Regulatory Explainer: 21st Century Cures Redux and What it Will Mean for FDA

ExplainersExplainersRegulatory NewsRegulatory News | 28 November 2016 |  By 

Lingering for more than two years, the revamped 21st Century Cures bill, unveiled in late November, has now been approved by the House and Senate and President Barack Obama has said he will sign it.

The 996-page bill includes major tweaks to the way in which the US Food and Drug Administration (FDA) regulates drugs, devices and biologics, while providing the agency with $500 million over 10 years to implement provisions that seek to move such products to patients more quickly, while maintaining the same standard for safety and effectiveness that the agency has adhered to in the past.

Proponents of the bill see a necessary modernization of the regulations, as well as major funding boosts not only for FDA but for the National Institutes of Health (NIH), which would stand to gain $4.8 billion over 10 years to aid the development of Vice President Joe Biden’s Precision Medicine Initiative, the Brain Research Through Advancing Innovative Neurotechnologies Initiative, cancer research and regenerative medicine using adult stem cells.

The bill also looks to help states tackling the growing opioid epidemic by providing $1 billion over two years for state grants to supplement opioid abuse prevention and treatment activities, such as improving prescription drug monitoring programs, implementing prevention activities, training for health care providers and expanding access to opioid treatment programs.

Despite the increases in funding, critics have said the bill and previous iterations, which passed the House in July 2015 but stalled in the Senate, would loosen the standards for drug and device approvals, speeding the approvals of such medical products to a point that could endanger patient safety.

How Congress Will Pay For 'Cures'

According to the Congressional Budget Office's review of the bill, the majority of the legislation will be paid for with funds from the Prevention and Public Health Fund, created under the Affordable Care Act (also known as Obamacare).

That fund has allocated more than $300 million to improve the public health immunization infrastructure, more than $100 million to raise awareness about the harms of tobacco use, as well as other allocations for Alzheimer's disease prevention education and outreach and grants to enhance diabetes prevention and to detect and respond to infectious diseases and other public health threats.

The legislation would also be paid for with a little more than $1 billion in funding from the Strategic Petroleum Reserve.

What's In It

Listed below, in the order in which they appear in the bill, are key sections that would have a major impact on FDA (for a review of the previous 21st Century Cures Act from April 2015, see this explainer) or revise the Federal Food, Drug, and Cosmetic Act (FDCA).

Sec. 1002 FDA Innovation Projects

From fiscal years (FYs) 2018 through 2026, FDA would be authorized to spend a total of $500 million (from $30 million in FY 2018 to $50 million in FY 2023 to $75 million by FY 2026) on a proposed work plan for such innovation projects.

FDA’s commissioner is tasked with seeking recommendations from the agency’s Science Board to decide what projects to pursue and within 180 days of the bill’s passage a work plan must be submitted to the House Committee on Health, Education, Labor, and Pensions, the Senate’s Committee on Appropriations, the House Committee on Energy and Commerce and the House Committee on Appropriations for each of the fiscal years.

Sec. 2034 Reducing Administrative Burden for Researchers

This section, among other major changes, requires NIH’s director, the Secretary of Agriculture and FDA’s commissioner to review and revise laboratory animal regulations and policies to reduce administration burden on investigators.

Sec. 2072 Global Pediatric Clinical Study Network

Encourages NIH and FDA to work with the EU, industry and others to establish a global pediatric clinical study network.

Sec. 3001 Patient Experience Data

This section of the bill builds on FDA’s progress in integrating patient perspectives into its decision making processes for drugs and devices.

Under Cures, FDA would be required to include a statement regarding any patient experience data that was used at the time of a drug’s approval and the bill defines patient experience data as “data collected by any persons (including patients, family members and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and drug manufacturers).”

