The 21st Century Cures Act contains significant new mandates for both the FDA and NIH that affect the pharmaceutical and biotechnology industries and are intended to advance drug research, discovery, approval, and promotion by streamlining regulatory processes and giving FDA authority to use new types of evidence to conduct risk-benefit analyses.

Although the 21st Century Cures Act (Act) provides for a substantial infusion of funds for both the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA), it also creates substantial new obligations to issue new guidances and reports on the progress of the new initiatives and how they are impacting US drug development. As a result, US Congressional oversight in 2017 and 2018 will likely be significant.

This LawFlash covers some of the key provisions of the Act and offers takeaways for industry and stakeholders. 

Expanded Research Budget; NIH/FDA Administrative/Regulatory Process Changes §§ 1001-2072

Key Components

• NIH and FDA will receive substantial funds to spend over the next 10 years (§ 1001)

• The largest areas of investment are the following:

  • Cancer Research ($1.8 billion)

  • Brain Research ($1.5 billion)

  • Precision Medicine ($1.4 billion)

  • Regenerative Medicine ($30 million)

  • Drug Discovery and Streamlining Processes ($500 million)

• NIH must provide a report within six months indicating how the money will be spent.

• NIH will be allowed to engage in nontraditional partnering (“other transaction authority”) with industry or other grantees on the Precision Medicine Initiative and use up to 50% of funds in the NIH Common Fund (High Risk-Reward Research); the scope of the partnering is open-ended, i.e., it could include direct investments or licensing deals with private firms or patient groups, exchange of scientific resources, or exchange of big data (§ 2036).

• NIH has the authority now to require its grantees to share data (§ 2014).

• The Office of Management and Budget (OMB) is back—with authority to establish a Research Policy Board Advisory Committee to oversee the effects of regulations on federal research. This may be an impactful review portal during the administration (§ 2034).

• More emphasis is placed on understanding the effects of drugs/therapies on pregnant and lactating women as well as minority populations, and ways to safely include such categories of individuals as subjects in clinical trials. Companies and academics that receive funding can expect to have this aspect of their clinical trial protocols closely scrutinized (§ 2041).

Key Takeaways

• Money is being allocated to move the FDA and NIH into a regulatory analysis mode that expedites drug approval and removes some of the obstacles standing in the way of the prompt movement of investigational drugs from clinical trials to market.

• Because NIH will have to decide relatively quickly with regard to funding allocations, private firms that want to leverage their research dollars should develop strategies to quickly get in the NIH queue to access funding.

• Access to federal funds may be available without burdensome regulatory requirements that present impediments to public-private partnering.

Opioid Abuse Assistance § 1003

Key Components

• States will receive money for addressing opioid abuse issues, including by enhancing drug monitoring and healthcare provider education programs.

Key Takeaways

• Pharma companies’ reporting on and distribution of this class of products could be affected by state agencies’ demand for distribution data and product marketing restrictions.

Precision Medicine §§ 2011-2014

Key Components

• Encourages the development of the “Precision Medicine Initiative” to augment existing efforts to address disease prevention, diagnosis, and treatment using novel technologies, including genomic technologies such as whole genomic sequencing.

• Allows the Secretary of Health and Human Services to coordinate with other federal departments and agencies, private industry, and others in carrying out the Precision Medicine Initiative.

• Underscores the importance of patient confidentially by requiring researchers involved in biomedical, behavioral, clinical, or other research who receive full or partial federal funding to obtain certificates of confidentiality.

 Key Takeaways

• With an array of stakeholders—federal and private—involved in carrying out the Precision Medicine Initiative, its potential for significant scientific advancement and new drug development is great.

• The new privacy protection requirements for human subjects may initially disrupt research flow but eventually may make subjects more willing to participate in clinical trials involving DNA sequencing and related research.

Clinicaltrials.gov Compliance §§ 2051-2053

Key Components

• Allows device manufacturers to request NIH to register trials and trust results before receiving FDA clearance or approval.

