21st Century Cures Act

On December 11, 2018, the Food and Drug Administrative (“FDA”) issued a draft guidance for comment entitled, “Biomarker Qualification: Evidentiary Framework” (the “Guidance”).  The Guidance provides insight regarding standards for biomarker qualification under the 21st Century Cures Act (“Cures Act”).

FDA defines the term “biomarker” as a “characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.” There are various types of biomarkers including, but not limited to: molecular – (i.e. blood glucose); radiographic (i.e. the size of a tumor); and physiologic (i.e. blood pressure), and each of these biomarkers fall into various categories, all of which are regulated by FDA. The term “biomarker qualification” is defined as “a conclusion, based on a formal regulatory process that within the stated context of use, can be relied upon to have a specific interpretation and application in medical product development and regulatory review.” Importantly, once a biomarker is qualified for a particular context of use, it becomes publicly available, and can be applied in any drug development program for that qualified context of use.

The Guidance discusses the evidentiary framework for supporting biomarker qualification, including needs assessments; context of use; and benefit-risk considerations, and how these considerations can relate to determine the type and level of evidence required to support the qualification of a biomarker. Additionally, the Guidance addresses general statistical and clinical considerations related to the correlation between the biomarker and outcome of interest, and general analytical considerations related to performance characteristics of the biomarker test.

Ultimately, the success of the Guidance in advancing biomarker qualification will turn on its contents and stakeholder input.  The Agency has asked for comments on the Guidance by February 9, 2019, to ensure that comments can be fully considered before the Guidance is finalized, although comments may be submitted on FDA guidance at any time. The formal announcement about the draft Guidance issued by FDA is available here.

Following up on its July 2017 guidance on the same topic (discussed in a previous blog post), FDA issued a proposed rule on November 15, 2018 to amend Agency regulations to allow Institutional Review Boards (“IRBs”) to waive or alter certain informed consent elements (or in some cases, waive the informed consent requirement altogether) for FDA-regulated, minimal risk clinical investigations (“Proposed Rule”).

What Clinical Investigations are Affected?

Importantly, the only clinical investigations affected by the Proposed Rule are those that are FDA-regulated and “minimal risk” – a term defined by FDA to mean that “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

Such minimal risk investigations may be approved by IRBs through an expedited review procedure.  Although FDA has designated specific categories of research that may be reviewed through this procedure, the designated activities are not automatically considered minimal risk just because they are on FDA’s list.  Rather, inclusion on the list simply means that the research activity is eligible for expedited review where the specific circumstances of the research involve no more than minimal risk.  Still, the designated research categories shed light on the types of studies that may be deemed minimal risk, including: research on a drug or device where an investigational new drug application (“IND”) or investigational device exemption (“IDE”), respectively, is not required; prospective collection of biological specimens for research purposes by noninvasive means (e.g., hair and nail clippings); collection of data from voice, video, digital, or image recordings made for research purposes; and research on individual or group characteristics or behavior, or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.

What is the Intent of the Proposed Rule?

Sometimes it’s not practicable for sponsors to obtain informed consent when conducting clinical investigations.  As current FDA regulations offer only very narrow exceptions to the informed consent requirements – for life threatening situations or emergency research –  the inability of an investigator to obtain subject informed consent would have previously brought potentially valuable investigations to a halt.  However, the Proposed Rule seeks to provide increased flexibility with respect to FDA’s informed consent requirements for certain minimal risk studies.

In particular, the Proposed Rule implements changes made to the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) by the 2016 21st Century Cures Act (“Cures Act”).  These changes authorize FDA to allow for exceptions to its standard informed consent requirements where the proposed clinical trial poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of the subject.  Specifically, under the Proposed Rule, FDA would allow IRBs to waive or alter informed consent requirements if the IRB finds and documents that:

  1. the clinical investigation involves no more than minimal risk to the subjects (see “minimal risk” definition above);
  2. the waiver or alteration will not adversely affect the rights and welfare of the subjects (in making this determination, the IRB may consider, for example, whether the waiver or alteration has the potential to negatively affect the subjects’ well-being or whether the subject population in general would likely object to a waiver or alteration being granted for the research in question);
  3. the clinical investigation could not practicably be carried out without the waiver or alteration (FDA defines “practicable” to mean (i) recruitment of consenting subjects does not bias the science and the science is no less rigorous as a result of restricting it to consenting subjects, or (ii) the research is not unduly delayed by restricting it to consenting subjects); and
  4. whenever appropriate, the subjects will be provided with additional pertinent information after participation.

