A clinical hold is an order issued by FDA to the sponsor of an IND application to delay a proposed clinical investigation or to suspend an ongoing investigation. All or some of the investigations conducted under an IND application may be placed on clinical hold.
This page describes grounds and procedures for imposition of clinical hold for clinical investigations that are not subject to exceptions from the informed consent regulations 21 CFR 50.23(d) and 21CFR 50.24. For the grounds for clinical hold imposition related to clinical investigations that are subject to exceptions from informed consent regulations refer to 21 CFR 312.42b(5) and (6).
When a proposed study is placed on clinical hold, subjects may not be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and given the investigational drug; patients already in the study are expected to be taken off therapy involving the investigational drug unless treatment continuation is specifically permitted by FDA in the interest of patient safety.
Grounds for imposition of clinical hold:
The grounds for imposition of clinical hold for a proposed or ongoing Phase 1 investigation include the following:
Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury; or
The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND; or
The investigator brochure is misleading, erroneous, or materially incomplete; or
The IND application does not contain sufficient information needed to assess the risks to subjects of the proposed studies; or
The IND application is for the study of an investigational drug intended to treat a life-threatening disease or condition that affects both genders, and men or women with reproductive potential who have the disease or condition being studied are excluded from eligibility because of a risk of reproductive toxicity (i.e., affecting reproductive organs) or developmental toxicity (i.e., affecting potential offspring).
However, this criterion does not apply to circumstances when: (1) proposed studies are pertinent only to one gender, (2) proposed studies are conducted in subjects who do not have the disease or condition for which the drug is being studied (e.g., some studies in healthy volunteers), (3) another study that does not exclude members of the other gender with reproductive potential is being conducted concurrently, has been conducted, or will take place with the same investigational product within a reasonable time agreed upon by FDA.
The grounds for imposition of clinical hold for a proposed or ongoing Phase 2 or Phase 3 investigation include the following:
Any of the conditions described above as for Phase 1 investigations; or
The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.
The grounds for imposition of clinical hold for an expanded access protocol include the following:
The pertinent Criteria for permitting the expanded access use to begin are not satisfied; or
The expanded access IND application or expanded access protocol does not comply with the requirements for Expanded Access submissions.
The grounds for imposition of clinical hold for any study that is not designed to be adequate and well-controlled include the following:
Any of the conditions described above that apply to Phase 1, 2, or 3 investigations; or
Situations when there is reasonable evidence the investigation that is not designed to be adequate and well-controlled is impeding enrollment in, or otherwise interfering with the conduct or completion of, a study that is designed to be an adequate and well-controlled investigation of the same or another investigational drug; or
Insufficient quantities of the investigational drug exist to adequately conduct both the investigation that is not designed to be adequate and well-controlled and the investigations that are designed to be adequate and well-controlled; or
The drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness; or
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
The drug has received marketing approval for the same indication in the same patient population; or
The sponsor of the study that is designed to be an adequate and well-controlled investigation is not actively pursuing marketing approval of the investigational drug with due diligence; or
The Commissioner determines that it would not be in the public interest for the study to be conducted or continued. FDA ordinarily intends that clinical holds in these circumstances would only apply to additional enrollment in non-concurrently controlled trials rather than to eliminating continued access to investigational drugs for individuals already receiving the investigational drug.
Procedures for clinical hold:
Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of clinical hold, FDA will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the IND applicant before issuing the clinical hold order. The clinical hold order is typically made by or on behalf of the Division Director from the Review Division with the responsibility for review of the IND application.
The clinical hold order may be made by telephone or other means of rapid communication or in writing. As soon as possible, and no more than 30 days after imposition of the clinical hold, a written explanation of the basis for the hold will be issued by FDA and sent to the applicant. The letter with the explanation will identify the studies under the IND application to which the hold applies, and will briefly explain the basis for the imposition of clinical hold.
Some examples of reasons for clinical hold are shown below:
Product has an impurity profile indicative of a potential health hazard or an impurity profile insufficiently defined to assess health hazard
Product cannot remain chemically stable throughout the testing program
Pharmacology and Toxicology:
Data from animal studies are not sufficient to support the anticipated exposure (dose, route of administration, and duration) for the proposed clinical trial
Poor quality non-GLP toxicology studies with difficult to interpret results and a safety signal that has not been sufficiently studied are proposed as pivotal toxicology studies to support use of the product in humans
Previously observed toxicities of the product are not addressed by the proposed safety assessments in a clinical protocol
For a product with a high potential for an unpredictable acute reaction, all subjects are dosed at the same time without consideration to staggered administration.
The IND application sponsor is expected to address the cited deficiencies in writing and submit a complete response to the issue(s) identified in the clinical hold letter in a separate submission. Once the complete response to all of the clinical hold deficiencies has been received, FDA will review the submission within 30 calendar days and determine whether the applicant’s response to clinical hold satisfactorily addresses the issues. The investigation may resume after FDA (usually the Division Director or their designee) has notified the applicant that the investigation may proceed.
An IND applicant may not proceed with a clinical trial on which a clinical hold has been imposed until the applicant has been notified by FDA that the hold has been lifted. For additional details regarding procedures related to clinical hold, refer to Guidance for Industry: Submitting and Reviewing Complete Responses to Clinical Holds (PDF - 26KB).
If an IND applicant disagrees with the reasons cited for the clinical hold, the applicant may request reconsideration of the decision through the Ombudsman and in accordance with Dispute Resolution procedures.
If all investigations covered by an IND application remain on clinical hold for 1 year or longer, the IND application may be considered by FDA for Inactive Status.