• Requires NIH to report on compliance relating to clinical trial results reporting, and requires federal fund grantees to submit clinical trial results.

Key Takeaways

• There will be more focus/enforcement around prompt clinical trial “results” reporting by industry.

• Federally funded trials will be required to be in compliance with the results reporting requirements.

Pediatric Therapies and Research Vouchers §§ 2071-2072,3013

Key Components

• FDA and NIH are required to work with other global regulatory authorities to establish a global pediatric clinical study network.

• NIH is required to continue to support the National Pediatric Research Network as a consortium to research rare pediatric diseases and birth defects.

• Pediatric review vouchers (PRVs) for development of pediatric drugs for rare diseases are reauthorized through 2020 unless the rare pediatric product application has been designated as a drug for a rare pediatric disease by September 30, 2020 and not later than September 30, 2022, approved.

 Key Takeaways

• Pediatric research and development continues to be a focal point for the US Congress. Although FDA did not support the PRV program, there was sufficient industry interest and support to overcome agency objections. However, FDA was given the authority to review how the PRV program affects other drug approval times and resources and to report the findings to Congress. This will continue to be a controversial program, particularly in view of the recent very high market value of vouchers.

Use of Real World Evidence or Patient Experience Data §§ 3001-3004, 3021-3024

Key Components

• The Act has numerous references to increasing reliance on patient experience data (PED) and real world evidence (RWE) to demonstrate safety and efficacy.

• PED has a broad definition that includes any data regarding patients’ experiences with a disease or condition. Such data—which can include information collected by manufacturers, patients, their families, or patient advocacy groups (§ 3001)—could include the impact of diseases/conditions on patients’ lives or their preferences for the treatment of diseases/conditions.

• FDA must include a statement about the PED it uses in the review of a drug at the time of approval.

• FDA is expected to draft guidelines over the next five years on the collection and use of PED, methods for collecting and analyzing how FDA will use PED in risk-benefit analyses, and the format for submitting PED to FDA.

• RWE is defined broadly as data regarding the usage or potential benefits or risks of a drug derived from sources other than randomized clinical trials, and can include information from safety surveillance systems, observational studies, registries, insurance/reimbursement claims, and patient outcomes research (§ 3022).

• FDA must implement a program for the potential use of RWE after consulting with stakeholders, including industry and patient advocacy groups.

 Key Takeaways

• RWE and PED will assume a larger role in drug approvals, and there will be ongoing development of methodologies to collect, analyze, and validate tools for use with PED and RWE.

• With respect to their drug development programs, companies should begin to consider where PED or RWE may be supportive and relevant, and the most appropriate and reliable ways to use such data.

FDA Acceptance of Drug Development Tools § 3011

Key Components

• The Act creates a new process for FDA review of new Drug Development Tools (DDTs).

• DDTs for specified uses can be proposed to FDA through a Letter of Intent (LOI) that, if accepted by FDA, allows submission of a DDT qualification plan and package for FDA review.

• DDTs can be biomarkers, clinical outcome assessments, or any other potential tool that aids drug review.

• FDA can prioritize its review of DDTs based on the disease implicated, support of the DDT by research consortia, and related issues.

• Upon review and acceptance by FDA, the DDT can be used by any entity (i.e., it is not an exclusive approval) to support an Investigational New Drug (IND) or New Drug Application (NDA).

• The qualification packages, including data, will be made publically available by FDA.

• The Act also requires FDA to create a taxonomy for biomarkers.

• Terms including “biomarker” and “surrogate endpoints” are defined broadly to ensure that FDA is thinking expansively about how these tools can assist in affirming drug safety and efficacy.

• Draft FDA guidelines must be issued within three years, to be followed by public hearings.

 Key Takeaways

• Congress intends for FDA to think expansively about how to determine if a drug is safe and effective.