As noted above, FDA already issued guidance for immediate implementation in July 2017 that states that FDA does not intend to object to IRBs waiving or altering informed consent requirements, as described in the guidance, for certain minimal risk clinical investigations (see our previous blog post).  However, FDA intends to withdraw this guidance after the Proposed Rule takes effect.

What are the Envisioned Benefits?

If finalized, the Proposed Rule would largely harmonize FDA regulations with the Common Rule, which governs human subject research conducted or supported by HHS and other federal agencies.  The Common Rule has included provisions allowing waiver of informed consent for minimal risk research since it was first issued in 1991.  We note, however, that January 2017 revisions to the Common Rule added a fifth criterion to the four listed above related to IRB waiver or alteration of informed consent (this fifth criterion requires that “if the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format”).  FDA is not proposing to adopt this fifth criterion at this time.

Beyond harmonization, the Proposed Rule should pave the way for certain minimal risk clinical investigations to proceed that otherwise would have never gotten off the ground, offering greater opportunities for sponsors and investigators to further their product development efforts and make positive contributions to the public health.

Comments on the Proposed Rule must be submitted to the docket by January 14, 2019.

On January 5, 2018, consistent with the 21st Century Cures Act’s focus on creating interoperability and correspondingly a Trusted Exchange, the Office of the National Coordinator for Health Information Technology (“ONC”) released its “Draft Trusted Exchange Framework” (“Draft Framework”).  The Draft Framework is intended to streamline the exchange of Electronic Health Information (“EHI”) so that both health care providers and patients have better access to health information, thus improving communication and quality health care.  EHI includes information beyond protected health information, such as health information from other consumer driven devices.  ONC has asked for public comments; the comment period is open until February 18, 2018.

ONC’s Draft Framework develops a mechanism to connect Health Integrated Networks (“Qualified HINs”) across the country. The ONC intends to select a single Recognized Coordinating Entity (“RCE”) through a competitive bidding process, which will be open in the spring of 2018.  The RCE’s responsibilities will be to develop the Common Agreement and operationalize the Trusted Exchange.  The Draft Framework includes the Principles of a Trusted Exchange (Part A) and the minimum terms and conditions that will be required for a Trusted Exchange (Part B) (the contractual terms that operationalize the principles of Part A).

The Draft Framework sets a number of conditions on Qualified HINs, some of which may require more direct interaction with patients than currently exists, or may require the Qualified HIN to disclose information that might otherwise be considered proprietary to the Qualified HIN. The biggest takeaways from the Principles (Part A) are:

  • Qualified HINs will be expected to use standards adopted or recognized by ONC’s Health IT Certification Program and Interoperability Standards Advisory (“ISA”) or industry standards readily available to all stakeholders;
    • Participants of Qualified HINs that provide services and functionality to providers are expected to follow the 2015 Edition Health IT Certification Criteria, 2015 Edition Base Electronic Health Record (EHR) Definition, and ONC Health IT Certification Program Modification final rule (“2015 Edition final rule”), and associated guidance for the certification of health IT; and
    • Qualified HINs and participants will be expected to implement processes that encourage more “person-centered” care;
  • Qualified HINs will be required to operate openly and transparently by:
    • Making terms and conditions for participation publicly available;
    • Supporting permitted uses and disclosures of EHI. Qualified HINs that only support HIPAA Treatment purpose exchanges, may want to support additional permitted purposes;
    • Making their privacy practices publicly available;
  • Qualified HINs must cooperate with and not discriminate among the various stakeholders across the continuum of care by not implementing policies, procedures, technology or fees that will obstruct access and exchange of EHI between other Qualified HINs, participants, and end users;
  • Qualified HINs must exchange EHI securely and in a manner that preserves data integrity by:
    • Including appropriate information to ensure the correct matching of individuals to their EHI; and
    • Ensuring providers and other organizations are confident that appropriate consents and authorizations have been captured;
  • Qualified HINs must ensure that individuals have easy access to their information by:
    • Ensuring full and consistent access to information; and
    • Having policies in place to allow an individual to withdraw or revoke his or her participation in the Qualified HIN; and
  • Qualified HINs will be expected to support the ability for participants to pull and push population level records—bulk transfer—in a single transaction rather than transmit one record at a time.

