(3) A licensed practioner who receives an investigational drug for treatment use under a treatment protocol is an "investigator" under the protocol and is responsible for meeting all applicable investigator responsibilities under this part and 21 CFR parts 50 and 56.

(b) Treatment IND submitted by licensed practitioner. (1) If a licensed medical practitioner wants to obtain an investigational drug subject to a controlled clinical trial for a treatment use, the practitioner should first attempt to obtain the drug from the sponsor of the controlled trial under a treatment protocol. If the sponsor of the controlled clinical investigation of the drug will not establish a treatment protocol for the drug under paragraph (a) of this section, the licensed medical practitioner may seek to obtain the drug from the sponsor and submit a treatment IND to FDA requesting authorization to use the investigational drug for treatment use. A treatment use under a treatment IND may begin 30 days after FDA receives the IND or on earlier notification by FDA that the treatment use under the IND may begin. A treatment IND is required to contain the following:

(i) A cover sheet (Form FDA 1571) meeting §312.23(g)(1).

(ii) Information (when not provided by the sponsor) on the drug's chemistry, manufacturing, and controls, and prior clinical and nonclinical experience with the drug submitted in accordance with $312.23. A sponsor of a clinical investigation subject to an IND who supplies an investigational drug to a licensed medical practitioner for purposes of a separate treatment clinical investigation shall be deemed to authorize the incorporation-by-reference of the technical information contained in the sponsor's IND into the medical practitioner's treatment IND.

(iii) A statement of the steps taken by the practitioner to obtain the drug under a treatment protocol from the drug sponsor.

(iv) A treatment protocol containing the same information listed in paragraph (a)(1) of this section.

(v) A statement of the practitioner's qualifications to use the investiga

tional drug for the intended treatment

use.

(vi) The practitioner's statement of familiarity with information on the drug's safety and effectiveness derived from previous clinical and nonclinical experience with the drug.

(vii) Agreement to report to FDA safety information in accordance with § 312.32.

(2) A licensed practitioner who submits a treatment IND under this section is the sponsor-investigator for such IND and is responsible for meeting all applicable sponsor and investigator responsibilities under this part and 21 CFR parts 50 and 56.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

[52 FR 19477, May 22, 1987, as amended at 57 FR 13249, Apr. 15, 1992]

§ 312.36 Emergency use of an investigational new drug.

Need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND in accordance with §312.23 or §312.34. In such a case, FDA may authorize shipment of the drug for a specified use in advance of submission of an IND. A request for such authorization may be transmitted to FDA by telephone or other rapid communication means. For investigational biological drugs, the request should be directed to the Division of Biological Investigational New Drugs (HFB-230), Center for Biologics Evaluation and Research, 8800 Rockville Pike, Bethesda, MD 20892, 301-443-4864. For all other investigational drugs, the request for authorization should be directed to the Document Management and Reporting Branch (HFD-53), Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, MD 20857, 301-443-4320. After normal working hours, eastern standard time, the request should be directed to the FDA Division of Emergency and Epidemiological Operations, 202-857-8400. Except in extraordinary circumstances, such authorization will be conditioned on the sponsor making an appropriate IND submission as soon

as practicable after receiving the authorization.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, 1990]

§ 312.38 Withdrawal of an IND.

(a) At any time a sponsor may withdraw an effective IND without prejudice.

(b) If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or otherwise disposed of at the request of the sponsor in accordance with §312.59.

(c) If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all participating investigators, and all reviewing Institutional Review Boards, together with the reasons for such withdrawal.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Subpart C-Administrative Actions

§ 312.40 General requirements for use of an investigational new drug in a clinical investigation.

(a) An investigational new drug may be used in a clinical investigation if the following conditions are met:

(1) The sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect under paragraph (b) of this section; and the sponsor complies with all applicable requirements in this part and parts 50 and 56 with respect to the conduct of the clinical investigations; and

(2) Each participating investigator conducts his or her investigation in compliance with the requirements of this part and parts 50 and 56.

(b) An IND goes into effect:

(1) Thirty days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in

the IND are subject to a clinical hold under § 312.42; or

(2) On earlier notification by FDA that the clinical investigations in the IND may begin. FDA will notify the sponsor in writing of the date it receives the IND.

(c) A sponsor may ship an investigational new drug to investigators named in the IND:

(1) Thirty days after FDA receives the IND; or

(2) On earlier FDA authorization to ship the drug.

(d) An investigator may not administer an investigational new drug to human subjects until the IND goes into effect under paragraph (b) of this section.

§ 312.41 Comment and advice on an IND.