• Companies or academic centers that develop biomarkers and other novel tools should be encouraged with regard to the value and use of their technologies. Public access to the technology, however, will and should prompt sponsors of the tools to seek IP protection for the technology well before submissions to FDA.

Targeted Drugs for Rare Diseases § 3012

Key Components

• Allows sponsors of genetically targeted or variant protein drugs to rely upon data previously used for approved products for rare diseases or conditions that are serious or life-threatening.

 Key Takeaways

• Allowing sponsors to leverage data from previously approved applications could alleviate the current challenges associated with the cost of bringing to market new indications for these rare disease products.

Expanded Access Programs § 3032

Key Components

• Drug manufacturers must have publically accessible policies for drugs treating serious or life-threatening conditions.

 Key Takeaways

• The requirement to post a company’s Expanded Access policy could assist patients in navigating available treatment options but may create new challenges to small biotech companies with limited clinical supplies of such drugs and significant patient demand.

Regenerative Medicine Therapies § 3033

Key Components

• Stem cell and related cell therapy types of products, and combination products using these therapies, which are not regulated solely as Human Cells, Tissues, and Cellular and Tissue-Based Products (HTC/Ps) under 21 CFR 1271 are eligible for designation as “Regenerative Advanced Therapies”—as long as there is an active IND—if the drug

  • treats, modifies, reverses, or cures a serious or life-threatening disease or condition; and

  • there is preliminary clinical evidence that the drug has the potential to address unmet medical needs for such disease or condition.

• Regenerative Advanced Therapies are eligible for expedited action and review, including use of potential surrogate intermediate or endpoints.

• They are also eligible for priority review and accelerated approval.

• To the extent that there are post-approval studies or data obligations negotiated as the basis for approval of the Regenerative Advanced Therapy, they can be fulfilled through clinical studies, registries, and other RWE.

 Key Takeaways

• The new pathway should assist the stem cell industry to move forward to market more quickly with more complex products for non-homologous indications—although the money dedicated to the effort is limited compared to other areas for research dollars.

Dissemination of Health Care Economic Information § 3037

Key Components

• The Act authorizes provision to “a payor, formulary committee, or other similar entity” responsible for “the selection of drugs for coverage or reimbursement” of health care economic information (HEI).

• The Act specifically eliminates the requirement that information provided to such entities be based only “on competent and reliable scientific evidence,” a provision that has been relied on by FDA to attempt to restrict the dissemination of healthcare information to evidence derived from controlled, double-blinded, clinical trials.

• The new Act expressly broadens evidence that can be provided to payors to also include HEI, and defines such information broadly to include the following:

…any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug. Such analysis may be comparative to the use of another drug, to another health care intervention, or to no intervention.

• The Act precludes dissemination of HEI that relates only to an unapproved, off-label indication.

 Key Takeaways

• This broad definition of HEI clearly allows for broad comparisons of therapies, including surgery, dietary changes, and exercise, as well as comparisons to other drugs or biologics. It also clearly contemplates the ability to use economic evidence and analyses, including outcomes effectiveness research and epidemiological and retrospective analyses. Unlike some other provisions of the new Act, this provision requires no implementing action by FDA.

• This provision strongly enhances the growing efforts in recent years of payors and manufacturers to successfully develop “risk-sharing” or “performance-based” agreements intended to more closely calibrate drug selection and use to patient outcomes—and could potentially aid in cost containment.

• The new authorization to disseminate HEI to assist payors, formulary committees, and others responsible for selecting drugs likely also will place additional pressure on FDA to implement changes in its restrictive rules regarding dissemination of truthful and non-misleading information regarding off-label uses of approved drugs and biologics.

Antimicrobial Innovation and Stewardship §§ 3041-3044

Key Components

• Requires further data reporting on antibiotic resistance trends.

