By Michelle L. Butler & James E. Valentine
The 21st Century Cures Act (Act) was passed by the House on November 30, 2016 and the Senate on December 7, 2016. The President signed it into law on December 13, 2016. The Act contains three primary titles that address acceleration of medical product discovery, development, and delivery. This post is part one of a two-part post that summarizes the relevant provisions related to development of drugs and biologics. Hyman, Phelps & McNamara, P.C. previously blogged on the medical device development provisions here . We expect to publish additional posts, including part two of the summary of drug and biologic provisions, a post summarizing the combination product provision, and a post summarizing relevant health care provisions.
Here is a summary of Subtitles A-D of Title III of the Act pertaining to Development.
Subtitle A—Patient-Focused Drug Development
Sec. 3001. Patient experience data.
Section 3001 amends the Federal Food, Drug, and Cosmetic Act (FDC Act) to require FDA to make public a brief statement regarding the patient experience data and related information, if any, submitted and reviewed as part of an approved NDA or BLA. This includes the following information:
- Data that are collected by any persons (e.g., by patients and caregivers, patient advocacy groups, drug manufacturers) that are intended to provide information about the patients’ experiences with a disease or condition, including related to the impact of the disease on patients’ lives and patient preferences with respect to treatment;
- Information on patient-focused drug development tools (e.g., Patient-Reported Outcome measures); and
- Other information FDA determines to be relevant.
This section is effective 180 days after the date of enactment of the Act.
Sec. 3002. Patient-focused drug development guidance.
Section 3002 builds on the previous section, requiring FDA to develop a plan to issue draft and final guidance documents, over the following 5 years, on the collection of patient experience data, as well as the use of such data and related information in drug development.
The section lays out a few different categories of information the guidance documents must address. First, the guidance documents must address the methodologies for collecting patient experience data, including:
- Methodological approaches for collection of relevant, objective, accurate, representative, and meaningful patient experience data throughout the drug development process for submission to and use by FDA;
- Methodological approaches for identification of what is most important to patients with respect to:
- Burden of disease;
- Burden of treatment; and
- Benefits and risks in the management of the patient’s disease;
- Approaches to identification and development of methods to measure impacts to patients that will help facilitate collection of patient experience data in clinical trials; and
- Methodologies, standards, and technologies for collection and analysis of clinical outcome assessments as part of FDA regulatory decision-making;
Second, the guidance documents must address how patient experience data will be used by FDA, including:
- The format and content required for submissions of patient experience data;
- How FDA will respond to such submissions, including a timeframe for response when such a submission is made outside of a regulatory application; and
- Importantly, how FDA anticipates using relevant patient experience data, including as part of its structured benefit-risk assessment framework, to inform its decision-making.
Lastly, the section includes a requirement for establishing, via guidance, a process for the public to propose draft guidance to FDA relating to patient experience data.
FDA has 18 months to issue the first such draft guidance document, and another 18 months after the public comment period on the draft guidance ends, to either issue a revised draft guidance or final guidance.
Sec. 3003. Streamlining patient input
Section 3003 attempts to reduce the administrative burden on FDA in collecting voluntarily-submitted patient experience data by exempting it from the Paperwork Reduction Act requirements (under Chapter 35 of title 44, United States Code).
Sec. 3004. Report on patient experience drug development.
Section 3004 requires FDA in June of 2021, 2026, and 2031 to put out a report that assesses the use of patient experience data and patient-focused drug development tools in NDA and BLA approvals.
Subtitle B—Advancing New Drug Therapies
Sec. 3011. Qualification of drug development tools.
Section 3011 amends the FDC Act by directing FDA to establish a process for the qualification of drug development tools (i.e., biomarker, clinical outcome measure) for a proposed context of use (e.g., for clinical trials in a particular disease or condition), specifically to include a letter of intent submission and review process, development and acceptance procedures for a qualification plan, and review of qualification packages. Drug development tools qualified under this section may be used for obtaining approval under an NDA or BLA, or supporting investigational use of a drug or biologic under an IND. The section also allows for FDA to rescind or modify a qualification determination based on new information that calls into question the basis for such qualification; however, it provides the sponsor of the drug development tool the opportunity to request a meeting to discuss the basis of the decision prior to the effective date of the rescission/modification.
