Pink Sheet Daily
August 12, 2013
Executive Summary
The agency says the FDAAA does not allow a REMS to state that a brand sponsor cannot use a limited distribution program to prevent generic drug maker’s access to a product for bioequivalence testing.
In response to a petition from Dr. Reddy's Laboratories Ltd., FDA indicated that a policy to force brand companies to sell products governed by a Risk Evaluation and Mitigation Strategy to generic firms for bioequivalence testing is not forthcoming from the agency.
Section 505-1(f)(8) of the Food, Drug and Cosmetics Act says that an element to assure safe use (ETASU) cannot be used “to block or delay approval” of an ANDA or 505(b)(2) application. The 2009 Dr. Reddy’s petition asked FDA to enforce that requirement of the law and to include in REMS a provision that the sponsor “will not use REMS restricted distribution elements to assure safe use to delay or block generic competition”.
FDA declined to do either in an Aug. 7 letter , which essentially says the agency’s hands are tied with regard to putting the restriction into a REMS, and notes that decisions about enforcement actions are reached on a case-by case basis.
Adding the requested provision to a REMS would raise the stakes for brand companies as the FDA Amendments Act of 2007, which created the REMS program, allows the agency to assess fines of up to $250,000 for failure to comply with REMS directives. Penalties for continuing violations are capped at $10 million.
FDA also points out that the agency is not the arbiter of anti-competitive practices. In response to Dr. Reddy’s request to refer to the Federal Trade Commission generic companies’ complaints about brand companies’ use of restricted distribution REMS as justification for refusing to sell drugs for bioequivalence testing, FDA said “that issues related to ensuring that marketplace actions are fair and do not block competition would be best addressed by the FTC.”
Even before the FDA decision, legal action over the issue had heated up. Actelion Pharmaceuticals Ltd. filed suit in September 2012 in the U.S. District Court for the District of New Jersey asking for a declaratory judgment that it does not have to provide Tracleer (bosentan) to Apotex Inc. or Roxane Laboratories Inc. for bioequivalency testing. The company argues that it has the right to determine who it does business with and providing the drug to the two generic firms would not comply with the REMS for the pulmonary arterial hypertension medication.
The two generic companies filed counterclaims alleging anti-competitive conduct by Acthelion, and Roxane expanded the case to include Zavesca (miglustat) for Gaucher disease.
Generic firms also are protesting that brand drug makers are using voluntary restricted distribution programs to bar access to reference listed drugs (RLD). Accord Healthcare Inc. and Intas Pharmaceuticals Ltd. made that claim in an April lawsuit seeking access to Acorda Therapeutics Inc.’s Ampyra (dalfampridine) for multiple sclerosis. The drug’s REMS does not include a restricted distribution program, but Acorda sells the medication only through certain distributors. The generic firms withdrew the suit only a month after its filing, suggesting the parties may have reached an agreement.
An out-of-court settlement also was reached in a 2008 suit by Lannett Co. Inc. seeking access to Celgene Corp.’s Thalomid (thalidomide) to support bioequivalence for an ANDA in the drug’s oncology setting. The U.S. District Court for the Eastern District of Pennsylvania twice denied a Celgene petition to dismiss the case. The two reached a settlement in 2011 but did not disclose the terms of their agreement. Lannett noted in its 2012 annual report that pilot bioequivalence studies were completed by the end of that year, with a pivotal study scheduled to begin shortly.
Sales To Generic Firms Not A Safety Issue
An obstacle for generic firms in seeking redress from FDA is that adding a statement to a REMS that a brand sponsor cannot delay or block generic competition does not fall within the REMS authorities. The agency can impose a risk management program on a drug when needed so that a drug’s benefits outweigh the risks, and the law lists what can be in a REMS, such as a Medication Guide, a communication plan and ETASU.
But Section 505-1(f)(8) fits into neither of those categories. It “is not intended to ensure that the benefits of a drug outweigh its risks, and is not one of the safety-related elements enumerated in the FD&C Act that may be included in a REMS,” the letter notes.