• Allows FDA to approve antimicrobial drugs (alone or in combination with other drugs) based on a limited population of patients with unmet needs if the drug treats a life-threatening infection. Note, an antimicrobial drug is a systemic drug (not biologic) unless otherwise identified by FDA.

• The drugs are not required to establish a favorable risk-benefit profile in a larger population.

• Drugs approved based on limited population data would have to be labeled as “Limited Population Antimicrobial ‘X’ Drug,” and promotional materials for the products must be preapproved by FDA.

• Emphasizes FDA is not allowed to restrict prescribers of the drug to prescribe only to the limited population.

• FDA is required to provide “prompt” advice to sponsors on what data is necessary for approval based on limited population data.

• Provides for approval of testing devices and dissemination of information on susceptibility interpretative criteria standards, and for FDA to maintain a website of such information.

• Requires antimicrobial labels to reference FDA’s susceptibility test interpretive criteria standards website rather than including the susceptibility test criteria on the label.

• Requires testing devices to be labeled with language noting that (1) the test provides advice about in vitro susceptibility, (2) the drugs may or may not have been proven safe and effective in adequate and well controlled trials, and (3) the clinical significance of the susceptibility information is unknown.

 Key Takeaways

• Congress’s concern about antibiotic resistance continues, as the threat of global resistance grows.

• Although the label of these products (which can also be non-systemic drugs) would be limited, FDA is precluded from restricting their use otherwise, which could encourage off-label use, creating public health and marketing challenges.

Vaccine-Related Provisions § 3091

Key Components

• As soon as FDA licenses a vaccine (either initially or for a new indication), the Center for Disease Control’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) must consider the use of the vaccine at its next scheduled meeting, although it is not required to make a recommendation.

• ACIP must make recommendations in a timely manner concerning the use of “certain vaccines,” including those that are (1) designated as a breakthrough therapy under Section 506 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) or (2) could be used in a public health emergency.

• The CDC Director must review the ACIP processes, evaluation criteria, and consistency in issuing recommendations on new and existing vaccines (including parts where flexibility is needed) on how to consistently review scientific and economic data, and to publish a report on the review no later than 18 months after the Act’s enactment. The CDC Director must solicit input from “vaccine stakeholders” and include recommendations to improve the consistency of ACIP’s processes.

• No later than one year after enactment, the Secretary of Health and Human Services, along with the NIH, FDA, CDC, and Biomedical Advanced Research and Development Authority (BARDA) must submit a report to Congress on ways to promote innovation in the development of vaccines against infectious diseases and the identification of obstacles (and proposed remedies) to vaccine innovation. The Secretary may consult with representatives of relevant federal agencies and other stakeholders.

• Vaccines recommended by the CDC for routine administration in pregnant women are to be included in the Vaccine Injury Table.

• The Act adds language to the National Vaccine Injury Compensation Provisions (42 U.S.C. Part 2) that both a woman who received a vaccine while pregnant as well as the child in utero (i.e., fetus) will be considered “persons” who were administered/received the vaccine, and both can file petitions for compensation. The definition of “child” referenced includes any child “born alive,” as defined to include “complete expulsion or extraction from his or her mother of that member, at any stage of development, who after such expulsion or extraction breathes or has a beating heart, pulsation of the umbilical cord, or definite movement of voluntary muscles, regardless of whether the umbilical cord has been cut, and regardless of whether the expulsion or extraction occurs as a result of natural or induced labor, cesarean section, or induced abortion.” For purposes of claim eligibility, it will now be important for births to be documented in medical records, according to the eligibility criteria in Title 1, Section 8 (a) and (b).

 Key Takeaways

• This provision creates a mandate for more timely and definitive action by the CDC on acceptance of new vaccines that may result in faster coverage, reimbursement, and greater market acceptance.

• The new protection—for both the pregnant women receiving the vaccine and the child in utero at the time of vaccine administration—allows the filing of two separate claims under the National Vaccine Compensation Program.