Sec. 3002 Patient-focused Drug Development Guidance

This section requires FDA to issue guidance regarding how to collect such patient experience data, with guidance documents addressing:

  • Appropriate ways to collect data for use in regulatory decisions;
  • How patients wishing to propose draft guidance to FDA may submit such documents;
  • How FDA will respond to patient experience data submissions to FDA;
  • The format and content for patient experience data submissions;
  • How FDA plans to use relevant patient experience data and related information when evaluating the risks and benefits of a drug.

Sec. 3003 Streamlining Patient Input

This section exempts FDA from going through the Paperwork Reduction Act clearance process when requesting information from patients regarding their disease or treatments, allowing the agency to obtain, what the bill calls “more timely feedback from patients.”

Sec. 3004 Report on Patient Experience Drug Development

This section requires FDA to report on its review of patient experience data and information on patient-focused drug development tools as part of approved drugs not later than 1 June of 2021, 2028 and 2031.

Sec. 3011 Qualification of Drug Development Tools

This section also follows on from FDA’s prior work from 2012 in which the agency created a new program known as the Drug Development Tools Qualification Program to qualify — i.e. validate as being useful and appropriate—new biomarkers, clinical outcome assessments, patient reported outcomes and animal models.

This section actually establishes a review pathway at FDA for such biomarkers and other development tools that can be used to help shorten drug development times, aiming to help reduce the high failure rate in drug development.

Under this section, FDA would be required to make publicly available on at least a biannual basis on its website, the following:

  • All drug development tools qualified, including all surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product;
  • information on each qualification submission under the qualification process;
  • whether external scientific experts were utilized in the development of a qualification plan or the review of a full qualification package;
  • formal written determinations in response to such qualification submissions;
  • summary reviews that document conclusions and recommendations for determinations to qualify drug development tools

Sec. 3012 Targeted Drugs for Rare Diseases

This section clarifies FDA’s authority on genetically targeted drugs for rare diseases, allowing sponsors of genetically targeted or variant protein targeted drugs to rely on data for the same or similar technology from previously approved applications by the same sponsor, though the section does not alter the existing approval standards for drugs.

Sec. 3013 Reauthorization of [PRV] Program to Encourage Treatments for Rare Pediatric Diseases

This section reauthorizes the pediatric rare disease priority review voucher (PRV) program, which FDA is opposed to, until 2020. For a full rundown on this and the other currently authorized PRV program for rare tropical diseases, see this explainer.

This section also notes that if a drug is designated as rare pediatric treatment that can win a voucher before 1 October 2020, it can continue to receive a voucher if approved before 1 October 2022.

Sec. 3014 GAO Study of Priority Review Voucher Programs

This section requires the Government Accountability Office (GAO) to study the current PRV programs to evaluate their impact on drug development and any unintended consequences.

In March, GAO published its first report on the pediatric PRV program, noting that it was still too early to tell if the program had stimulated the development of new drugs to treat or prevent such diseases.

Sec. 3015 Amendments to the Orphan Drug Grants

This section updates the orphan drug grant program to clarify that grants may be used for observational studies that help understand the natural history of a rare disease and in the development of such a therapy.

Sec. 3016 Grants for Studying Continuous Drug Manufacturing

This section also builds off FDA’s work on encouraging the use of continuous drug manufacturing and allows FDA to issue grants to further the study of continuous manufacturing for drugs.

Sec. 3021 Novel Clinical Trial Designs

This section, following the release of draft guidance from February 2010, requires FDA to hold a public meeting and issue additional guidance assisting sponsors in incorporating adaptive designs and novel statistical modeling into new drug applications.

Sec. 3022 Real World Evidence

In July, FDA released draft guidance with plans to use real world evidence or data in making medical device regulatory decisions.

This section requires FDA to evaluate the use of real world evidence to help support the approval of a new indication for a previously approved drug and to help support or satisfy post-approval study requirements.

These new proposed requirements come as Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), has joked that "data gathered from healthcare has always had one characteristic, it's not very good," though she has emphasized that the agency is very familiar with it, "warts and all."

