21st Century Cures: Food and Drug Administration (FDA) Drug Provisions

On December 7, 2016, the US Congress approved the 21st Century Cures Act, substantial legislation intended to accelerate “discovery, development and delivery” of medical therapies by encouraging biomedical research investment and facilitating innovative review and approval processes, among other things. The massive bill, however, also served as a vehicle for a variety of other health-related measures, including portions of:

• Advancing Targeted Therapies for Rare Diseases Act of 2016,
• Patient-Focused Impact Assessment Act of 2016,
• Promise for Antibiotics and Therapeutics for Health (PATH) Act,
• Combination Products Regulatory Fairness Act of 2016, and
• FDA and NIH Workforce Authorities Modernization Act.

These bills were introduced, but not advanced by the Senate.

On December 13, 2016, President Obama signed the bill into law. This On the Subject summarizes the Food and Drug Administration (FDA) provisions in title III that pertain to drugs.

Overview of the Drug Provisions in the Cures Act

The drug provisions of the Cures Act are generally friendly to sponsors and manufacturers, and largely impose additional requirements on FDA. In general, the Cures Act provisions seek to:

• Expedite the review process for certain drugs,
• Facilitate the recognition of drug outcome measures,
• Encourage the consideration of data beyond that produced in randomized clinical trials to support approval,
• Create a new priority review voucher (PRV) for material threat medical countermeasures,
• Extend the current rare pediatric disease PRV program,
• Clarify the scope of permissible dissemination of health care economic information (HCEI) by manufacturers, and
• Require manufacturer publication of expanded access policies.

Why These Provisions Matter

Changes to the Review and Approval Process Generally

The Cures Act does not modify the statutory standard for the approval of a new drug or biologic. As outlined below, however, the Cures Act included several provisions that may impact the types of evidence FDA will consider when deciding whether individual products meet the statutory standard.

The codification of FDA’s current guidance-based qualification process for Drug Development Tools (DDT)—e.g., biomarkers, clinical outcome assessments, and other methods, materials or measures—may benefit drug developers and biomedical research consortia, promote drug innovation and expedite review of regulatory applications. The Cures Act requires FDA to create a process by which a sponsor, consortia or other requestor can seek to qualify a DDT for its proposed context of use. A DDT is qualified if FDA determines its proposed context of use can be relied upon to have a specific interpretation and application in drug development and regulatory review. Qualified DDTs may be used to support or obtain approval or licensure of a drug or biologic, or to support an investigational use. Companies developing drugs for conditions that lack well-established outcome measures, or for which existing measures fail to assess critical performance parameters, may benefit from an established process for the qualification of DDTs. FDA has also stated that companies can pool resources and data to develop a DDT, which may reduce the cost associated with development and recognition of such measures.

Notwithstanding objections from certain consumer advocacy groups, the statute also requires FDA to establish a program to evaluate the potential use of “real world evidence”—i.e., data regarding the usage or potential benefits or risks of a drug that is derived from sources other than randomized clinical trials—in support of applications for new indications for FDA-approved drugs and/or to support or satisfy post-approval marketing requirements. FDA must, in consultation with industry, advocacy groups and others, draft a framework for the program’s implementation, and then implement the program within two years of the law’s enactment.

Drug and biologics developers may also benefit from a provision that allows FDA to rely on a “qualified data summary”—a summary of clinical data that demonstrates the safety and effectiveness of a drug with respect to a qualified indication—to support the approval of applications for new uses of previously approved products. A qualified indication is an indication for a drug that FDA determines is appropriate for summary level review; the Cures Act does not, however, provide guidance on how FDA should assess whether an indication is “appropriate” for such review. A supplemental application is eligible for summary level review if (1) there is existing data available and acceptable to FDA that demonstrates the safety of the drug; and (2) data used to develop the qualified data summaries are submitted to FDA as part of the supplemental application.

Changes to the Review and Approval Process for Certain Drugs

Sponsors of drugs that FDA designates as regenerative advanced therapies (RAT)—e.g., cell therapies, therapeutic tissue engineering products, human cell and tissue products—may benefit from a provision authorizing priority review and accelerated approval. For a sponsor’s drug to be designated a RAT by FDA, the drug must be intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that the drug has the potential to address unmet medical needs for such disease or condition. A new drug application (NDA) or biologics license application (BLA) for a RAT may be eligible for accelerated approval through reliance on surrogate or intermediate endpoints reasonably likely to predict long term clinical benefit or data from a meaningful number of sites.

