21 cfr 312 – investigational new drug (ind) · pdf filethe safety of quinine drug...

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21 CFR Ch. I (4–1–99 Edition)§ 310.547

for marketing. In the absence of an ap-proved new drug application or abbre-viated new drug application, such prod-uct is also misbranded under section502 of the act.

(c) Clinical investigations designedto obtain evidence that any drug prod-uct labeled, represented, or promotedfor OTC use for the treatment and/orprevention of nocturnal leg musclecramps is safe and effective for the pur-pose intended must comply with the re-quirements and procedures governingthe use of investigational new drugsset forth in part 312 of this chapter.

(d) After February 22, 1995, any suchOTC drug product initially introducedor initially delivered for introductioninto interstate commerce that is not incompliance with this section is subjectto regulatory action.

[59 FR 43252, Aug. 22, 1994]

§ 310.547 Drug products containingquinine offered over-the-counter(OTC) for the treatment and/or pre-vention of malaria.

(a) Quinine and quinine salts havebeen used OTC for the treatment and/orprevention of malaria, a serious andpotentially life-threatening disease.Quinine is no longer the drug of choicefor the treatment and/or prevention ofmost types of malaria. In addition,there are serious and complicating as-pects of the disease itself and some po-tentially serious and life-threateningrisks associated with the use of quinineat doses employed for the treatment ofmalaria. There is a lack of adequatedata to establish general recognition ofthe safety of quinine drug products forOTC use in the treatment and/or pre-vention of malaria. Therefore, quinineor quinine salts cannot be safely andeffectively used for the treatment and/or prevention of malaria except underthe care and supervision of a doctor.

(b) Any OTC drug product containingquinine or quinine salts that is labeled,represented, or promoted for the treat-ment and/or prevention of malaria isregarded as a new drug within themeaning of section 201(p) of the act, forwhich an approved application or ab-breviated application under section 505of the act and part 314 of this chapteris required for marketing. In the ab-sence of an approved new drug applica-

tion or abbreviated new drug applica-tion, such product is also misbrandedunder section 502 of the act.

(c) Clinical investigations designedto obtain evidence that any drug prod-uct labeled, represented, or promotedfor OTC use for the treatment and/orprevention of malaria is safe and effec-tive for the purpose intended mustcomply with the requirements and pro-cedures governing the use of investiga-tional new drugs set forth in part 312 ofthis chapter.

(d) After April 20, 1998, any such OTCdrug product initially introduced orinitially delivered for introduction intointerstate commerce that is not incompliance with this section is subjectto regulatory action.

[63 FR 13528, Mar. 20, 1998]

PART 312—INVESTIGATIONAL NEWDRUG APPLICATION

Subpart A—General Provisions

Sec.312.1 Scope.312.2 Applicability.312.3 Definitions and interpretations.312.6 Labeling of an investigational new

drug.312.7 Promotion and charging for investiga-

tional drugs.312.10 Waivers.

Subpart B—Investigational New DrugApplication (IND)

312.20 Requirement for an IND.312.21 Phases of an investigation.312.22 General principles of the IND submis-

sion.312.23 IND content and format.312.30 Protocol amendments.312.31 Information amendments.312.32 IND safety reports.312.33 Annual reports.312.34 Treatment use of an investigational

new drug.312.35 Submissions for treatment use.312.36 Emergency use of an investigational

new drug.312.38 Withdrawal of an IND.

Subpart C—Administrative Actions

312.40 General requirements for use of an in-vestigational new drug in a clinical in-vestigation.

312.41 Comment and advice on an IND.312.42 Clinical holds and requests for modi-

fication.

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Food and Drug Administration, HHS § 312.2

312.44 Termination.312.45 Inactive status.312.47 Meetings.312.48 Dispute resolution.

Subpart D—Responsibilities of Sponsorsand Investigators

312.50 General responsibilities of sponsors.312.52 Transfer of obligations to a contract

research organization.312.53 Selecting investigators and monitors.312.54 Emergency research under § 50.24 of

this chapter.312.55 Informing investigators.312.56 Review of ongoing investigations.312.57 Recordkeeping and record retention.312.58 Inspection of sponsor’s records and

reports.312.59 Disposition of unused supply of inves-

tigational drug.312.60 General responsibilities of investiga-

tors.312.61 Control of the investigational drug.312.62 Investigator recordkeeping and

record retention.312.64 Investigator reports.312.66 Assurance of IRB review.312.68 Inspection of investigator’s records

and reports.312.69 Handling of controlled substances.312.70 Disqualification of a clinical investi-

gator.

Subpart E—Drugs Intended to Treat Life-threatening and Severely-debilitatingIllnesses

312.80 Purpose.312.81 Scope.312.82 Early consultation.312.83 Treatment protocols.312.84 Risk-benefit analysis in review of

marketing applications for drugs to treatlife-threatening and severely-debilitatingillnesses.