This section requires FDA to post publicly and update at least twice a year on FDA.gov the stage of the review process for submissions, the date of the most recent change in status, whether external scientific experts were utilized by FDA in the development or review of the package, and the submissions themselves, including any data and evidence contained in such submissions and updates to them. FDA must also post its formal written determinations in response to submissions and summary reviews. Finally, FDA must post a list of all drug development tools qualified and all surrogate endpoints which were the basis of an NDA or BLA approval.
The section requires FDA, within 2 years of the date of enactment of the Act, to host a public meeting to solicit input from stakeholders on the qualification process. Then, FDA is required, in consultation with biomedical research consortia and other stakeholders, no later than 3 years after the date of enactment, to issue guidance to implement this section. The guidance must contain a framework that provides standards and scientific approaches to support the development of biomarkers, as well as the requirements and process for the qualification program. Finally, a report on the qualification program is required within 5 years of the date of enactment.
Overall, this section provides FDA and stakeholders an opportunity to assess and reform the drug development tools qualification program that CDER has already developed and for which CDER has issued guidance.
Sec. 3012. Targeted drugs for rare diseases.
To facilitate the development, review, and approval of genetically targeted drugs to meeting unmet medical needs in rare diseases that are serious and life-threatening, Section 3012 amends the FDC Act to allow FDA, consistent with its existing approval standards, for a genetically targeted drug (i.e., a drug that modulates function of a gene) or a variant protein targeted drug to rely on data and information that was previously developed by the same sponsor and that was submitted by that sponsor in support of one or more previously approved NDAs or BLAs if the new drug relies on the same or similar technology as the approved drug.
Sec. 3013. Reauthorization of program to encourage treatments for rare pediatric diseases.
Section 3013 amends the FDC Act to extend the authorization of the Rare Pediatric Disease Priority Review Voucher program (see FDA webpage here). This allows a drug that is designated as a drug for a rare pediatric disease prior to September 30, 2020 to receive a priority review voucher upon approval of an NDA or BLA prior through September 20, 2022. The program was set to expire December 31, 2016.
This section also removed the mandate for a GAO report on the effectiveness of the program at incentivizing the development of rare to treat or prevent rare pediatric diseases, which was previously required under Section 3 of the Advancing Hope Act.
Sec. 3014. GAO study of priority review voucher programs.
Section 3014 requires GAO to conduct a study and issue a report that evaluates all three priority review voucher programs: tropical disease, rare pediatric disease, and medical countermeasure. The report must cover the following topics:
- For each voucher that has been issued, whether the voucher impacted the sponsor’s decision to develop the drug and to what extent the drug addressed an unmet need;
- For each voucher that has been used, the value of the voucher, if transferred (i.e., sold), and the length of time between voucher issuance and use;
- The resource burden on FDA to review drugs for which vouchers were used, including its impact on the review of other applications;
- Whether there are improvements to the programs that would appropriately incentivize drugs that would not otherwise be developed, or developed in as timely a manner; and
- Whether the sunset of the rare pediatric disease and medical countermeasure programs has an impact on the programs, including any potential unintended consequences.
This report must be submitted to Congress by January 31, 2020.
Sec. 3015. Amendments to the Orphan Drug grants.
Section 3015 amends the Orphan Drug Act to expand the Orphan Drug Grant program so that prospectively planned and designed observational studies and other natural history analysis can qualify, so long as the studies/analyses are used to (a) develop or validate a drug development tool related to a rare disease or condition or (b) understand the full spectrum of disease manifestations, including genotypic and phenotypic variability and identifying and defining distinct subpopulations affected by a rare disease or condition. Previously the Orphan Drug Grant program was limited to clinical and preclinical studies in rare diseases.
Sec. 3016. Grants for studying continuous drug manufacturing.
Section 3016 authorizes HHS to award grants to academic institutions and nonprofit organizations to study and recommend improvements to the process of continuous manufacturing of drugs and biologics.