The Draft Framework is ONC’s most significant push toward interoperability among electronic health care systems and most likely will affect all stakeholders in the health IT industry and their participants at some point.

The passage of the 21st Century Cures Act (“Cures Act”) and revisions to the Common Rule (45 CFR Part 46) (“Common Rule”) in the last year mandated significant changes to informed consent laws.  As a result of these changes, sponsors of research (“Sponsors”), institutions conducting research (“Institutions”), and the institutional review boards (“IRBs”) approving research will need to review policies and practices involving informed consent.  As explained below, a recently published FDA guidance document makes a first step toward implementing some of these changes by permitting waiver of certain consent requirements for low risk research involving human subjects. Additionally, a recent ruling by the Pennsylvania Supreme Court discussed below reminds investigators, Institutions, and Sponsors performing clinical research in Pennsylvania that state informed consent laws and common law must also be considered before conducting clinical research involving human subjects.  The following brief discussion provides some insight into how Sponsors, Institutions, and IRBs should take into account varying sources of law when determining when to require consent for research involving human subjects.

FDA Guidance on Waivers of Consent

On July 13, the United States Food and Drug Administration (“FDA”) issued a guidance document titled “IRB Waiver on Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects” (“Consent Guidance”).  The Consent Guidance states that “FDA does not intend to object to a sponsor initiating, or an investigator conducting, a minimal risk clinical investigation for which an IRB waives or alters the informed consent requirements” to the extent that the IRB documents that: the research “involves no more than minimal risk;” the waiver “will not adversely affect the rights and welfare of the subjects;” the research “could not practicably be carried out without the waiver;” and “subjects will be provided with additional pertinent information after participation,” if appropriate.  The Consent Guidance is an initial step toward implementing Section 3024 of the Cures Act, which amended the Food, Drugs, and Cosmetic Act to provide FDA with the authority to exempt certain research of drugs or medical devices from informed consent requirements if the research poses “no more than minimal risk” to human subjects and includes “appropriate safeguards to protect the rights, safety, and welfare” for participating subjects.  However, current FDA regulations do not provide IRBs with the power to waive consent except in certain circumstances involving an emergency or a life-threatening situation.  While FDA’s guidance documents contain disclaimers that the documents, themselves, lack any authority and cannot be relied upon, Sponsors, Institutions, and IRBs should be confident moving forward under the Consent Guidance as it stems directly from authority granted to FDA under the Cures Act and is consistent with the approach taken by the revised Common Rule.  The FDA is expected to provide updates to its own human research subject protection regulations in 21 CFR Parts 50 and 56, which based on the Consent Guidance will include “minimal research” provisions similar to the Consent Guidance and the revised Common Rule.  These rules will also address new provisions regarding identifiable biospecimens, which are not addressed under the Consent Guidance.  Once these new rules are established, FDA has stated that it will withdraw the Consent Guidance.

