Focus on Clinical Trials: FDA Issues New Guidance on Data Monitoring Committees, Charging for Investigational Drugs, and Informed Consent

In February 2024, the U.S. Food & Drug Administration (“FDA”) published several draft and final guidance documents addressing important topics related to clinical research. On February 13, FDA issued a draft guidance document entitled “Use of Data Monitoring Committees in Clinical Trials” (“DMC Draft Guidance”), which would be the first update to FDA’s guidance on the use of DMCs since 2006. Two days later, FDA published final guidance entitled “Charging for Investigational Drugs Under an IND: Questions and Answers.” That guidance finalizes revised draft guidance of the same title issued in 2022 and replaces a 2016 final guidance document. Then, on February 29, FDA and the Office for Human Research Protections (“OHRP”) within the U.S. Department of Health and Human Services (“HHS”) jointly released new draft guidance for sponsors, investigators, and institutional review boards (“IRBs”), entitled “Key Information and Facilitating Understanding in Informed Consent” (“Informed Consent Draft Guidance”).

This alert provides a summary of key provisions and changes in each of these guidance documents.

DMC Draft Guidance

The DMC Draft Guidance would replace a final guidance issued by FDA in 2006 titled, “Establishment and Operation of Clinical Trial Data Monitoring Committees.” Like the 2006 guidance, the DMC Draft Guidance addresses the role of a DMC and considerations in using DMCs in FDA-regulated clinical trials.

DMCs, sometimes also referred to as data and safety monitoring boards (“DSMB”) or data and safety monitoring committees (“DSMC”), are independent committees established by a clinical trial sponsor to review accumulating data and recommend to the sponsor whether to continue, modify, or stop a trial. The general principles embodied in the existing 2006 guidance on DMCs are largely unchanged in the DMC Draft Guidance. FDA continues to emphasize the importance of a DMC’s independence from others with a stake in the study’s conduct or outcome, including the study sponsor and investigators, and in avoiding significant financial conflicts of interest. FDA also continues to emphasize the importance of maintaining the confidentiality of unblinded data and analyses provided to a DMC to avoid introducing bias in ongoing studies.

However, the DMC Draft Guidance would streamline and update FDA’s existing guidance to reflect more recent changes in how sponsors use DMCs. Whereas DMCs were originally developed for monitoring large-scale, randomized, multicenter trials targeting improved survival or reduced risk of major morbidity, FDA notes that DMCs are increasingly utilized in a wider variety of study types, including moderately sized trials, multiregional clinical trials, early phase trials in serious conditions, and trials that may not involve risk of serious morbidity or mortality to study subjects, such as trials for rare diseases and trials in vulnerable populations (e.g., neonates). FDA also identifies changes since 2006 in the roles that DMCs play in clinical trials, noting increased use of DMCs to implement adaptive trial designs, to oversee an entire program rather than a single trial, and to review aggregate data for IND safety reporting.

Some key substantive changes in the DMC Draft Guidance include:

• New content to address the role of DMCs in implementing adaptive trial designs. As described in the DMC Draft Guidance, clinical trials employing an adaptive design may use a dedicated independent committee to make adaptation recommendations or assign that role to the DMC. The draft guidance suggests that assigning this role to the DMC might best be reserved for group sequential designs or other relatively simple adaptive designs. FDA emphasizes that, although a DMC can have such responsibilities, its primary responsibility should continue to be subject safety and trial integrity.
• Additional examples of scenarios where a DMC may be useful. FDA had previously described circumstances where use of a DMC might be appropriate, including where study subjects are at risk of serious morbidity or mortality (e.g., hospitalization, heart attack, stroke, death), or where it might be particularly challenging to assess causality between the study drug and a serious adverse reaction (e.g., myocardial infarction in an older population). The DMC Draft Guidance adds examples of single-arm trials and situations where there is limited experience in a therapeutic area as other circumstances that might be appropriate for using DMCs.
• Strengthening certain recommendations. In several places, the DMC Draft Guidance states that DMCs “should” follow certain practices, where the 2006 guidance uses less prescriptive language. For example, the DMC Draft Guidance says that IRBs “should inquire” whether a DMC has been established for trials with a possibility of serious morbidity or involvement of vulnerable populations, and, if so, seek information about its scope and composition as part of its oversight. By comparison, the 2006 guidance says that IRBs “may inquire” about the existence of a DMC. Likewise, FDA strengthened its recommendations in the DMC Draft Guidance to state that all DMCs “should operate” under a written charter that clearly states the purpose of the DMC, the specific questions it is expected to address, and the possible recommendations it can make to the sponsor during the trial. The 2006 guidance, on the other hand, states that DMCs “typically operate” under a written charter that includes well-defined standard operating procedures. FDA similarly strengthened language around financial conflicts in the DMC Draft Guidance, stating that DMC members “should have no” ongoing financial relationship with a trial’s commercial sponsor or its direct competitors. By comparison, the 2006 guidance recommends that DMC members “generally have no” ongoing financial relationship with a trial’s commercial sponsor and does not include any recommendation regarding the sponsor’s direct competitors.
• New discussion addressing the role of DMCs in assessing causality for purposes of IND safety reporting. Clinical trial programs typically require employing a safety team, independent of the team conducting the study, to review accumulating safety data and make recommendations to the sponsor on submission of safety reports to FDA and participating investigators. The safety team can be internal to the sponsor or managed by a contract research organization, but it should be unblinded to the interventions assigned to subjects who have serious adverse events in order to assess causality and make a reporting recommendation. The safety team should not have access to data on effectiveness. As described in the DMC Draft Guidance, however, in some settings it may be appropriate for a DMC to provide input to the sponsor on whether an observed difference in safety events between the investigational and control arms in a study suggests a likely causal relationship between the investigational product and the adverse event.
• New discussion on training of DMC members. In the DMC Draft Guidance, FDA underscores the importance of adequately preparing DMC members for their role, including ensuring they understand that the roles and responsibilities of DMC membership differ from participation in a clinical trial as an investigator. Sponsors are strongly encouraged to consider the learning and training requirements of members selected to serve on a DMC before involvement in their first DMC meeting and subsequently thereafter, as needed. This topic was not addressed in the 2006 guidance.