Similarly, sponsors of antibacterial and antifungal drugs intended to treat serious or life-threatening infections in a limited population of patients with unmet needs may benefit from the creation of a new “limited population” approval pathway. The new pathway is designed to expedite approval of these drugs without requiring large-scale clinical trials or testing in specific populations. The labeling and advertisements for such drugs must contain a statement that the drug’s safety and effectiveness has only been demonstrated with respect to a “limited population,” and the promotional materials for such drugs must be submitted to FDA prior to dissemination. FDA Commissioner Robert Califf explained that the drugs are to be “used narrowly … while additional evidence is generated to assess safety and effectiveness for broader use.”

Sponsors of genetically targeted or variant protein targeted drugs—drugs for the treatment of rare diseases or serious or life-threatening conditions which, respectively, may modulate the function of a gene or modulate the function of a product of a mutated gene—may benefit from a provision that enables FDA to permit a sponsor to rely on data previously developed and submitted by the sponsor (or another sponsor, with the appropriate right of reference) as part of an approved NDA or BLA. The law is intended to address the challenge of conducting clinical trials in small populations of patients, especially subgroups of patients with the same disease or condition but different genetic mutations. To be eligible under this provision, drugs must incorporate or use the same or similar technology as the drug in the previously approved application.

Priority Review Voucher Programs

Sponsors of material threat medical countermeasures may benefit from the law’s creation of a new Priority Review Voucher (PRV) program, which entitles the holder of a PRV to expedited FDA review of a subsequent drug product application within six months, which is four months faster than the standard review process. A sponsor would receive a PRV upon approval of an application for a material threat medical countermeasure application that (1) prevents or treats harm from biological, chemical, radiological or nuclear agents that present a material threat against the US population sufficient to affect national security or (2) mitigates, prevents or treats harm from a condition that may result in adverse health consequences or death, and may be caused by administering a drug or biologic against an agent that presents a national security threat. Like other PRV programs, holders must notify FDA before using the PRV, and the program sunsets on a date certain (October 1, 2023). PRVs issued under this program are also transferable, which, given the robust market for PRVs issued under other authorities, may make the program a significant incentive toward the development of “material threat” medicines.

Sponsors of drugs for rare pediatric diseases may benefit from the extension of the corresponding PRV program through September 30, 2020.

Dissemination of Health Care Economic Information

Manufacturers and others who disseminate “health care economic information” (HCEI) related to drugs and devices may benefit from the clarification and expansion of permissible communications. HCEI will not be considered false or misleading labeling if it (1) is disseminated to persons to whom such information may be communicated; (2) relates to approved indications and is based on competent and reliable scientific evidence; and (3) includes a “conspicuous and prominent statement describing any material differences” between HCEI and FDA-approved labeling. As compared with previous interpretations of labeling, advertising and misbranding provisions in the Federal Food Drug and Cosmetic Act (FFDCA) which restricted the content and contexts in which HCEI could be disseminated, the Cures Act provides greater flexibility. The Cures Act expands the audience to whom HCEI may be communicated (to include payors and similar entities with expertise in health care economic analysis that select drugs for coverage or reimbursement), expands the types of analysis that may be shared (to include clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis, as well as separate or aggregated consequences from the represented health outcomes), and liberalizes the previous requirement that HCEI “directly relate” to approved indications (now HCEI must only “relate” to such indications). The provision does not apply, however, to any analysis that relates only to unapproved indications.

Susceptibility Test Interpretive Criteria

Holders of existing NDAs and BLAs must remove susceptibility test interpretive criteria, which characterize the susceptibility of bacteria or other microorganisms to the antimicrobial drug tested and categorize a drug’s susceptibility (i.e., susceptible, intermediate, resistant), from approved drug labeling and replace the information with a reference to the newly-mandated FDA interpretive criteria website. Similarly, antimicrobial drugs approved after the website is created must reference the website in their labeling in lieu of susceptibility test interpretive criteria. The statute requires FDA to include certain disclaimers about the limits of safety and efficacy of such drugs, the clinical significance of susceptibility information and approved product labeling, on the website. Antimicrobial drug manufacturers and others may benefit from a provision permitting FDA to consider information provided by “interested third parties” when evaluating new or updated susceptibility test interpretive criteria standards.