Recent Case Law

While Federal laws and regulations shape many aspects of informed consent, state laws may impose additional nuances that providers must understand. For example, a recent decision by the Pennsylvania Supreme Court will impact the manner in which informed consent must be obtained by physicians practicing in the state of Pennsylvania.  In Shinal v. Toms, M.D., 162 A.3d 429 (2017), Court held that physicians may no longer rely upon information provided by non-physicians to satisfy physician obligations under the MCARE Act, 40 Pa.  Stat. § 1303, et seq, which imposes a duty on physicians to obtain informed consent before performing certain procedures.  The specific law at issue was Section 504 of the MCARE Act, which creates a duty for a physician “to a patient to obtain the informed consent of the patient” before performing surgery, administering radiation or chemotherapy, administering a blood transfusion, inserting a surgical device, or “administering an experimental medication, using an experimental device or using an approved medication or device in an experimental manner.”  In Shinal v. Toms, M.D., 162 A.3d 429 (2017), the plaintiff asserted that Section 504 required Dr. Toms, the plaintiff’s surgeon, to provide all information and receive a patient’s informed consent personally in order to fulfill the physician’s duty for obtaining informed consent under the statute.  After an initial discussion with Dr. Toms regarding certain surgical options, the plaintiff later called to ask additional questions regarding different surgical procedures and was directed to a nurse to have her questions answered.  The plaintiff argued that her consent for the surgery was not sufficiently informed because the information provided to her about her surgical options should have been provided by Dr. Toms.  The Court agreed, and its 4-3 decision held that physicians in Pennsylvania must directly “disclose the information required to obtain informed consent.”

While Shinal involved consent for a surgical procedure, Section 504 of the MCARE Act also requires physicians to obtain informed consent  before administering an experimental drug or device.  This ruling will undoubtedly require many Institutions in Pennsylvania to change how informed consent is obtained from potential subjects in clinical trials, as it is common practice within the industry for physician investigators to delegate the informed consent process, or at least certain portions of the consent discussion with potential research subjects, to members of the Institution’s study staff.  Sponsors will likewise want to investigate the consent processes of Institutions conducting research on their behalf in Pennsylvania and review informed consent templates used by these Institutions to ensure they reflect the holding in Shinal.

The position expressed by the Shinal Court that only information provided by a licensed physician may be considered in determining whether the physician fulfilled his or her duty to provide informed consent appears to be unique among the states.  Nevertheless, it demonstrates to Sponsors, Institutions, and IRBs the importance of looking beyond FDA regulations and the Common Rule when developing and maintaining standard operating procedures and templates for obtaining informed consent.  Even if certain research may meet “minimal risk” rules at a federal level, Institutions must still abide by applicable state laws with regard to the requisite consent required before treating patients within the study.

On May 9, 2017, Scott Gottlieb, M.D. was confirmed by the Senate as the new Commissioner of the Food and Drug Administration (“FDA”).  As Commissioner, he will be immediately responsible for shaping FDA policy on a number of current issues, including addressing and implementing several mandates stemming from the 21st Century Cures Act, (“Cures Act”), which was signed into law on December 13, 2016 with tremendous bipartisan support. The Cures Act contains over 200 sections that create new obligations for FDA; however, most pressing for Commissioner Gottlieb are three requirements that must be fulfilled within 180 days of the Cures Act’s passage (June 11th, 2017).

These requirements are:

  • Submission of a work plan to the Committee on Health, Education, Labor, and Pensions and the Committee on Appropriations of the Senate and the Committee on Energy and Commerce and the Committee on Appropriations of the House of Representatives for any projects, which will use funding from the FDA Innovation Account created under Section 1002 of the Cures Act;
  • Development of “a plan to issue draft and final versions of one or more guidance documents, over a period of 5 years, regarding the collection of patient experience data, and the use of such data and related information in drug development” pursuant to Section 3002 of the Cures Act, which is codified at 21 U.S.C. 360bbb-8c; and
  •  Publication of “a list of reusable device types” pursuant to Section 3059 of the Cures Act, which is codified at 21 U.S.C. 360.

Commissioner Gottlieb has a long professional history in the pharmaceutical industry working in both the public and private sectors. His firsthand experience as a former Deputy Commissioner at the FDA provides him with unique insights into the internal workings of the administration. As a former consultant advising on FDA policies to the pharmaceutical industry, Commissioner Gottlieb is also familiar with recent issues and trends affecting the industry, many of which are addressed within the Cures Act.  Despite having only one month to organize and address the mandates of the three above-referenced sections of the Cures Act, we believe Commissioner Gottlieb will likely meet these deadlines based on his prior knowledge and experience.

