Title 21

SECTION 312.42

312.42 Clinical holds and requests for modification.

§ 312.42 Clinical holds and requests for modification.

(a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. 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 placed on the investigational drug; 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.

(b) Grounds for imposition of clinical hold - (1) Clinical hold of a Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that:

(i) Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;

(ii) 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;

(iii) The investigator brochure is misleading, erroneous, or materially incomplete; or

(iv) The IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.

(v) The IND 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 or potential risk from use of the investigational drug of reproductive toxicity (i.e., affecting reproductive organs) or developmental toxicity (i.e., affecting potential offspring). The phrase “women with reproductive potential” does not include pregnant women. For purposes of this paragraph, “life-threatening illnesses or diseases” are defined as “diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted.” The clinical hold would not apply under this paragraph to clinical studies conducted:

(A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies evaluating the excretion of a drug in semen or the effects on menstrual function);

(B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive potential is being conducted concurrently, has been conducted, or will take place within a reasonable time agreed upon by the agency; or

(2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that:

(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v) of this section apply; or

(ii) The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.

(3) Clinical hold of an expanded access IND or expanded access protocol. FDA may place an expanded access IND or expanded access protocol on clinical hold under the following conditions:

(i) Final use. FDA may place a proposed expanded access IND or treatment use protocol on clinical hold if it is determined that:

(A) The pertinent criteria in subpart I of this part for permitting the expanded access use to begin are not satisfied; or

(B) The expanded access IND or expanded access protocol does not comply with the requirements for expanded access submissions in subpart I of this part.

(ii) Ongoing use. FDA may place an ongoing expanded access IND or expanded access protocol on clinical hold if it is determined that the pertinent criteria in subpart I of this part for permitting the expanded access are no longer satisfied.

(4) Clinical hold of any study that is not designed to be adequate and well-controlled. FDA may place a proposed or ongoing investigation that is not designed to be adequate and well-controlled on clinical hold if it finds that:

(i) Any of the conditions in paragraph (b)(1) or (b)(2) of this section apply; or

(ii) 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

(iii) 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

(iv) The drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness; or

(v) 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

(vi) The drug has received marketing approval for the same indication in the same patient population; or

(vii) 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

(viii) 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 under paragraphs (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this section would only apply to additional enrollment in nonconcurrently controlled trials rather than eliminating continued access to individuals already receiving the investigational drug.

(5) Clinical hold of any investigation involving an exception from informed consent under § 50.24 of this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed consent under § 50.24 of this chapter on clinical hold if it is determined that:

(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or

(ii) The pertinent criteria in § 50.24 of this chapter for such an investigation to begin or continue are not submitted or not satisfied.

(6) Clinical hold of any investigation involving an exception from informed consent under § 50.23(d) of this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed consent under § 50.23(d) of this chapter on clinical hold if it is determined that:

(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or

(ii) A determination by the President to waive the prior consent requirement for the administration of an investigational new drug has not been made.

(c) Discussion of deficiency. 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 sponsor before issuing the clinical hold order.

(d) Imposition of clinical hold. The clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order will identify the studies under the IND to which the hold applies, and will briefly explain the basis for the action. The clinical hold order will be made by or on behalf of the Division Director with responsibility for review of the IND. As soon as possible, and no more than 30 days after imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold.

(e) Resumption of clinical investigations. An investigation may only resume after FDA (usually the Division Director, or the Director's designee, with responsibility for review of the IND) has notified the sponsor that the investigation may proceed. Resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfies the agency that the investigation(s) can proceed. FDA may notify a sponsor of its determination regarding the clinical hold by telephone or other means of rapid communication. If a sponsor of an IND that has been placed on clinical hold requests in writing that the clinical hold be removed and submits a complete response to the issue(s) identified in the clinical hold order, FDA shall respond in writing to the sponsor within 30-calendar days of receipt of the request and the complete response. FDA's response will either remove or maintain the clinical hold, and will state the reasons for such determination. Notwithstanding the 30-calendar day response time, a sponsor may not proceed with a clinical trial on which a clinical hold has been imposed until the sponsor has been notified by FDA that the hold has been lifted.

(f) Appeal. If the sponsor disagrees with the reasons cited for the clinical hold, the sponsor may request reconsideration of the decision in accordance with § 312.48.

(g) Conversion of IND on clinical hold to inactive status. If all investigations covered by an IND remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under § 312.45.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19477, May 22, 1987; 57 FR 13249, Apr. 15, 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, Dec. 14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR 34971, June 1, 2000; 74 FR 40942, Aug. 13, 2009]