legally forced to do so.