Research · 6 min read
What a Clinical Hold Is, and What Triggers One
It is an order that stops dosing. The regulation lists the grounds, and only some of them are about safety — one is that the investigator brochure was misleading, and another is that a study was getting in the way of a better-designed one.
Key takeaways
- A clinical hold is an FDA order to delay a proposed investigation or suspend an ongoing one, and on an ongoing study patients should ordinarily be taken off the investigational drug.
- The grounds include unreasonable risk, an unqualified investigator, a misleading or materially incomplete investigator brochure, and insufficient information to assess risk.
- For phase 2 and 3, a further ground is a protocol clearly deficient in design to meet its stated objectives — a design failure, not a safety failure.
- Studies not designed to be adequate and well-controlled can be held for interfering with a controlled trial's enrollment or drug supply, or where controlled trials already strongly suggest lack of effectiveness.
- FDA will ordinarily attempt to resolve a deficiency with the sponsor first unless patients face immediate and serious risk, and must give a written basis within 30 days of imposing a hold.
- A hold is distinct from a sponsor's own five-working-day duty to discontinue a risky investigation, and from disqualification proceedings against an individual investigator.
Answer first: it is an order to delay or suspend, and it reaches the participants
The definition is the first sentence of 21 CFR 312.42. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. It may apply to one or more of the investigations covered by a single application.
The practical consequences are stated in the same paragraph, and they differ depending on when the order lands. When a proposed study is placed on hold, subjects may not be given the investigational drug. When an ongoing study is placed on hold, no new subjects may be recruited to the study and placed on the drug, and patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety.
That final clause is the exception that proves how the rule is meant to work. Stopping is the default, and continuing is what requires permission — but the permission exists precisely because abrupt withdrawal can itself be the greater risk for some people.
The background rule that makes any of this possible is 21 CFR 312.20: a sponsor may not begin a covered clinical investigation until an investigational new drug application is in effect. A hold operates on that permission.
The grounds for an early-phase hold
Section 312.42(b)(1) lists what FDA may find in order to place a proposed or ongoing phase 1 investigation on hold.
That human subjects are or would be exposed to an unreasonable and significant risk of illness or injury. That the clinical investigators named in the application are not qualified by reason of their scientific training and experience to conduct the investigation described. That the investigator brochure is misleading, erroneous, or materially incomplete. That the application does not contain sufficient information required under the content regulation to assess the risks to subjects of the proposed studies.
And one that is about who is being left out rather than who is being harmed. Where the application is for a drug intended to treat a life-threatening disease or condition affecting both genders, and men or women with reproductive potential who have the condition are excluded from eligibility because of a risk or potential risk of reproductive or developmental toxicity, that exclusion is itself a ground for a hold. The regulation defines life-threatening illnesses for this purpose as diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted, and states that the phrase women with reproductive potential does not include pregnant women. It then carves out narrow exceptions, including studies pertinent only to one gender and studies in one gender where a study not excluding the other is being conducted concurrently, has been conducted, or will take place within a reasonable time agreed with the agency.
For a proposed or ongoing phase 2 or phase 3 investigation, section 312.42(b)(2) adds one further ground on top of all of the above: that the plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.
That is a design ground, not a safety ground. A study can be stopped because it could not answer its own question.
The grounds that treat controlled trials as a scarce resource
Paragraph (b)(4) applies to any study that is not designed to be adequate and well-controlled, and its list goes well beyond risk.
FDA may place such a study on hold if any of the earlier grounds apply, or if there is reasonable evidence the study is impeding enrollment in, or otherwise interfering with the conduct or completion of, a study designed to be an adequate and well-controlled investigation of the same or another investigational drug. Or if insufficient quantities of the investigational drug exist to adequately conduct both. Or if the drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness. Or if another drug under investigation or approved for the same indication and available to the same patient population has demonstrated a better potential benefit-risk balance. Or if the drug has received marketing approval for the same indication in the same patient population. Or if the sponsor of the study designed to be adequate and well-controlled is not actively pursuing marketing approval with due diligence. Or if the Commissioner determines that it would not be in the public interest for the study to be conducted or continued.
The regulation attaches a moderating note to three of those. FDA ordinarily intends that holds on the interference, drug-supply and better-alternative grounds would apply only to additional enrollment in nonconcurrently controlled trials, rather than eliminating continued access for individuals already receiving the drug.
Two further categories exist for investigations involving an exception from informed consent, where a hold may be imposed if the specific criteria for such an investigation to begin or continue are not submitted or not satisfied.
How a hold is imposed, and how it comes off
The regulation builds in a step before the order. Whenever FDA concludes that a deficiency exists that may be grounds for a hold, it will — unless patients are exposed to immediate and serious risk — attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the order.
The order itself may be made by telephone or other means of rapid communication, or in writing. It will identify the studies to which the hold applies and briefly explain the basis. It is made by or on behalf of the division director responsible for reviewing the application, and as soon as possible, and no more than 30 days after imposition, that director will provide the sponsor a written explanation of the basis for the hold.
