Research · 7 min read
Who Is Answerable for a Trial, and What Monitoring Means
Two roles carry the obligations, and the regulation defines both. One signs a form promising specific things. The other selects that person, watches the study, and has to act within five working days if the drug turns out to be dangerous.
Key takeaways
- Sponsor, investigator and sponsor-investigator are defined roles in 21 CFR 56.102, and each carries separately enforceable duties.
- 21 CFR 312.50 makes the sponsor responsible for investigator selection, information, monitoring, protocol adherence, and prompt notification of significant new adverse effects or risks.
- The signed investigator statement itemised at 312.53(c)(1) is where the site-level commitments are created, including personally conducting or supervising the study and reporting adverse experiences.
- Where an investigator is not complying, the sponsor must promptly secure compliance or cut off drug shipments, end participation, and notify FDA.
- A sponsor that determines its drug presents an unreasonable and significant risk must discontinue and notify FDA, all review boards and every investigator who ever participated, within five working days.
- Investigator records must document that consent was obtained before participation and must be retained for two years after approval for the studied indication or after discontinuation.
Answer first: sponsor and investigator are defined roles, not job titles
The definitions are at 21 CFR 56.102. A sponsor is a person or other entity that initiates a clinical investigation but does not actually conduct it — the test article is administered or dispensed under the immediate direction of another individual. A person other than an individual, such as a corporation or agency, that uses its own employees to conduct an investigation it initiated is a sponsor, and those employees are investigators.
An investigator is an individual who actually conducts a clinical investigation, meaning the person under whose immediate direction the test article is administered or dispensed to a subject, or, where a team conducts the investigation, the responsible leader of that team.
There is a third, hybrid role. A sponsor-investigator is an individual who both initiates and actually conducts an investigation. The regulation notes that the term does not include any person other than an individual — not a corporation or agency — and that a sponsor-investigator carries the obligations of both roles.
The reason those definitions matter to a reader is that they tell you who to look for. A company that pays for a study and a physician who runs it at a site have different, separately enforceable duties, and the regulations name them separately.
What the sponsor is on the hook for
Section 312.50 states the general responsibilities in one sentence, and it is worth reading as a list. Sponsors are responsible for selecting qualified investigators; providing them with the information they need to conduct an investigation properly; ensuring proper monitoring of the investigations; ensuring that the investigations are conducted in accordance with the general investigational plan and protocols; maintaining an effective application; and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug.
Section 312.53 turns the first of those into concrete steps. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug, and shall ship investigational drugs only to investigators participating in the investigation. It must also, before permitting an investigator to begin, obtain a curriculum vitae or other statement of qualifications showing the education, training and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation; a clinical protocol, whose required detail differs by phase; financial disclosure information sufficient for the certification or disclosure required by the financial-interest rules; and a signed investigator statement.
Monitoring gets its own line at 312.53(d): a sponsor shall select a monitor qualified by training and experience to monitor the progress of the investigation. Monitoring, in this regulation, is a named function with a named person behind it.
The form the investigator signs, and what it commits them to
The signed investigator statement listed at 312.53(c)(1) is where most of the site-level obligation is created, and its contents are itemised in the regulation.
It records the investigator's name and address, the protocol identifiers, the name and address of any medical school, hospital or other research facility where the investigation will be conducted, the name and address of any clinical laboratory facilities to be used, and the name and address of the review board responsible for the study.
It then records commitments. That the investigator will conduct the studies in accordance with the relevant, current protocols and will only make changes after notifying the sponsor, except when necessary to protect the safety, rights or welfare of subjects. That they will comply with all requirements regarding the obligations of clinical investigators. That they will personally conduct or supervise the investigation. That they will inform any potential subjects that the drugs are being used for investigational purposes, and will ensure that the informed consent and review board requirements are met. That they will report adverse experiences to the sponsor. That they have read and understand the information in the investigator's brochure, including the potential risks and side effects. And that they will ensure all associates, colleagues and employees assisting are informed about their obligations in meeting those commitments.
A further commitment concerns the review board: that a compliant board will be responsible for initial and continuing review and approval, that the investigator will promptly report all changes in the research activity and all unanticipated problems involving risks to human subjects or others, and that no changes will be made without board approval except where necessary to eliminate apparent immediate hazards.
Section 312.60 states the same obligations in summary form. An investigator is responsible for ensuring the investigation is conducted according to the signed statement, the investigational plan and applicable regulations; for protecting the rights, safety and welfare of subjects under the investigator's care; and for the control of drugs under investigation. And the investigator shall obtain the informed consent of each human subject to whom the drug is administered.
Monitoring in practice: what the sponsor must do when something is wrong
Section 312.56 converts monitoring from a word into a set of duties with consequences.
The sponsor shall monitor the progress of all clinical investigations being conducted under its application. It shall review and evaluate the evidence relating to safety and effectiveness as it is obtained from the investigator, make the required safety reports, and make annual reports on the progress of the investigation.
Where an investigator is not complying, the response is prescribed rather than discretionary. A sponsor who discovers that an investigator is not complying with the signed agreement, the general investigational plan, or the applicable requirements shall promptly either secure compliance or discontinue shipments of the investigational drug to that investigator and end the investigator's participation. If participation is ended, the sponsor shall require the investigator to dispose of or return the drug, and shall notify FDA.
And where the drug itself is the problem, there is a clock. A sponsor who determines that its investigational drug presents an unreasonable and significant risk to subjects shall discontinue the investigations presenting that risk; notify FDA, all review boards, and all investigators who have at any time participated in the investigation; assure the disposition of all outstanding stocks; and furnish FDA with a full report of its actions. The sponsor shall discontinue as soon as possible, and in no event later than five working days after making the determination.
