FDA clinical hold: the grounds in 21 CFR 312.42 and how to respond to a hold letter

At a glance

• A clinical hold is an FDA order to the sponsor to delay a proposed clinical investigation or suspend an ongoing one, and it can cover one or more of the studies under an IND (21 CFR 312.42(a)).
• FDA can impose a hold only on the grounds listed in 312.42(b), which differ for Phase 1, Phase 2 and 3, expanded access, studies not designed to be adequate and well-controlled, and studies using an exception from informed consent.
• Under a hold, no new subjects may start the investigational drug, and subjects already on it should come off unless FDA specifically permits otherwise for their safety.
• If the sponsor asks in writing for the hold to be removed and submits a complete response, FDA must answer in writing within 30 calendar days, either lifting or keeping the hold and giving reasons (312.42(e)).
• The study cannot restart until FDA says it may, and a sponsor who disagrees with the reasons can ask for reconsideration under 312.48.

What a clinical hold is

Section 312.42(a) defines a clinical hold as “an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation.” The order can apply to one or more of the investigations covered by an IND.

The regulation does not use the words full and partial. FDA’s guidance on complete responses to clinical holds (October 2000) does. It calls a hold on all clinical work under an IND a complete clinical hold. A partial clinical hold covers only part of the work: one protocol, or part of a protocol, is stopped while other protocols or parts continue. In practice a partial hold might stop dose escalation above a level, or enrollment of one population, while the rest of the program runs.

The order goes to the sponsor, so stopping the sites is the sponsor’s job. In an investigator-initiated study that sponsor is often a sponsor-investigator, who carries both sets of obligations under Part 312 (312.3). For a single academic site there is no sponsor team to absorb the work, so the same person handles the letter, the response and the patients.

The grounds FDA can use

The grounds depend on what is being held. Section 312.42(b) lists them by phase and context.

What is held	FDA may hold it if	Citation
Phase 1 study, proposed or ongoing	Subjects are or would be exposed to an unreasonable and significant risk of illness or injury	312.42(b)(1)(i)
	The named investigators are not qualified by scientific training and experience	312.42(b)(1)(ii)
	The investigator brochure is misleading, erroneous or materially incomplete	312.42(b)(1)(iii)
	The IND lacks the information 312.23 requires to assess the risks to subjects	312.42(b)(1)(iv)
	For a drug for a life-threatening disease affecting both genders, men or women with reproductive potential who have the disease are excluded because of reproductive or developmental toxicity risk, subject to listed exceptions	312.42(b)(1)(v)
Phase 2 or 3 study	Any Phase 1 ground applies	312.42(b)(2)(i)
	The plan or protocol is clearly deficient in design to meet its stated objectives	312.42(b)(2)(ii)
Expanded access IND or protocol	The subpart I criteria are not met, or the submission does not comply with subpart I, or for ongoing use the criteria are no longer met	312.42(b)(3)
Study not designed to be adequate and well-controlled	A Phase 1 or Phase 2/3 ground applies, or the study interferes with a well-controlled study, competes for scarce drug supply, the drug has strong evidence of lack of effectiveness, a better option exists, the drug is approved for the same use, the controlled-study sponsor is not pursuing approval with due diligence, or the Commissioner finds it not in the public interest	312.42(b)(4)
Study using the 50.24 exception from informed consent	A Phase 1 or Phase 2/3 ground applies, or the 50.24 criteria are not submitted or not met	312.42(b)(5)
Study using the 50.23(d) exception	A Phase 1 or Phase 2/3 ground applies, or the required presidential waiver has not been made	312.42(b)(6)

Two rows catch sponsors out. The “clearly deficient in design” ground in (b)(2)(ii) is listed for Phase 2 and 3 studies and is not among the Phase 1 grounds. And the investigator brochure ground in (b)(1)(iii) carries into every later phase through (b)(2)(i). A brochure that is misleading, erroneous or materially incomplete is a hold ground in its own right, which is why the investigator’s brochure deserves the same review as the protocol. For holds under (b)(4)(ii), (iii) and (v), the regulation says FDA ordinarily intends the hold to apply only to additional enrollment in nonconcurrently controlled trials, not to cut off people already receiving the drug.

How a hold is imposed

A hold usually follows a conversation. When FDA concludes that a deficiency may be grounds for a hold, it will, unless patients are exposed to immediate and serious risk, try to discuss and resolve the matter with the sponsor before issuing the order (312.42(c)). That call is the cheapest point to fix the problem, so a reviewer’s question in the first weeks after submission deserves a same-day answer.

The order itself can come by telephone or other rapid means, or in writing. It identifies the studies it covers, briefly explains the basis, and is made by or on behalf of the Division Director responsible for the IND. As soon as possible, and no more than 30 days after the hold, the Division Director provides a written explanation of the basis (312.42(d)).

Timing has two cases. A new IND goes into effect 30 days after FDA receives it unless FDA notifies the sponsor that the investigations are subject to a clinical hold (312.40(b)(1)), so a hold can arrive inside that window, before anyone is dosed. Holds also apply to ongoing investigations, so one can arrive mid-trial, for example after a safety signal reported under the IND safety reporting rules. The IND application guide covers the 30-day review itself and the submission gaps that lead to holds, and the pre-IND meeting guide covers settling those questions before you file.