Resumption has a defined route. An investigation may resume only after FDA has notified the sponsor that it may proceed, and authorization follows when the sponsor corrects the cited deficiencies or otherwise satisfies the agency. If a sponsor requests removal in writing and submits a complete response to the issues identified, FDA must respond in writing within 30 calendar days of receiving the request and the complete response, either removing or maintaining the hold and stating the reasons. Notwithstanding that response time, the sponsor may not proceed until notified that the hold has been lifted.
A sponsor that disagrees with the reasons may request reconsideration. And if all investigations under an application remain on hold for one year or more, the application may be placed on inactive status.
What a hold does and does not tell a reader
A hold is a regulatory event with a stated basis, and the basis is what carries the meaning. The list above includes an unreasonable risk of illness or injury, an unqualified investigator, a misleading investigator brochure, an insufficient submission, a protocol clearly deficient in design, and a study competing for participants with a better-designed one. Those are very different facts, and collapsing them into "the trial was stopped" loses all of the information.
It is also worth knowing what a hold is not. It is not the same as a sponsor's own decision to stop. Under 21 CFR 312.56, a sponsor that determines its investigational drug presents an unreasonable and significant risk to subjects must itself discontinue the investigations presenting that risk, notify FDA, all review boards and all investigators who have at any time participated, and do so no later than five working days after making the determination. That is a sponsor action, not an agency order.
And it is not the same as action against a person. Under 21 CFR 312.70, where 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 may begin a proceeding that can end with the investigator being declared ineligible to receive investigational articles — and applications containing data reported by such an investigator become subject to examination to determine whether unreliable data essential to an investigation or an approval were submitted.
Three distinct mechanisms, three distinct meanings. A page that describes any of them should say which one it means, and what the stated basis was.
Sources
- 21 CFR 312.42 — Clinical holds and requests for modificationThe definition of a clinical hold and its effect on proposed and ongoing studies including the patient-safety exception; the phase 1 grounds including unreasonable risk, unqualified investigators, a misleading, erroneous or materially incomplete investigator brochure, insufficient information to assess risk, and the reproductive-potential exclusion ground with its definition of life-threatening and its carve-outs; the additional phase 2 and 3 ground of a protocol clearly deficient in design; the full list of grounds for studies not designed to be adequate and well-controlled together with the note limiting three of them to additional enrollment; the discussion-of-deficiency step; the manner of imposition and the 30-day written explanation; the resumption procedure and 30-calendar-day response requirement; the right to request reconsideration; and the conversion to inactive status after one year.
- 21 CFR 312.20 — Requirement for an IND, and 21 CFR 312.56 — Review of ongoing investigationsThat a sponsor may not begin a covered clinical investigation until an application is in effect; and the sponsor's own duty, on determining its investigational drug presents an unreasonable and significant risk to subjects, to discontinue the investigations presenting that risk and notify FDA, all review boards and all investigators no later than five working days after the determination.
- 21 CFR 312.70 — Disqualification of a clinical investigatorThat repeated or deliberate failure to comply with the research regulations, or repeated or deliberate submission of false information in a required report, can lead to a proceeding ending in an investigator being declared ineligible to receive test articles, and that submissions containing such an investigator's data become subject to examination for unreliable data essential to an investigation or an approval.
Frequently asked questions
What is a clinical hold?
Under 21 CFR 312.42(a), an order issued by FDA to a sponsor to delay a proposed clinical investigation or suspend an ongoing one. On a proposed study, subjects may not be given the drug. On an ongoing study, no new subjects may be recruited and patients already enrolled should be taken off the investigational drug unless FDA specifically permits otherwise in the interest of patient safety.
Is a hold always about safety?
No. The listed grounds include an unqualified investigator, an investigator brochure that is misleading, erroneous or materially incomplete, an application lacking sufficient information to assess risk, and — for phase 2 and 3 — a protocol clearly deficient in design to meet its stated objectives.
Can a study be held because of its effect on another study?
Yes. For a study not designed to be adequate and well-controlled, grounds include reasonable evidence that it is impeding enrollment in or interfering with the conduct or completion of an adequate and well-controlled investigation, or that insufficient drug exists to conduct both.
Does FDA warn a sponsor first?
Ordinarily yes. The regulation says that whenever FDA concludes a deficiency may be grounds for a hold it will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the order.
How does a hold get lifted?
An investigation may resume only after FDA notifies the sponsor it may proceed. If the sponsor requests removal in writing with a complete response to the issues identified, FDA must reply in writing within 30 calendar days, removing or maintaining the hold and stating the reasons. The sponsor may not proceed until notified the hold is lifted.
Is a hold the same as a company stopping its own trial?
No. Under 21 CFR 312.56 a sponsor that determines its drug presents an unreasonable and significant risk must discontinue the affected investigations itself and notify FDA, all review boards and all investigators within five working days of that determination. That is a sponsor decision; a hold is an agency order.