We will continue to monitor and provide insight on Commissioner Gottlieb’s activity as FDA Commissioner, and the implementation of key Cures Act provisions as they develop. For insight into how Commissioner Gottlieb has historically viewed key issues impacting the FDA, and mandates under the Cures Act, please view our previously published client alert.

On January 19, 2017, the United States Food and Drug Administration (“FDA”) unveiled a new drug designation process for regenerative advanced therapies, an important first step toward implementation of the regenerative medicine provisions of the 21st Century Cures Act.  Products for which a designation as a regenerative advanced therapy (“RAT”) is obtained are eligible for accelerated approval under the 21st Century Cures Act, which was signed into law by former President Obama on December 13, 2016 with sweeping bipartisan support.

The accelerated approval provisions for RATs under the 21st Century Cures Act are intended to facilitate expedited review and approval of stem cell therapies and other cellular and tissue products for use in serious or life threatening diseases, which are currently subject to regulation as unapproved drugs. Under the 21st Century Cures Act, regenerative medicine therapies eligible for a RAT designation may include any “cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those products regulated solely under Section 361 of the Public Health Service Act (“PHS”), and part 1271 of Title 21, Code of Federal regulations.”[1]

Under the 21st Century Cures Act, the sponsor of a product must show the following to be eligible for a RAT designation:

  • The drug is a regenerative medicine therapy;
  • The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition;[2] and
  • Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.

Pursuant to the FDA website on the Regenerative Advanced Therapy Designation, a sponsor requesting a RAT designation for its product must make such a request either concurrently with submission of an Investigational New Drug application (“IND”), or as an amendment to an existing IND. Consistent with requests for fast track and breakthrough therapy designations, the FDA only requires that a sponsor describe the preliminary clinical evidence that supports a RAT designation, and does not require the sponsor to submit primary data.  Information that will be considered includes: a description of any available therapies for the disease or condition already in existence, the study design, the population studied, the endpoints used, and a description of the study results and statistical analyses.

The RAT designation process will be overseen by the newly created Office of Tissues and Advanced Therapies (OTAT). The OTAT will manage the application process for RAT designation, and will notify the sponsor within 60 days of receiving an application as to whether the RAT designation is granted. If a sponsor does not receive a RAT designation for its product the OTAT will provide an explanation in writing of its rationale for the denial.

A sponsor that obtains a RAT designation for its product is entitled to meet with the FDA early in its development program to discuss the potential use of surrogate or intermediate endpoints that may be used to support accelerated approval of the product. RATs may be eligible for accelerated approval based upon surrogate or intermediate endpoints reasonably likely to predict a long-term clinical benefit, and based on data obtained from a “meaningful number of sites” with subsequent expansion to additional sites, along with the collection of additional data in the post-market phase.

The implementation of the RAT designation process will enable manufacturers to begin to take advantage of the less burdensome review process enabled by the 21st Century Cures Act.  While some patient advocates have expressed concern that the availability of an accelerated approval pathway for regenerative medicine products may impede the development of robust evidence establishing their safety and effectiveness, and may ultimately result in patient harm, 21st Century Cures’ accelerated approval provisions are likely to be a harbinger of a new wave of regenerative medicine therapies that provide additional options for patients facing serious or life threatening conditions.

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[1] 21st Century Cures Act Sec., Sec. 3033(8).  Human Cells, tissues, and cellular and tissue-based products (HCT/Ps) are regulated solely under section 361 of the PHS Act and the regulations of 21 C.F.R. Part 1271 if all of the following criteria are met: the HCT/P is minimally manipulated, intended for homologous use (as reflected in labeling and advertising), is not manufactured by combining cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving or storage agent, and does not have a systemic effect nor is dependent upon the metabolic activity of living cells for its primary function. Therefore, if a product meets all of the aforementioned criteria, the HCT/P will still be regulated under 21 C.F.R. Part 1271 and will not be subject to regulation as a drug product.

[2] The FDA will use its standard definitions found in its Expedited Program Guidance as a guide to determining whether a product meets the required criteria, such as whether a condition is “serious or life-threatening” or whether a drug is “intended to treat a serious disease or condition.”