Subtitle C—Modern Trial Design And Evidence Development
Sec. 3021. Novel clinical trial designs.
Section 3021 requires FDA to conduct a public meeting and, subsequently, issue or update guidance that addresses the use of complex adaptive and other novel trial designs for the development and regulatory review of NDAs and BLAs. The guidance document must include:
- Use of such clinical trial designs, including how these designs can satisfy the substantial evidence of effectiveness standard under the FDC Act;
- How sponsors can obtain feedback from FDA on technical issues related to modeling and simulations;
- The types of qualitative and quantitative information that should be submitted for review; and
- Recommended analysis methodologies.
The public meeting must be held within 18 months of the date of enactment of the Act and the draft guidance must be issued within 18 months of the public meeting. FDA must also finalize the guidance no later than one year after the public comment period on the draft guidance closes.
Sec. 3022. Real world evidence.
Section 3022 amends the FDC Act to establish a program at FDA to evaluate the potential use of real world evidence to (a) help support the approval of new indications for an approved drug and (b) help support or satisfy postapproval (i.e., Phase 4) study requirements. The section defines real world evidence to mean “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than clinical trials” but is contemplated to potentially include ongoing safety surveillance, observational studies, registries, claims data, and patient-centered outcomes research activities. The primary purpose of the program is to development a framework that provides for:
- The sources of real world evidence;
- Gaps in data collection activities;
- Standards and methodologies for collection and analysis; and
- Priority areas, challenges, and potential pilot opportunities.
In developing the framework, FDA must consult with stakeholders through various approaches. A draft framework must be established within two years of the date of enactment of the Act.
In addition, within 5 years of the date of enactment, FDA must issue draft guidance on the circumstances under which sponsors of drugs may rely on real world evidence and the appropriate standards and methodologies for collection and analysis for such purposes. FDA must also finalize the guidance no later than 18 months after the public comment period on the draft guidance closes.
Importantly, the provision states that it does not alter the current approval standards under the FDC Act and the Public Health Service Act (PHS Act) or the authority to require postapproval studies or clinical trials or the standards of evidence under which studies or trials are evaluated. For some insights into how FDA may approach implementation of this section, last week FDA leadership published an article in the New England Journal of Medicine on the use of real world evidence.
Sec. 3023. Protection of human research subjects.
In an attempt to simplify and facilitate compliance by researchers that are subject to human subjects protections regulations, Section 3023 seeks to harmonize the difference between and modernize HHS and FDA regulations in a number of ways, including reducing regulatory duplication and modernizing to account for multisite and cooperative research projects, while still incorporating local considerations through communication engagement mechanisms. The section also directs HHS and FDA to allow researchers to use joint or shared IRB review, including relying upon an independent IRB or the IRB of another entity other than the sponsor of the research. In harmonizing and modernizing their regulations and guidance, HHS and FDA must consult with stakeholders.
Such harmonization must occur within 3 years of the date of enactment of the Act. In addition, within 2 years from the date of enactment, HHS must submit a progress report to Congress.
Sec. 3024. Informed consent waiver or alteration for clinical investigations.
Section 3024 amends the FDC Act to alter the informed consent requirements for both drugs and medical devices such that a waiver of informed consent may now be granted for “proposed clinical testing [that] poses no more than minimal risk to…human beings and includes appropriate safeguards…”
Subtitle D—Patient Access To Therapies And Information
Sec. 3031. Summary level review.
Section 3031 amends the FDC Act to allow FDA to rely upon “qualified data summaries” to support the approval of a supplemental application if (a) there are existing data available and acceptable to FDA to demonstrate safety of the drug and (b) all data used to develop the qualified data summaries are submitted to FDA as part of the supplemental application.
The section also requires FDA to, annually, to post on FDA.gov:
- The number of applications reviewed under this provision;
- The average time for completion of review under this provision;
- The average time for completion of review of supplemental applications where FDA did not use this review flexibility; and
- The number of applications reviewed under this provision where FDA still made use of full data sets in addition to the qualified data summary.
Sec. 3032. Expanded access policy.