Guidance on Charging for Investigational Drugs

FDA’s final guidance on charging for investigational drugs (“Final Guidance”) provides recommendations related to FDA’s regulations on charging for investigational drugs under an investigational new drug application (“IND”). Those regulations, located at 21 C.F.R. § 312.8, went into effect in 2009.¹ The regulations provide the criteria for authorizing charging for an investigational drug in a clinical trial and in the expanded access context, as well as criteria for determining what costs can be recovered when charging for an investigational drug.

After issuing the charging regulations in 2009, FDA published guidance addressing frequently asked questions, which it finalized in 2016. Then in August 2022, FDA published revised draft guidance to, most notably, include additional recommendations related to (1) the need for submission of a statement by an independent certified public accountant under certain circumstances and (2) distribution of the manufacturing, administrative, or monitoring costs from the first year over the expected duration of the expanded access IND or protocol. The Final Guidance finalizes the 2022 draft guidance with only very minor changes.

Informed Consent Draft Guidance

Two separate sets of federal rules exist that may govern human subjects research in the United States. Human subjects research conducted or supported by certain federal government departments or agencies (e.g., the Environmental Protection Agency, HHS, and National Science Foundation) is governed by the requirements of 45 C.F.R. Part 46, Subpart A, referred to as the “Common Rule.” Separate FDA regulations apply to clinical investigations (1) that are subject to FDA’s investigational product application requirements (either an investigational device exemption or an investigational new drug application) or (2) the results of which will be submitted to, or held for inspection by, FDA in support of an application for a research or marketing permit.²

In 2017, HHS, together with 15 other federal departments and agencies, issued a final rule to revise and modernize the Common Rule (the “Revised Common Rule”).³ Among other things, the Revised Common Rule requires informed consent documents to “begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research.”⁴ It also requires that “informed consent as a whole must present information in sufficient detail relating to the research and be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate.”⁵

Subsequently, in September 2022, FDA issued two proposed rules intended to harmonize certain of its regulations with the Revised Common Rule,⁶ as required under the 21st Century Cures Act.⁷ We have discussed these harmonization efforts in several prior alerts, including an alert discussing FDA’s 2022 proposed rules and another alert discussing FDA’s recently finalized rule on IRB waiver of informed consent for certain minimal risk research. Among other things, FDA’s 2022 proposed rule would add identical provisions to those in the Revised Common Rule requiring that informed consent begin with the presentation of key information about the research and present information in a way that facilitates understanding.⁸

FDA and OHRP jointly issued the Informed Consent Draft Guidance to assist sponsors, investigators, and IRBs in complying with the provisions on key information and facilitating understanding in the Revised Common Rule and FDA’s proposed rule.

Key Information Recommendations. The Informed Consent Draft Guidance provides several helpful recommendations to assist in crafting the “key information” section of the informed consent. It notes that the key information section should be relatively short (generally no more than a few pages). It also provides recommendations for information that generally would be appropriate for inclusion, as well as a sample key information section for reference. However, it underscores that the recommendations are not requirements, that there are multiple strategies that may address the regulatory requirement, and that the information included in the key information section will vary depending on the particulars of the research.

In general, the key information section would not be expected to include every element of informed consent. Which basic and additional consent elements should be included in the key information section may vary, though the agencies expect that the following topics are likely to be considered key information:

• Voluntary participation and right to discontinue participation;
• Purpose of the research, expected duration, and procedures to be followed;
• Reasonably foreseeable risks and discomforts;
• Reasonably expected benefits;
• Appropriate alternative procedures;
• Compensation and medical treatments for research-related injuries; and
• Costs related to subject participation.

For each of these topics, the Informed Consent Draft Guidance provides additional recommendations regarding content and how the information is presented. Depending on the particulars of the research, some of these topics may not be key information, whereas other elements of informed consent or supplemental information may be considered key information. While not required, the Informed Consent Draft Guidance notes that interested parties may choose to consult in advance with patient advocacy groups or prospective subjects about their views on key information to support development of the informed consent document.

Facilitating Understanding. The Informed Consent Draft Guidance also addresses the provision in the Revised Common Rule and FDA’s proposed rule requiring that informed consent “must present information in sufficient detail relating to the research and be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate.” To help present key information in a simple, concise format, the Draft Guidance recommends that parties consider organizing information within a defined border, which they refer to as “bubbles,” or another format that makes the content easy to read and understand. Other formatting approaches that the Draft Guidance recommends considering for the key information and the rest of the consent form, as appropriate, include formatting text into two columns, using bullet points to simplify long explanations, and including ample white space.

Additionally, the Draft Guidance recommends following “plain language principles” throughout the informed consent. Plain language principles generally involve a combination of text-based and visual approaches (e.g., pictures and diagrams), organizing information with the most important points first, breaking complex information into understandable groups, using simple language, and defining technical terms.

Next Steps

The new draft and final guidance documents released in February reflect a continued focus by FDA and HHS on modernizing the regulation of clinical trials. For those wishing to comment on the DMC Draft Guidance, comments are due by April 15, 2024. Comments on the Informed Consent Draft Guidance are due by April 30, 2024.