312.85 Phase 4 studies.312.86 Focused FDA regulatory research.312.87 Active monitoring of conduct and

evaluation of clinical trials.312.88 Safeguards for patient safety.

Subpart F—Miscellaneous

312.110 Import and export requirements.312.120 Foreign clinical studies not con-

ducted under an IND.312.130 Availability for public disclosure of

data and information in an IND.312.140 Address for correspondence.312.145 Guidelines.

Subpart G—Drugs for Investigational Use inLaboratory Research Animals or inVitro Tests

312.160 Drugs for investigational use in lab-oratory research animals or in vitrotests.

AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,355, 371; 42 U.S.C. 262.

SOURCE: 52 FR 8831, Mar. 19, 1987, unlessotherwise noted.


§ 312.1 Scope.

(a) This part contains procedures andrequirements governing the use of in-vestigational new drugs, including pro-cedures and requirements for the sub-mission to, and review by, the Foodand Drug Administration of investiga-tional new drug applications (IND’s).An investigational new drug for whichan IND is in effect in accordance withthis part is exempt from the premar-keting approval requirements that areotherwise applicable and may beshipped lawfully for the purpose of con-ducting clinical investigations of thatdrug.

(b) References in this part to regula-tions in the Code of Federal Regula-tions are to chapter I of title 21, unlessotherwise noted.

§ 312.2 Applicability.

(a) Applicability. Except as providedin this section, this part applies to allclinical investigations of products thatare subject to section 505 of the FederalFood, Drug, and Cosmetic Act or to thelicensing provisions of the PublicHealth Service Act (58 Stat. 632, asamended (42 U.S.C. 201 et seq.)).

(b) Exemptions. (1) The clinical inves-tigation of a drug product that is law-fully marketed in the United States isexempt from the requirements of thispart if all the following apply:

(i) The investigation is not intendedto be reported to FDA as a well-con-trolled study in support of a new indi-cation for use nor intended to be usedto support any other significant changein the labeling for the drug;

(ii) If the drug that is undergoing in-vestigation is lawfully marketed as a


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21 CFR Ch. I (4–1–99 Edition)§ 312.3

prescription drug product, the inves-tigation is not intended to support asignificant change in the advertisingfor the product;

(iii) The investigation does not in-volve a route of administration or dos-age level or use in a patient populationor other factor that significantly in-creases the risks (or decreases the ac-ceptability of the risks) associatedwith the use of the drug product;

(iv) The investigation is conducted incompliance with the requirements forinstitutional review set forth in part 56and with the requirements for informedconsent set forth in part 50; and

(v) The investigation is conducted incompliance with the requirements of§ 312.7.

(2)(i) A clinical investigation involv-ing an in vitro diagnostic biologicalproduct listed in paragraph (b)(2)(ii) ofthis section is exempt from the re-quirements of this part if (a) it is in-tended to be used in a diagnostic proce-dure that confirms the diagnosis madeby another, medically established, di-agnostic product or procedure and (b) itis shipped in compliance with § 312.160.

(ii) In accordance with paragraph(b)(2)(i) of this section, the followingproducts are exempt from the require-ments of this part: (a) blood groupingserum; (b) reagent red blood cells; and(c) anti-human globulin.

(3) A drug intended solely for tests invitro or in laboratory research animalsis exempt from the requirements ofthis part if shipped in accordance with§ 312.160.

(4) FDA will not accept an applica-tion for an investigation that is ex-empt under the provisions of paragraph(b)(1) of this section.

(5) A clinical investigation involvinguse of a placebo is exempt from the re-quirements of this part if the inves-tigation does not otherwise requiresubmission of an IND.

(6) A clinical investigation involvingan exception from informed consentunder § 50.24 of this chapter is not ex-empt from the requirements of thispart.

(c) Bioavailability studies. The applica-bility of this part to in vivo bio-availability studies in humans is sub-ject to the provisions of § 320.31.

(d) Unlabeled indication. This partdoes not apply to the use in the prac-tice of medicine for an unlabeled indi-cation of a new drug product approvedunder part 314 or of a licensed biologi-cal product.

(e) Guidance. FDA may, on its owninitiative, issue guidance on the appli-cability of this part to particular in-vestigational uses of drugs. On request,FDA will advise on the applicability ofthis part to a planned clinical inves-tigation.

[52 FR 8831, Mar. 19, 1987, as amended at 61FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999]

EFFECTIVE DATE NOTE: At 64 FR 401, Jan.5, 1999, § 312.2 was amended by removing ‘‘or507’’ from paragraph (a) and by removing ‘‘orantibiotic drug’’ from paragraph (d), effec-tive May 20, 1999.

§ 312.3 Definitions and interpretations.

(a) The definitions and interpreta-tions of terms contained in section 201of the Act apply to those terms whenused in this part:

(b) The following definitions of termsalso apply to this part:

Act means the Federal Food, Drug,and Cosmetic Act (secs. 201–902, 52Stat. 1040 et seq., as amended (21 U.S.C.301–392)).

