Review Board Oversight and Informed Consent Documents
A study needs two permissions before a subject is enrolled: the board's and the subject's. The board applies seven criteria to the protocol, and the consent document is measured element by element against a list in the regulation.
The rule in short
Under 21 CFR Part 56 a clinical investigation may not begin until an institutional review board has approved it, applying the criteria in 56.111 covering minimized risk, favorable risk-benefit balance, equitable subject selection, informed consent, data monitoring, privacy and safeguards for vulnerable subjects. Part 50 governs consent: 50.20 sets general conditions, 50.25 lists the required elements, and 50.27 requires a signed document.
Human subject protection in drug and device research rests on two permissions. A board independent of the investigator must approve the study before it starts, and each subject must give informed consent before taking part. The regulations state both requirements as conditions rather than as goals, which means a study that omits either is deficient however well it was conducted otherwise.
The board and how it is constituted
Part 56 of Title 21 requires that a clinical investigation not begin until a review board has reviewed and approved it. The board must have at least five members with varying backgrounds sufficient to review the research commonly conducted at the institution. At least one member's primary concerns must be in scientific areas and at least one member's in nonscientific areas, and at least one member must not be affiliated with the institution or with the immediate family of anyone affiliated with it.
Conflicts are handled by exclusion. A member with a conflicting interest may not participate in the review of that project except to provide information requested by the board. Boards act at convened meetings with a majority present, including at least one member whose primary concerns are nonscientific, and approve by majority vote of those present. Written procedures, minutes recording the vote, and retained records are required, and boards must keep those records for a stated period after completion of the research.
What the board must find
Section 56.111 states the criteria. Risks to subjects must be minimized by using procedures consistent with sound research design that do not unnecessarily expose subjects to risk, and by using procedures already being performed for diagnostic or treatment purposes where appropriate. Risks must be reasonable in relation to anticipated benefits and to the importance of the knowledge that may reasonably be expected to result.
The remaining criteria address who is enrolled and what happens afterward. Selection of subjects must be equitable, taking into account the purposes of the research and the setting. Informed consent must be sought from each subject or the subject's legally authorized representative and must be documented. Where appropriate, the research plan must make adequate provision for monitoring the data collected to ensure subject safety, and adequate provisions must protect privacy and the confidentiality of data. Where some or all subjects are likely to be vulnerable to coercion or undue influence, additional safeguards must be included.
Boards must conduct continuing review at intervals appropriate to the degree of risk and not less than once per year. They may observe, or have a third party observe, the consent process and the research itself. Where research is not being conducted in accordance with the board's requirements, or has been associated with unexpected serious harm to subjects, the board may suspend or terminate its approval, and must report that action promptly to the investigator, the institution and the agency.
The general conditions on consent
Section 50.20 sets the frame. No investigator may involve a human being as a subject unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. The consent must be sought under circumstances that give the prospective subject sufficient opportunity to consider whether to participate and that minimize the possibility of coercion or undue influence.
Two constraints on the document itself do most of the practical work. The information must be in language understandable to the subject or the representative, which is why boards send back documents written at a technical reading level. And no consent may include exculpatory language through which the subject waives or appears to waive any legal rights, or releases the investigator, the sponsor, the institution or its agents from liability for negligence.
The elements the document must contain
Section 50.25(a) lists eight basic elements. A statement that the study involves research, an explanation of its purposes and expected duration, a description of the procedures and identification of any that are experimental. A description of reasonably foreseeable risks or discomforts. A description of benefits reasonably to be expected. Disclosure of appropriate alternative procedures or courses of treatment.
The remaining four address the subject's position rather than the science. A statement describing the extent to which confidentiality of records will be maintained, noting the possibility of agency inspection. For research involving more than minimal risk, an explanation of whether compensation and medical treatments are available if injury occurs. An explanation of whom to contact about the research, about subjects' rights, and in the event of a research-related injury. And a statement that participation is voluntary, that refusal involves no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue at any time without penalty or loss.
Section 50.25(b) adds six elements to be provided where appropriate, covering unforeseeable risks, circumstances in which the investigator may end a subject's participation, additional costs, the consequences and procedures for orderly withdrawal, a commitment to provide significant new findings, and the approximate number of subjects.
| Route | What the subject signs | Who approves it | When it is available |
|---|---|---|---|
| Standard written consent | The full document embodying the required elements | The review board | The default in all research |
| Short form | A short written statement that the elements were presented orally | Board-approved summary, with a witness present | Where an oral presentation is used |
| Emergency use for one patient | Nothing, where the exception conditions are certified | Investigator and an independent physician certify in writing | Life-threatening situation, no alternative, no time to obtain consent |
| Planned emergency research | Nothing at enrollment; later consent from the subject or representative | Board approval plus community consultation and public disclosure | Narrow category with an independent data monitoring committee |
| Consent by a representative | The full document, signed by the representative | The review board, with capacity procedures specified | Where the subject cannot consent personally |
How consent and oversight fit the wider filing
Board approval and consent are conditions of conducting research, not substitutes for the agency's own gate. A study of an investigational drug needs both, and the sequence and waiting period on the agency side are described in the investigational application and the clinical hold. Deficiencies in consent are among the grounds on which a board suspends a study and among the findings that surface during an inspection of a clinical site.