Sec. 3023 Protection of Human Research Subjects

This section requires the Secretary of the Department of Health and Human Services (HHS) to harmonize differences between the human subject regulations under the Common Rule and the FDCA. It also aims to streamline the institutional review board process for trials that are being conducted at multiple sites.

Sec. 3024 Informed Consent Waiver or Alteration for Clinical Investigations

This section provides FDA with the flexibility to waive or alter informed consent requirements for clinical trials with minimal risk, similar to existing flexibility for HHS and NIH under the Common Rule .

Sec. 3031 Summary Level Review

This section allows FDA to rely upon qualified data summaries to support the approval of an application for a new indication of an already approved drug. “Sponsors of the application still must submit all information to FDA,” the bill says.

Sec. 3032 Expanded Access Policy

Following the approval of a number of state Right-to-Try bills, this section requires that pharmaceutical companies have publicly accessible compassionate use policies for drugs treating serious or life-threatening conditions.

Compassionate use, also known as expanded access, is a process by which physicians can request that FDA allow the use of an investigational drug outside of a clinical trial for a patient with a terminal illness or no other treatment options. But the process can only be initiated if the company developing the drug and the physician treating the patient agree to move forward and make the FDA request.

Sec. 3033 Accelerated Approval for Regenerative Advanced Therapies

This section allows FDA to grant accelerated approval for regenerative therapeutic products and directs FDA to consider the unique characteristics of such therapies and provide a rationale with a determination of whether or not to grant accelerated approval. This section, however, does not change the standards of evidence or limit any other of the authorities of FDA.

Sec. 3034 Classification of Devices Used with Regenerative Advanced Therapies

This section establishes that devices used with a regenerative therapeutic product will be considered moderate risk devices, unless the FDA determines that the device or intended use requires a higher risk classification.

Sec. 3035 Updated Regenerative Medicine Guidance and Regulations

This section requires FDA to update guidance and regulations on regenerative therapeutic products and hold a public meeting to encourage innovation.

Sec. 3036 Standards for Regenerative Medicine and Advanced Therapies

This section requires FDA to consult with stakeholders and the National Institute of Standards and Technology (NIST) to establish standards, to support the development, evaluation, and review of regenerative medicine and advanced therapies products.

This section also defines “regenerative medicine and advanced therapies” as including cell therapy gene therapy, gene-modified cell therapy, therapeutic tissue engineering products, human cell and tissue products and combination products using any such therapies or products.

Sec. 3038 Combination Product Innovation

This section aims to improve the regulation of medical products that contain both a drug or biologic and a device, known as combination products by requiring that FDA meet with sponsors and agree early in development how to best study the combination product to meet the standard for approval.

This section also clarifies how dispute resolutions work when the different centers of FDA do not agree, and it includes provisions for reporting on combo product regulations.

Sec. 3042 Limited Population Pathway

This section provides FDA with more flexibility to approve antimicrobial drugs based on a limited population if the drug treats a life-threatening infection.

If FDA approves a drug based on a limited population, the labeling and advertising of an antimicrobial drug shall contain “Limited Population” along with a proprietary name of the drug.

This section also gives FDA the authority to review and approve promotional materials of a drug approved based on a limited population at least 30 days prior to drug dissemination.

Sec. 3044 Susceptibility Test Interpretive Criteria for Microorganisms

This section provides FDA with the authority to rely on third party experts when updating guidelines for how much of a drug to use and which infections the drug is useful in treating.

Sec. 3051 Breakthrough Devices

As FDA’s Center for Devices and Radiological Health (CDRH) has worked to create a new expedited access program for breakthrough devices, this section of the bill establishes a breakthrough device pathway, which builds on the existing priority review device pathway.

Sec. 3052 Humanitarian Device Exemption

This section provides FDA with the authority to apply the humanitarian device exemption to devices that treat diseases and conditions that affect up to 8,000 individuals in the US. The current cap is 4,000.