As an alternative, the agency says it notifies brand sponsors of the prohibition in approval letters: “We remind you that section 505-1(f)(8) of the FD&C Act prohibits holders of an approved covered application with elements to assure safe use from using any element to block or delay approval of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could result in enforcement action.”
The Dr. Reddy’s petition also asked the agency to write guidance on how a generic firm can obtain a letter from FDA saying the company has agreed that distribution restrictions in a REMS will be met during bioequivalence testing, and to take enforcement action against brand companies that receive a copy of the letter but still refuse to sell, at fair market value, drugs for bioequivalence testing.
FDA denied the request for enforcement on two grounds. First, “decisions with regard to initiating enforcement actions are generally made by the agency on a case-by-case basis and are within the discretion of the agency.” Secondly, the letter notes that requests for enforcement action “are not within the scope of FDA’s citizen petition procedures.”
Guidance On Generic Protocol Submissions
As to the guidance request, the agency agreed to write guidance on the procedures and content of requests by a generic firm for FDA confirmation that the protocol for bioequivalence testing complies with distribution restrictions imposed through a REMS and will ensure safe use of a product.
The agency noted that it has in the past reviewed generic companies’ study protocols and associated documents, such as informed consent forms, to ensure that protection of study subjects’ safety is comparable to that achieved by the REMS for the reference listed drug and notified generic makers of agency findings.
At the request of generic companies, the agency also has informed RLD sponsors of the findings and “indicated that FDA will not consider it a violation of the REMS for the RLD sponsor to provide (or authorize the provision of) a sufficient quantity of the drug to allow the potential applicant to conduct testing necessary to support its ANDA.”
But FDA notes that some protocol and related document submissions required revisions due to incompleteness or inadequacy. Guidance “clarifying both the procedure for requesting FDA review and the proper contents of protocol submissions could improve the quality of initial submissions and reduce associated review time.”
Executive Summary
The agency says the FDAAA does not allow a REMS to state that a brand sponsor cannot use a limited distribution program to prevent generic drug maker’s access to a product for bioequivalence testing.
In response to a petition from Dr. Reddy's Laboratories Ltd., FDA indicated that a policy to force brand companies to sell products governed by a Risk Evaluation and Mitigation Strategy to generic firms for bioequivalence testing is not forthcoming from the agency.
Section 505-1(f)(8) of the Food, Drug and Cosmetics Act says that an element to assure safe use (ETASU) cannot be used “to block or delay approval” of an ANDA or 505(b)(2) application. The 2009 Dr. Reddy’s petition asked FDA to enforce that requirement of the law and to include in REMS a provision that the sponsor “will not use REMS restricted distribution elements to assure safe use to delay or block generic competition”.
FDA declined to do either in an Aug. 7 letter , which essentially says the agency’s hands are tied with regard to putting the restriction into a REMS, and notes that decisions about enforcement actions are reached on a case-by case basis.
Adding the requested provision to a REMS would raise the stakes for brand companies as the FDA Amendments Act of 2007, which created the REMS program, allows the agency to assess fines of up to $250,000 for failure to comply with REMS directives. Penalties for continuing violations are capped at $10 million.
FDA also points out that the agency is not the arbiter of anti-competitive practices. In response to Dr. Reddy’s request to refer to the Federal Trade Commission generic companies’ complaints about brand companies’ use of restricted distribution REMS as justification for refusing to sell drugs for bioequivalence testing, FDA said “that issues related to ensuring that marketplace actions are fair and do not block competition would be best addressed by the FTC.”
Even before the FDA decision, legal action over the issue had heated up. Actelion Pharmaceuticals Ltd. filed suit in September 2012 in the U.S. District Court for the District of New Jersey asking for a declaratory judgment that it does not have to provide Tracleer (bosentan) to Apotex Inc. or Roxane Laboratories Inc. for bioequivalency testing. The company argues that it has the right to determine who it does business with and providing the drug to the two generic firms would not comply with the REMS for the pulmonary arterial hypertension medication.