The documents also carry forward. Consent forms, board correspondence and monitoring records become part of the file supporting a marketing application, discussed in the new drug application and its review cycle, and inspection of clinical sites is part of the process described in quality systems and how inspections proceed. Safety information generated during the study feeds the reporting obligations set out in adverse event and malfunction reporting.
Points to carry away
- No clinical investigation may begin before the review board has approved it.
- Approval requires that risks be minimized and reasonable in relation to anticipated benefits.
- A consent document must contain the eight basic elements stated in 21 CFR 50.25(a).
- Consent may not include exculpatory language waiving a subject's legal rights.
- Continuing review must occur at intervals suited to the risk and at least annually.
- A board may suspend or terminate approval of research that departs from its requirements.
Questions readers ask
Can a board approve a study by a chair acting alone?
Only where expedited review is available, and then only for defined categories. Research that appears on the published list of minimal risk categories, and minor changes to previously approved research during the approved period, may be reviewed by the chair or by one or more experienced reviewers designated by the chair. The reviewer exercising expedited review may approve or require modifications, but may not disapprove; a disapproval requires review by the convened board. All other research requires a meeting with a quorum present and approval by a majority of those present.
Who may sign when the subject cannot?
A legally authorized representative, meaning an individual or body authorized under applicable law to consent on the prospective subject's behalf to participation in the procedures involved. Who qualifies is a question of state law rather than of the federal regulation, and it varies. The representative's consent does not extinguish the subject's role: where a subject retains some capacity, assent is generally sought as well, and a subject's objection is respected. Boards ordinarily require a protocol to state in advance how capacity will be assessed and who may serve.
Does a subject have to be told the study is registered publicly?
For an applicable clinical trial, yes. The consent document must include a specific statement informing the subject that a description of the trial will be available on a public clinical trials registry, that the registry entry will not include information identifying the subject, and that the entry will be updated. The regulation prescribes the substance of this statement rather than leaving it to the drafter. Sponsors running trials that fall within the registry definition should treat it as a checklist item, because its absence is a documentable deficiency on inspection.
Sources
- eCFR — 21 CFR Part 56, Institutional Review BoardsBoard composition, procedures, review categories, records and enforcement.
- eCFR — 21 CFR 56.109, IRB Review of ResearchThe board's authority to approve, require modifications or disapprove, and to require consent documentation.
- eCFR — 21 CFR 56.111, Criteria for IRB Approval of ResearchThe seven findings a board must make before approving a study.
- eCFR — 21 CFR Part 50, Protection of Human SubjectsThe consent requirements, the exceptions and the protections for children in research.
- eCFR — 21 CFR 50.20, General Requirements for Informed ConsentUnderstandable language, freedom from coercion and the bar on exculpatory language.
- eCFR — 21 CFR 50.25, Elements of Informed ConsentThe eight basic elements, the six additional elements and the registry statement.
- eCFR — 21 CFR 50.27, Documentation of Informed ConsentThe signed written document, the short form alternative and the copy to the signer.
Liberty Law Library is a publication, not a law firm. This article states general rules and cites its sources; it is not advice about any particular case, and the law differs by state and changes over time.
More in Drug & Device Regulation
Premarket Notification Compared With Premarket Approval
Premarket notification under 21 U.S.C. 360(k) asks whether a device is substantially equivalent to a legally marketed predicate, meaning the same intended use and either the same technological characteristics or different ones raising no different questions of safety and effectiveness. Premarket approval under 21 U.S.C. 360e asks whether valid scientific evidence provides reasonable assurance of safety and effectiveness.
Labeling: Required Content, Format and Changes
Labeling under 21 U.S.C. 321(m) includes all written, printed or graphic matter on an article, its containers or wrappers, or accompanying it. A product is misbranded under 21 U.S.C. 352 where its labeling is false or misleading in any particular. Prescription labeling follows 21 CFR 201.56 and 201.57, over-the-counter labeling follows 201.66, and changes are made through the supplement categories in 21 CFR 314.70.
Supply Chain Tracing and the Duty to Verify
The drug supply chain provisions at 21 U.S.C. 360eee and following require that transaction information and a transaction statement accompany each change of ownership, that trading partners be authorized, and that product bear an identifier permitting package-level verification. A firm with reason to believe product is counterfeit, diverted, stolen or otherwise unfit must quarantine and investigate it.