(a) FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about FDA's need for more data or information.

(b) On the sponsor's request, FDA will provide advice on specific matters relating to an IND. Examples of such advice may include advice on the adequacy of technical data to support an investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application.

(c) Unless the communication is accompanied by a clinical hold order under §312.42, FDA communications with a sponsor under this section are solely advisory and do not require any modification in the planned or ongoing clinical investigations or response to the agency.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

§ 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.

(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 paragraph (b)(1)(i) through (iv) 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 a treatment IND or treatment protocol.

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

(A) The pertinent criteria in §312.34(b) for permitting the treatment use to begin are not satisfied; or

(B) The treatment protocol or treatment IND does not contain the information required under §312.35 (a) or (b) to make the specified determination under §312.34(b).

(ii) Ongoing use. FDA may place an ongoing treatment protocol or treatment IND on clinical hold if it is determined that:

(A) There becomes available a comparable or satisfactory alternative drug or other therapy to treat that stage of the disease in the intended patient population for which the investigational drug is being used;

(B) The investigational drug is not under investigation in a controlled clinical trial under an IND in effect for the trial and not all controlled clinical trials necessary to support a marketing application have been completed, or a clinical study under the IND has been placed on clinical hold:

(C) The sponsor of the controlled clinical trial is not pursuing marketing approval with due diligence;

(D) If the treatment IND or treatment protocol is intended for a serious disease, there is insufficient evidence of safety and effectiveness to support such use; or

(E) If the treatment protocol or treatment IND was based on an immediately life-threatening disease, the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug:

(1) May be effective for its intended use in its intended population; or

(2) Would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury.

(iii) FDA may place a proposed or ongoing treatment IND or treatment protocol on clinical hold if it finds that any of the conditions in paragraph (b)(4)(i) through (b)(4)(viii) of this section apply.

(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 wellcontrolled and the investigations that are designed to be adequate and wellcontrolled; 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 wellcontrolled 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.

(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 ex

posed 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. If, by the terms of the clinical hold order, resumption of the affected investigation is permitted without prior notification by FDA once a stated correction or modification is made, the investigation may proceed as soon as the correction or modification is made. In all other cases, an investigation may only resume after the Division Director (or the Director's designee) with responsibility for review of the IND has notified the sponsor that the investigation may proceed. In these cases resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfied the agency that the investigation(s) can proceed. Resumption of a study may be authorized by telephone or other means of rapid communication.

(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]

§312.44 Termination.

(a) General. This section describes the procedures under which FDA may terminate an IND. If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in paragraph (d) of this section, a termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section after first attempting to resolve differences informally or, when appropriate, through the clinical hold procedures described in § 312.42.

(b) Grounds for termination—(1) Phase 1. FDA may propose to terminate an IND during Phase 1 if it finds that:

(i) Human subjects would be exposed to an unreasonable and significant risk of illness or unjury.

(ii) The IND does not contain sufficient information required under § 312.23 to assess the safety to subjects of the clinical investigations.

(iii) The methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety.

(iv) The clinical investigations are being conducted in a manner substantially different than that described in the protocols submitted in the IND.

(v) The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation or permitted by §312.7.

(vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part.

(vii) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with §312.32 or fails to make any other report required under this part.

(viii) The sponsor fails to submit an accurate annual report of the investigations in accordance with § 312.33.

(ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.

(x) The IND has remained on inactive status for 5 years or more.

(xi) The sponsor fails to delay a proposed investigation under the IND or to suspend an ongoing investigation that has been placed on clinical hold under § 312.42(b)(4).

(2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that:

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

(ii) The investigational plan or protocol(s) is not reasonable as a bona fide scientific plan to determine whether or not the drug is safe and effective for use; or

(iii) There is convincing evidence that the drug is not effective for the purpose for which it is being investigated.

(3) FDA may propose to terminate a treatment IND if it finds that:

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

(ii) Any of the conditions in §312.42(b)(3) apply.

(c) Opportunity for sponsor response. (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in writing, and invite correction or explanation within a period of 30 days.

(2) On such notification, the sponsor may provide a written explanation or correction or may request a conference with FDA to provide the requested explanation or correction. If the sponsor does not respond to the notification within the allocated time, the IND shall be terminated.

(3) If the sponsor responds but FDA does not accept the explanation or correction submitted, FDA shall inform the sponsor in writing of the reason for the nonacceptance and provide the sponsor with an opportunity for a regulatory hearing before FDA under part 16 on the question of whether the IND should be terminated. The sponsor's request for a regulatory hearing must be made within 10 days of the sponsor's