Section 3032 amends the FDC Act to require the manufacturer or distributer of an investigational drug for a serious or life-threatening disease to make available (e.g., on its website) its policy regarding evaluating and responding to requests for expanded access. Such policies must include:
- Contact information to facilitate communication about requests for expanded access;
- Procedures for making expanded access requests;
- The general criteria used to evaluate such requests for individual patients, and for responses to such requests; and
- A hyperlink or other reference to the clinical trial record (i.e., on ClinicalTrials.gov) containing information about the expanded access for the investigational drug as required under the PHS Act.
Manufacturer or distributor may revise its policy at any time.
The provision states that the posting of a policy “shall not serve as a guarantee of access to any specific investigational drug by an individual patient.” The section applies to a manufacturer or distributor with respect to an investigational drug on the later of (a) 60 days after the date of enactment of the Act or (b) the first initiation of a phase 2 or phase 3 study for that investigational drug.
Sec. 3033. Accelerated approval for regenerative advanced therapies.
Section 3033 amends the FDC Act to create a process and requirements for designation of a drug as a regenerative therapy. A drug is eligible for this designation if:
- It meets the definition of a regenerative advanced therapy: “ cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the [PHS Act] and part 1271 of title 21, Code of Federal Regulations”;
- The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
- Preliminary clinical evidence indicates the drug has the potential to address an unmet medical need.
The sponsor of drug may request such a designation concurrently with or any time after submission of an IND. FDA has 60 days after the receipt of a designation request to determine if the drug meets the criteria. The effect of designation is that FDA must take actions to expedite development and review of the drug, including early interactions to discuss the potential for accelerated approval. In addition, a designated drug may be eligible for priority review or accelerated approval under current FDA regulatory standards, and if approved under accelerated approval would be subject to a confirmatory study.
Sec. 3034. Guidance regarding devices used in the recovery, isolation, or delivery of regenerative advanced therapies.
Section 3034 requires FDA to issue guidance clarifying how, for regenerative advanced therapies, FDA will evaluate devices used in the recovery, isolation, or delivery of regenerative advanced therapies. The guidance must address:
- How FDA intends to simplify and streamline regulatory requirements for combination device and cell or tissue products;
- What, if any, intended uses or specific attributes would result in a device used with a regenerative therapy product to be classified as a class III device;
- When FDA considers it necessary, if ever, for the intended use of the device to be limited to a specific intended use with only one particular type of cell; and
- The least burdensome approach to demonstrate how a device may be used with more than one cell type.
The section requires FDA to issue draft guidance within one year from the date of enactment of the Act. FDA must also finalize the guidance no later than one year after the public comment period on the draft guidance closes.
Sec. 3035. Report on regenerative advanced therapies.
Section 3035 requires HHS, annually before March 1st of the calendar year, to report to Congress on the previous calendar year:
- The number and type of applications for approval of regenerative advanced therapies filed, approved/licensed, withdrawn, or denied; and
- How many such applications were granted accelerated approval or priority review.
Sec. 3036. Standards for regenerative medicine and regenerative advanced therapies.
Section 3036 amends the FDC Act to require HHS to consult with the National Institute of Standards and Technology (NIST) and stakeholders to coordinate and prioritize the development of standards and consensus definition terms, to support the development, evaluation, and review of regenerative medicine products, including with respect to manufacturing processes and controls. Specifically, the section directs HHS to:
- Identify opportunities to advance development of these therapies; and
- Identify opportunities for the development of laboratory regulatory science research and documentary standards that would help support development and review.
In addition, within one year after the development of standards, HHS must review relevant regulations and guidance and, through a public process, update them as appropriate.
Sec. 3037. Health care economic information.
Section 3037 amends the FDC Act to clarify the scope of permissible manufacturer communications regarding health care economic information to certain entities. Health care economic data consists of any analysis that identifies, measures, or describes the economic consequences (e.g., based on separate or aggregated clinical consequences of the represented health outcomes) of the use of a drug. Such analysis may be compared to the use of another drug or health care intervention, or to no intervention. The provision expands the safe harbor in response to issues identified with FDAMA 114, which should reduce the risk to manufacturers associated with disseminating health care economic information.