Combination Products

In response to complaints that FDA improperly regulated certain combination products as drugs or biologics based on an overly restrictive application of the “primary mode of action” test, the Cures Act prohibits FDA from determining that a combination product’s primary mode of action is that of a drug or biologic solely because the combination product has any chemical action within or on the human body. Chemical action in the body is a statutory concept that distinguishes a drug or biologic from a medical device. The Cures Act requires FDA to determine how a combination product will be regulated based on a new statutory definition of “primary mode of action,” which focuses on the single mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.

What Is Required by These Cures Act Provisions

Stakeholder-Related Requirements

Manufacturers or distributors of investigational drugs for serious diseases or conditions must make publicly available their expanded access policies on requests for such drugs within 60 days of the law’s enactment or the initiation of a phase 2 or phase 3 study of an investigational drug, whichever date is later.

Requirements Imposed on FDA

FDA must issue guidance on:

• The collection and use of patient experience data— data intended to provide information about patients’ experiences with a disease or condition—in drug development (draft guidance due 18 months after enactment);
• The process for qualification of DDTs (draft guidance due three years after enactment);
• The circumstances under which drug sponsors and FDA may rely on real world evidence (draft guidance due five years after enactment);
• Pre-submission interactions with sponsors developing combination products and submissions of information with meeting requests (final guidance due four years after enactment); and
• The criteria, processes and considerations for demonstrating safety and effectiveness of limited population antibacterial and antifungal drugs (draft guidance due 18 months after enactment).

The agency may also issue updated guidance and regulations within one year of developing standards to support the development, evaluation and review of regenerative medicine therapies and RATs.

FDA must issue the following reports assessing:

• The use of patient experience data in regulatory decision-making (by June 1 of 2021, 2025 and 2031);
• The qualification process for DDTs (five years after enactment);
• Approval of RATs, as well as the number of applications for which FDA granted accelerated approval or priority review (by March 1 of each year);
• Approvals of antibacterial or antifungal drugs under the limited population pathway (every two years); and
• The implementation of the new statute on the susceptibility test interpretive criteria (two years after enactment).

The Cures Act also requires FDA to take other actions:

• Issue a draft framework for implementation of a program to evaluate real world evidence;
• Post information on the review of supplemental applications that rely on qualified data summaries;
• Develop standards and consensus definitions related to the development, evaluation and review of regenerative medicine therapies and RATs;
• Provide advice to sponsors of limited population drugs on data needed for approval;
• Identify, list and update susceptibility test interpretive criteria and susceptibility test interpretive criteria standards on the new FDA interpretive criteria website; and
• Post guidelines of best practices for drug safety surveillance using the FDA Adverse Event Reporting System and criteria for public posting of adverse event signals.

Action Steps for Drug Manufacturers and Other Stakeholders

Manufacturers should re-evaluate the extent to which they hold promising data but set aside certain FDA submissions due to an inability to run the randomized controlled trials that would likely have been required. Insofar as one or more of the additional sources of evidence recognized in the Cures Act could support an application, sponsors should consider citing the Cures Act in negotiations with the agency regarding the amount and type of evidence required to support a successful application.

Manufacturers should also evaluate the extent to which new drugs or new indications for old drugs may be candidates for an expedited review pathway or a PRV, and evaluate the extent to which they have the data to support such applications or can generate the required information. Sponsors of genetically targeted drugs and variant protein targeted drugs should consider what previously submitted data may be used in support of subsequent NDAs and BLAs.

With regard to marketing and labeling, manufacturers should re-evaluate whether the relaxed restrictions on HCEI might make it more feasible to proactively address payor and other reimbursement issues that they previously declined to discuss due to regulatory concerns.

Finally, insofar as many of the above provisions require FDA to take steps to implement the changes envisioned by Congress, stakeholders such as manufacturers, clinical trial sponsors, academic institutions, clinicians, industry organizations and standard setting organizations should consider participating in public meetings or other outreach efforts by FDA to develop or revise applicable standards, guidance documents and regulations.