Sec. 3053 Recognition of Standards

This section establishes a process at FDA for the submission, review and recognition of standards established by a nationally or internationally recognized standard organization for purposes of medical device review, including the IMDRF.

Sec. 3054 Certain Class I and Class II Devices

Requires FDA to update lists regarding the appropriate regulation of Class I and Class II devices.

Sec. 3055 Classification Panels

This section aims to improve FDA’s device classification panel review process to ensure adequate expertise among panel members to assess the device and allow for presentation by the device sponsor to the panel, among other things.

Sec. 3056. Institutional Review Board Flexibility

This section strikes the requirement that a sponsor of a device trial always use a local institutional review board. This change will allow the use of centralized models.

Sec. 3057 CLIA Waiver Improvements

Requires that the FDA update its existing regulatory guidance to clarify the criteria for waiving Clinical Laboratory Improvement Amendment (CLIA) requirements, which aims to expand patient access to point-of-care diagnostics.

Sec. 3058 Least Burdensome Device Review

This section requires an audit by the FDA ombudsman and an assessment of the measurements used to track the implementation of the least burdensome requirements. It also clarifies that FDA reviewers shall consider the least burdensome appropriate means necessary for demonstrating a reasonable assurance of safety and effectiveness when requesting additional information from manufacturers during the pre-market approval process.

Sec. 3059 Cleaning Instructions and Validation Data Requirement

Following serious patient issues linked to infections from reusable devices and the release of guidance from 2015, this section encourages and clarifies that FDA requires cleaning and validation data for reusable medical devices.

Sec. 3060 Clarifying Medical Software Regulation

This section identifies five specific categories of medical software that, given certain conditions, will not be regulated as a medical device by FDA based on their low level of risk to patients. This section also provides FDA with the authority to regulate software in these categories if there is found to be safety concerns.

In October, FDA opened for public consultation a harmonized guidance on the clinical evaluation of software as a medical device developed by IMDRF.

Sec. 3086 Encouraging Treatments for Agents that Present a National Security Threat

This section, following House E&C committee passage of a similar provision last July, creates a new PRV program to encourage the development of drugs and vaccines for agents that present national security threats, also known as medical countermeasures. The program would sunset on 1 October 2023.

Improving Scientific Expertise and Outreach at FDA

A couple of sections under this header would increase the number of positions available in the Silvio O. Conte Senior Biomedical Research Service, allow increased salaries, and make changes to the qualifications to include engineers so the service can better serve FDA and other HHS agencies. It also requires GAO to conduct a study of the program, including the impact of the changes made.

FDA also gains new authority to appoint “outstanding and qualified candidates” to scientific, technical or professional positions that support the development, review and regulation of medical products and allows FDA’s commissioner to determine and fix the annual pay rate up to a limit to help attract and retain qualified employees.

The changes come as FDA is currently struggling to fill more than 500 vacant positions and a lot of that needed expertise can come from within industry.

Sec. 3073 Establishment of FDA Intercenter Institutes

This section requires FDA to pilot one or more intercenter institute(s) to help develop and implement processes for the coordination of activities in major disease areas between the drug, biologics and device centers.

In August, FDA initiated a new pilot project linking its intercenter consult request process for combo products.

Sec. 3074 Scientific Engagement

This section improves FDA and NIH scientists’ ability to attend scientific conferences so they can keep up with the newest advancements in science and collaborate with one another.

Sec. 3075 Drug Surveillance

This section edits FDA’s drug surveillance program to allow for more focus on risk.

Sec. 3076 Reagan-Udall Foundation for FDA

This section aims to modernizes FDA’s independent, non-profit organization, known as the Reagan-Udall Foundation, which was first established by Congress to help FDA keep up with the pace of science.

21st Century Cures Act Bill Text (as of 25 November)

Summary of the Sections of the Bill

Editor's note: This explainer was updated on 11/29 with information from the Congressional Budget Office on paying for the bill and on 12/8 with the updates on teh House and Senate passage of the bill.


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