Hatch-Waxman Comments – Status Report (Part II)

Last week I summarized some of the recommendations for FDA in the first 67 comments to the Hatch-Waxman docket that opened in July.  Today’s entry discusses the recommendations that relate to use and distribution restrictions, citizen petitions, and what some call “product hopping.”

I have sorted by topic and, within each topic, attempted to lump like with like.

Risk Evaluation and Mitigation Strategies (REMS); general

These comments relate to use and distribution restrictions, imposed as part of a REMS under the authority of section 505-1 of the FDCA.  Here is the statutory provision, which refers to these restrictions as “elements to assure safe use” (ETASU).

Commenters stated that FDA should:

  • Provide accurate, up-to-date information on the purpose and use of REMS programs to inform calls for revision of regulatory policy, because the debate over appropriate use of REMS with ETASU is clouded by misperception and inaccuracies
  • Ensure that generic developers demonstrate the same rigor as is required of innovators in implementing the REMS requirements for abuse-deterrent opioids
  • Carefully review REMS applications that require restricted distribution, and approve restricted distribution only when truly warranted for safety reasons
  • Develop and publish customized guidance for medicines based on the different types of safety risk that REMS with ETASU are designed to mitigate
  • Collect and issue best practices for REMS
  • Communicate and share information with the FTC to identify instances where REMS and ETASU are being used for anticompetitive reasons; report all manufacturers who engage in REMS abuse to the FTC
  • Exercise existing misbranding authorities in cases where an innovator is using a REMS, directly or indirectly, to delay the development or approval of a generic drug
  • Prohibit companies from declaring information about REMS to be proprietary
  • Work with the FTC to examine the possibility that REMS programs may be used as a tool to limit the number of entities providing certain medications, which may effectively dictate the pharmacy a patient attends – and ultimately affect patient access and choice; determine whether this limits competition and harms consumers.

REMS; providing samples for testing purposes

Commenters stated that FDA should:

  • Explain the legal basis for the agency’s letters certifying a generic applicant’s safety and handling protocols and for the agency’s conclusion that it will not consider sales to a generic company a violation of the innovator’s REMS.
  • Finalize the draft guidance on sample access in a way that reflects the facts that (1) the innovator company has made a commitment to ensure safe handling, distribution, and dosing of the product, (2) the innovator has little protection against claims arising out of action or inaction of a generic company if misuse leads to the adverse event sought to be mitigated by the ETASU, and (3) smaller biologics manufacturers in particular will need to balance sample requests with anticipated patient demands over the same time horizon.
  • Finalize the draft guidance, and require generic applicant protocols to include adequate information on adverse event monitoring and reporting, quality assurance, quality control, compliance systems, programs to address patient injury, and storage, handling, and disposal of product
  • Address the process for (or permissibility of) providing samples to a prospective generic applicant in the absence of an FDA letter
  • Issue regulations outlining the procedures FDA will follow to revise or revoke a letter to a generic applicant certifying its safety and handling protocols, if information becomes available indicating the company can no longer control the product appropriately
  • Publicize letters to innovators stating that a generic company’s proposed study protocols contain sufficient protections such that sale of the medicine to the generic company for purposes of bioequivalence testing would not violate the REMS
  • Clarify that FDA approval is not required for a generic manufacturer to access samples for the purpose of bioequivalence testing; finalize the draft guidance, which stated that requesting or obtaining an FDA letter is not a legal requirement for a REMS holder to sell samples
  • To assist negotiations for purchase of samples of drugs under REMS with ETASU, provide guidance that standardizes the procedures and controls for safe handling and use, specifies the quantitative measures to evaluate and validate the REMS, and specifies methods for filing this information with FDA
  • Compel the sale of samples sufficient for bioequivalence testing by three generic manufacturers as a condition of drug approval
  • Implement a policy, with CMS, that makes participation in Medicare, Medicaid, and other federal health care reimbursement programs contingent on selling the reference product to generic and biosimilar companies promptly, on commercially reasonable terms, for testing under the regulatory supervision of FDA.
  • Issue a policy confirming that it is a condition of approval that the reference product be sold to generic and biosimilar companies promptly, on commercially reasonable terms, for testing under the regulatory supervision of FDA.
  • Require the submission of sample deposits sufficient for bioequivalence testing by three generic manufacturers, as a condition of drug approval, assuming that safe sample collection and storage would be feasible and not unduly burdensome.
  • Require brand companies to make their approved products available to generic and biosimilar companies. Prohibit use of any REMS or limited distribution network to block access.