What can continue, and what cannot

Section 312.42(a) sets the rule for subjects:

• On a proposed study under hold, subjects may not be given the investigational drug.
• On an ongoing study under hold, no new subjects may be recruited and placed on the drug. Patients already in the study should be taken off therapy involving the investigational drug unless FDA specifically permits otherwise in the interest of patient safety.

So the default for current subjects is to stop dosing, and continued treatment needs FDA’s specific permission. If stopping abruptly would harm someone, raise it with FDA at once rather than deciding alone. The rule speaks to the investigational drug, so ask FDA to confirm how follow-up visits and safety monitoring should continue for subjects who come off it.

A partial hold leaves the unaffected protocols or parts running, so the first task is to read exactly which studies, arms or cohorts the order names.

A hold is not the same as a sponsor or DSMB decision to pause. A data safety monitoring board can recommend a pause, and the sponsor can act on it, but only FDA can impose or lift a clinical hold.

Day-one playbook: responding to a hold

1. Read the order and confirm its scope. List which studies, protocols or cohorts are held, and which are not. Under a partial hold, the unaffected work continues.
2. Stop what the order stops. Tell every investigator on the held studies the same day: no new subjects on the drug, and current subjects off the drug unless FDA has permitted otherwise. Record when and how each site was told.
3. Tell the IRBs. Part 312 does not script this step, but each IRB approved the study on the basis that it could proceed, and its members need to know that it cannot. The ethics committee guide covers how to keep that relationship working.
4. Wait for, then work from, the written explanation. It must arrive within 30 days (312.42(d)). Build a table with one row per cited deficiency, the evidence or change that answers it, and the owner.
5. Decide what you will change. Some deficiencies need new data, some need a protocol amendment, and some need a clearer explanation of what was already in the IND. Decide early whether to answer everything at once or narrow the program to what you can support now.
6. Submit a complete response. The 30-day clock in 312.42(e) runs only when the sponsor requests in writing that the hold be removed and submits a complete response to the issues in the order. FDA’s 2000 guidance asks sponsors to type CLINICAL HOLD COMPLETE RESPONSE in large bold letters at the top of the cover letter, and to keep any material on non-hold issues out of it. FDA’s IND clinical hold web page asks for the complete response as a separate submission. Number it in the IND’s serial sequence like any other submission (312.23(e)), and see the Form FDA 1571 guide for the cover form.
7. Track FDA’s reply. FDA must respond in writing within 30 calendar days of receiving the request and complete response, either removing or keeping the hold, with reasons (312.42(e)). Under the 2000 guidance, if FDA judges the response incomplete it tells you what is missing and the clock does not start, and an amendment sent during the 30 days may lead the division to restart the clock.
8. Restart only on FDA’s word. An investigation may resume only after FDA notifies the sponsor that it may proceed, whatever the 30-day timing (312.42(e)). Notify sites and IRBs before the first new dose.

If you disagree: dispute resolution

A sponsor who disagrees with the reasons for a hold may request reconsideration under 312.48 (312.42(f)). That section has two tracks. For administrative or procedural disputes, the sponsor starts with the review division, beginning with the consumer safety officer assigned to the application, and can then go to the ombudsman (312.48(b)). For scientific or medical disputes, the sponsor discusses the matter directly with the responsible reviewers and can request a meeting with reviewing officials and management, addressed to the division director (312.48(c)(1)). The sponsor may suggest outside experts, and FDA may refer major unresolved policy issues to an advisory committee (312.48(c)(3)).

Disagreeing does not lift the hold. You can prepare the complete response and the dispute at the same time, and the response can succeed on its own.

Hold, non-hold comments and termination

These three FDA actions carry very different weight:

FDA action	What it requires of the sponsor	Citation
Comment and advice	Nothing. Unless a clinical hold order accompanies it, an FDA communication about IND deficiencies or data needs is advisory and requires no change and no response	312.41(a), 312.41(c)
Clinical hold	Stop the held work until FDA says it may proceed	312.42(a), 312.42(e)
Termination	End all investigations under the IND and recall or dispose of unused drug	312.44(a)

FDA’s 2000 guidance describes “nonhold issues” as points FDA may raise in the hold letter, in a separate, clearly marked section, or in a separate letter. They do not count toward the complete response. Answer them in a separate amendment.

A hold that is never lifted has its own path. If every investigation under an IND stays on clinical hold for 1 year or more, FDA may place the IND on inactive status (312.42(g), 312.45(a)). An IND inactive for 5 years or more may be terminated (312.45(e)). Termination normally begins with an FDA proposal and a chance for the sponsor to respond (312.44(a)), and FDA in general first tries informal resolution or the clinical hold procedures.

Is there a public clinical hold list?

No. FDA does not disclose the existence of an IND unless it has already been publicly disclosed or acknowledged (312.130(a)), and Part 312 provides no public register of holds. When a hold becomes public, the information usually comes from the sponsor, for example a company announcement. The guide to why there is no FDA IND database covers what can and cannot be looked up.

For a site, that means the sponsor’s notice is the only reliable source. For a sponsor, it means investors, partners and patients learn about the hold from you or not at all, so decide in advance who tells them and when.

Sources

• 21 CFR Part 312, Investigational New Drug Application, eCFR text up to date as of 14 April 2026
• FDA guidance: Submitting and Reviewing Complete Responses to Clinical Holds, October 2000, Revision 1
• FDA: IND Application Procedures, Clinical Hold