The two generic companies filed counterclaims alleging anti-competitive conduct by Acthelion, and Roxane expanded the case to include Zavesca (miglustat) for Gaucher disease.
Generic firms also are protesting that brand drug makers are using voluntary restricted distribution programs to bar access to reference listed drugs (RLD). Accord Healthcare Inc. and Intas Pharmaceuticals Ltd. made that claim in an April lawsuit seeking access to Acorda Therapeutics Inc.’s Ampyra (dalfampridine) for multiple sclerosis. The drug’s REMS does not include a restricted distribution program, but Acorda sells the medication only through certain distributors. The generic firms withdrew the suit only a month after its filing, suggesting the parties may have reached an agreement.
An out-of-court settlement also was reached in a 2008 suit by Lannett Co. Inc. seeking access to Celgene Corp.’s Thalomid (thalidomide) to support bioequivalence for an ANDA in the drug’s oncology setting. The U.S. District Court for the Eastern District of Pennsylvania twice denied a Celgene petition to dismiss the case. The two reached a settlement in 2011 but did not disclose the terms of their agreement. Lannett noted in its 2012 annual report that pilot bioequivalence studies were completed by the end of that year, with a pivotal study scheduled to begin shortly.
Sales To Generic Firms Not A Safety Issue
An obstacle for generic firms in seeking redress from FDA is that adding a statement to a REMS that a brand sponsor cannot delay or block generic competition does not fall within the REMS authorities. The agency can impose a risk management program on a drug when needed so that a drug’s benefits outweigh the risks, and the law lists what can be in a REMS, such as a Medication Guide, a communication plan and ETASU.
But Section 505-1(f)(8) fits into neither of those categories. It “is not intended to ensure that the benefits of a drug outweigh its risks, and is not one of the safety-related elements enumerated in the FD&C Act that may be included in a REMS,” the letter notes.
As an alternative, the agency says it notifies brand sponsors of the prohibition in approval letters: “We remind you that section 505-1(f)(8) of the FD&C Act prohibits holders of an approved covered application with elements to assure safe use from using any element to block or delay approval of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could result in enforcement action.”
The Dr. Reddy’s petition also asked the agency to write guidance on how a generic firm can obtain a letter from FDA saying the company has agreed that distribution restrictions in a REMS will be met during bioequivalence testing, and to take enforcement action against brand companies that receive a copy of the letter but still refuse to sell, at fair market value, drugs for bioequivalence testing.
FDA denied the request for enforcement on two grounds. First, “decisions with regard to initiating enforcement actions are generally made by the agency on a case-by-case basis and are within the discretion of the agency.” Secondly, the letter notes that requests for enforcement action “are not within the scope of FDA’s citizen petition procedures.”
Guidance On Generic Protocol Submissions
As to the guidance request, the agency agreed to write guidance on the procedures and content of requests by a generic firm for FDA confirmation that the protocol for bioequivalence testing complies with distribution restrictions imposed through a REMS and will ensure safe use of a product.
The agency noted that it has in the past reviewed generic companies’ study protocols and associated documents, such as informed consent forms, to ensure that protection of study subjects’ safety is comparable to that achieved by the REMS for the reference listed drug and notified generic makers of agency findings.
At the request of generic companies, the agency also has informed RLD sponsors of the findings and “indicated that FDA will not consider it a violation of the REMS for the RLD sponsor to provide (or authorize the provision of) a sufficient quantity of the drug to allow the potential applicant to conduct testing necessary to support its ANDA.”
But FDA notes that some protocol and related document submissions required revisions due to incompleteness or inadequacy. Guidance “clarifying both the procedure for requesting FDA review and the proper contents of protocol submissions could improve the quality of initial submissions and reduce associated review time.”