REMS; single shared systems for use and distribution restrictions

Commenters stated that FDA should:

  • Recognize that an established REMS with ETASU may remain in effect until a generic product (under a single, shared system) becomes commercially available — to avoid confusing users with in anticipation of generic launches that could be some time off
  • Work first to finalized a shared system (or waiver) with the innovator and first generic applicant, before moving forward with approvals of subsequent ANDAs
  • Recognize that an agreed single, shared system may meet the statutory requirements and be approved before engagement with other generic applicants
  • Take action to identify and halt potential use of REMS to block generic competition through protracted shared REMS negotiations
  • End negotiations between innovator and generic companies over a single shared system when innovators unfairly prolong the negotiations
  • Support the use of industry working groups that can develop proposals for shared REMS systems and act as a facilitator to resolve problems
  • Be judicious in exercising waiver authority for shared REMS, because waiving the requirement has the potential to create inefficiencies
  • Decline to issue waivers of the single, shared system requirement, because multiple REMS would burden healthcare providers and their patients
  • Do not waive the requirement for a single, shared REMS, because this will discourage the use of generic drugs (by prompting providers to prescribe only the brand product) and will impose significant administrative and compliance burdens on pharmacists
  • More broadly exercise the existing statutory waiver authority the burdens of a single, shared system outweigh its benefits
    • Consider, for instance, the efforts and good faith of the parties in attempting to reach agreement.  Consider whether the parties have the capabilities and resources to create and implement their own systems by the time of generic approval.  Consider official action indicated (OAI) from inspections, which might indicate merging with or incorporating a company into a single, shared system might not be advisable.
  • Flexibly interpret the statutory term “single, shared system” to facilitate agreements on these systems, including novel models thereof
  • Adopt a more flexible approach to the issue of waiving the shared system requirement when evaluating impasses that arise in negotiations (for instance, don’t wait for both statutory triggers to be met, before making a waiver determination), so long as this does not weaken the REMS safety standard or otherwise come at the expense of patient safety or public health
  • Where waiver is granted, ensure that patients and providers understand which safety measures are shared and which diverge
  • Allow more generic manufacturers to create their own REMS
  • Ensure that FDA oversight of single, shared systems is focused on safety rather than governance and other operational issues, so that the agency does not impose unnecessary burdens on negotiations.
    • Cease mandating that single, shared systems have a shared governance structure.  Acknowledge that companies may employ a variety of approaches to governance and operational issues.  Defer these business decisions to the parties.

Citizen Petitions

These recommendations relate to petitions subject to section 505(q) of the FDCA, which ask the agency to take (or not take) an action relating to a generic drug application or biosimilar biologic license application.  (For more information, see this guidance.)  Commenters argued that FDA should:

  • Refrain from imposing additional regulations on the use of citizen petitions as a tool for communicating important information to the agency, given the public health role that petitions play and the First Amendment right to petition the agency
  • Disallow citizen petitions that reference generic drug applications
  • Require a preliminary finding that citizen petitions will likely be granted, based on compelling evidence, in order to proceed to a full review
  • Expand the certifications and verifications required on a petition subject to 505(q) to include (1) broad representations as to how and when the information on which the petition is based first became known to the party, (2) certifications that all unfavorable information has been disclosed, and (3) affirmation that the petition is not interposed to delay competition.
  • Create a “parallel track” for generic drug approval and citizen petition review, so that a petition cannot in any way affect the timing of generic approval.
  • Require that all citizen petitions affecting a generic drug application be submitted within one year of the generic drug application being filed.
  • Establish a presumption that innovator petitions pertaining to generic applications filed within nine months of the expiration of the primary patent on the innovative drug are a delaying tactic
  • Refer drug manufacturers to the Federal Trade Commission if they are suspected to be “abusing” the citizen petition process.
  • Develop procedures to minimize agency resources spent evaluating and rejecting petitions from manufacturers that routinely submit merit-less petitions.
  • Establish procedures to identify and make publicly available information on manufacturers or their proxies that frequently submit petitions that lack valid concerns and are routinely denied
  • Consider fines, punishments, or suspensions for attorneys who file frivolous citizen petitions

“Product Hopping”

These comments refer to, as one commenter put it, “introducing minor changes to a drug’s formulation to limit substitution and shift patients to the new drug before a generic comes to market.”

Commenters argued that FDA should:

  • Create a new classification under the Orange Book — “therapeutically substitutable” products — which are not therapeutically equivalent but nevertheless have no clinically meaningful differences in safety or efficacy
  • Compile data on drug modifications, including the nature of each modification and how close to patent expiry it occurs
  • Conduct a study on whether there are health risks involved in the substitution of a lower priced generic that has the same active ingredient and therapeutic effect, but has other differences
  • Allocate agency resources to new cures, generics, and biosimilars, rather than non-innovative life cycle changes of drugs and biologics
  • Use whatever leverage is available to approve only new products that provide a clinically meaningful benefit over original products
  • Explore ways to ensure that minor formulation changes do not earn exclusivity
  • Closely scrutinize applications that propose new dosage forms, new combinations, and new formulations and that are filed within 18 months prior to the first anticipated generic drug application filing or while the first generic application is under consideration; if treatment with the original product represents the standard of care, encourage the manufacturer to conduct randomized controlled trials of the modified product compared to the original product
  • Create a voluntary program in which drug companies are encouraged to submit comparative data on modified products; use this information to identify problematic modifications and forward them to the FTC and state attorneys general for further investigation and possible antitrust litigation
  • Consider ways of using pharmacists to limit the impact of “product hopping”

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