Two features of that paragraph are worth naming. The notification reaches every investigator who has at any time participated, not only those currently enrolling. And the trigger is the sponsor's own determination — the duty does not wait for an agency order.
The records that make any of this checkable
Section 312.62 requires the investigator to maintain adequate records of the disposition of the drug, including dates, quantity and use by subjects, and to return unused supplies to the sponsor or otherwise provide for their disposition when the investigation ends.
It also requires case histories: adequate and accurate records of all observations and other data pertinent to the investigation on each individual administered the drug or employed as a control. The regulation spells out what case histories include — the case report forms and supporting data such as signed and dated consent forms and medical records, for example the physician's progress notes, the individual's hospital charts and the nurses' notes. And it adds one specific requirement: the case history for each individual shall document that informed consent was obtained prior to participation.
Retention runs long. Records must be kept for two years following the date a marketing application is approved for the drug for the indication under investigation; or, if no application is to be filed or the application is not approved for that indication, until two years after the investigation is discontinued and FDA is notified.
Section 312.68 gives FDA access. An investigator shall, on request from a properly authorized officer or employee at reasonable times, permit access to and copying and verification of those records. Subject names need not be divulged unless the records of particular individuals require more detailed study, or unless there is reason to believe the records do not represent actual case studies or actual results obtained.
Where compliance fails badly enough, 21 CFR 312.70 provides a proceeding. If FDA has information that an investigator has repeatedly or deliberately failed to comply with the research regulations, or has repeatedly or deliberately submitted false information in a required report, the agency furnishes written notice and an opportunity to explain, and — if the explanation is not accepted — an opportunity for a regulatory hearing on whether the investigator remains eligible to receive test articles. An investigator found ineligible is ineligible to conduct any clinical investigation supporting an application for a research or marketing permit for FDA-regulated products.
The consequences then run back into the data. Applications containing data reported by such an investigator are subject to examination to determine whether unreliable data essential to an investigation or essential to an approval were submitted, and the regulation sets out what follows if, with the unreliable data removed, what remains is inadequate.
Sources
- 21 CFR 56.102 — DefinitionsThe definitions of sponsor, investigator and sponsor-investigator, including that a corporation using its own employees is a sponsor while those employees are investigators, and that a sponsor-investigator must be an individual and carries both sets of obligations.
- 21 CFR 312.50 — General responsibilities of sponsors, and 21 CFR 312.53 — Selecting investigators and monitorsThe six general sponsor responsibilities; the duty to select only investigators qualified by training and experience and to ship investigational drugs only to participating investigators; the items a sponsor must obtain before an investigator begins, including the curriculum vitae, clinical protocol and financial disclosure information; the itemised contents and commitments of the signed investigator statement including the review board commitment; and the duty to select a monitor qualified by training and experience.
- 21 CFR 312.56 — Review of ongoing investigations, and 21 CFR 312.60 — General responsibilities of investigatorsThe sponsor's duty to monitor all investigations and to review and evaluate incoming safety and effectiveness evidence; the prescribed response to investigator noncompliance including discontinuing shipments, ending participation, requiring disposal or return and notifying FDA; the five-working-day duty on determining the drug presents an unreasonable and significant risk, with notification to FDA, all review boards and all investigators who have at any time participated; and the investigator's general responsibilities including obtaining informed consent from each subject.
- 21 CFR 312.62 — Investigator recordkeeping and record retention, 21 CFR 312.68 — Inspection of investigator's records and reports, and 21 CFR 312.70 — Disqualification of a clinical investigatorThe drug disposition records; the definition and required contents of case histories including the requirement that each case history document that consent was obtained prior to participation; the two-year retention rules; FDA's access to and verification of those records and the limited circumstances in which subject names must be divulged; and the disqualification procedure for repeated or deliberate noncompliance or submission of false information, its consequences for eligibility, and the resulting examination of applications containing that investigator's data.
Frequently asked questions
What is the difference between a sponsor and an investigator?
Under 21 CFR 56.102, a sponsor initiates a clinical investigation but does not conduct it, while an investigator is the individual under whose immediate direction the test article is administered or dispensed, or the responsible leader of a team. An individual who does both is a sponsor-investigator and carries both sets of obligations.
What is a sponsor responsible for?
Under 21 CFR 312.50: selecting qualified investigators, providing them with the information they need, ensuring proper monitoring, ensuring the investigations follow the general investigational plan and protocols, maintaining an effective application, and ensuring FDA and all participating investigators are promptly informed of significant new adverse effects or risks.
What does an investigator sign?
A signed investigator statement whose required contents are itemised at 21 CFR 312.53(c)(1), including facility and laboratory addresses, the reviewing board, and commitments to follow the protocol, personally conduct or supervise the investigation, meet the consent and review board requirements, report adverse experiences, and ensure assisting staff know their obligations.
What must a sponsor do if an investigator is not complying?
Under 21 CFR 312.56(b), promptly either secure compliance or discontinue shipments of the investigational drug to that investigator and end their participation — and if participation is ended, require disposal or return of the drug and notify FDA.
What happens if the drug turns out to present an unreasonable risk?
Under 21 CFR 312.56(d), the sponsor must discontinue the investigations presenting the risk; notify FDA, all review boards and all investigators who have at any time participated; assure disposition of outstanding stocks; and furnish FDA a full report — no later than five working days after making the determination.
How long are trial records kept?
Under 21 CFR 312.62(c), two years after a marketing application is approved for the indication under investigation, or, if no application is filed or it is not approved for that indication, two years after the investigation is discontinued and FDA is notified.