Clinical investigation means any ex-periment in which a drug is adminis-tered or dispensed to, or used involv-ing, one or more human subjects. Forthe purposes of this part, an experi-ment is any use of a drug except for theuse of a marketed drug in the course ofmedical practice.

Contract research organization means aperson that assumes, as an independentcontractor with the sponsor, one ormore of the obligations of a sponsor,e.g., design of a protocol, selection ormonitoring of investigations, evalua-tion of reports, and preparation of ma-terials to be submitted to the Food andDrug Administration.

FDA means the Food and Drug Ad-ministration.

IND means an investigational newdrug application. For purposes of thispart, ‘‘IND’’ is synonymous with ‘‘No-tice of Claimed Investigational Exemp-tion for a New Drug.’’

Investigational new drug means a new


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drug or biological drug that is used ina clinical investigation. The term alsoincludes a biological product that isused in vitro for diagnostic purposes.The terms ‘‘investigational drug’’ and‘‘investigational new drug’’ are deemedto be synonymous for purposes of thispart.

Investigator means an individual whoactually conducts a clinical investiga-tion (i.e., under whose immediate di-rection the drug is administered or dis-pensed to a subject). In the event an in-vestigation is conducted by a team ofindividuals, the investigator is the re-sponsible leader of the team. ‘‘Sub-investigator’’ includes any other indi-vidual member of that team.

Marketing application means an appli-cation for a new drug submitted undersection 505(b) of the Act or a product li-cense application for a biological prod-uct submitted under the Public HealthService Act.

Sponsor means a person who takes re-sponsibility for and initiates a clinicalinvestigation. The sponsor may be anindividual or pharmaceutical company,governmental agency, academic insti-tution, private organization, or otherorganization. The sponsor does not ac-tually conduct the investigation unlessthe sponsor is a sponsor-investigator. Aperson other than an individual thatuses one or more of its own employeesto conduct an investigation that it hasinitiated is a sponsor, not a sponsor-in-vestigator, and the employees are in-vestigators.

Sponsor-Investigator means an indi-vidual who both initiates and conductsan investigation, and under whose im-mediate direction the investigationaldrug is administered or dispensed. Theterm does not include any person otherthan an individual. The requirementsapplicable to a sponsor-investigatorunder this part include both those ap-plicable to an investigator and a spon-sor.

Subject means a human who partici-pates in an investigation, either as arecipient of the investigational newdrug or as a control. A subject may bea healthy human or a patient with adisease.

[52 FR 8831, Mar. 19, 1987, as amended at 64FR 401, Jan. 5, 1999]

EFFECTIVE DATE NOTE: At 64 FR 401, Jan.5, 1999, § 312.3 was amended by removing ‘‘,antibiotic drug,’’ from the paragraph defin-ing ‘‘Investigational new drug’’ and by re-moving the phrase ‘‘, a request to provide forcertification of an antibiotic submittedunder section 507 of the Act,’’ from the para-graph defining ‘‘Marketing application’’, ef-fective May 20, 1999.

§ 312.6 Labeling of an investigationalnew drug.

(a) The immediate package of an in-vestigational new drug intended forhuman use shall bear a label with thestatement ‘‘Caution: New Drug—Lim-ited by Federal (or United States) lawto investigational use.’’

(b) The label or labeling of an inves-tigational new drug shall not bear anystatement that is false or misleading inany particular and shall not representthat the investigational new drug issafe or effective for the purposes forwhich it is being investigated.

§ 312.7 Promotion and charging for in-vestigational drugs.

(a) Promotion of an investigational newdrug. A sponsor or investigator, or anyperson acting on behalf of a sponsor orinvestigator, shall not represent in apromotional context that an investiga-tional new drug is safe or effective forthe purposes for which it is under in-vestigation or otherwise promote thedrug. This provision is not intended torestrict the full exchange of scientificinformation concerning the drug, in-cluding dissemination of scientificfindings in scientific or lay media.Rather, its intent is to restrict pro-motional claims of safety or effective-ness of the drug for a use for which itis under investigation and to precludecommercialization of the drug before itis approved for commercial distribu-tion.

(b) Commercial distribution of an inves-tigational new drug. A sponsor or inves-tigator shall not commercially dis-tribute or test market an investiga-tional new drug.

(c) Prolonging an investigation. Asponsor shall not unduly prolong an in-vestigation after finding that the re-sults of the investigation appear to es-tablish sufficient data to support amarketing application.


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21 CFR Ch. I (4–1–99 Edition)§ 312.10

(d) Charging for and commercializationof investigational drugs—(1) Clinicaltrials under an IND. Charging for an in-vestigational drug in a clinical trialunder an IND is not permitted withoutthe prior written approval of FDA. Inrequesting such approval, the sponsorshall provide a full written explanationof why charging is necessary in orderfor the sponsor to undertake or con-tinue the clinical trial, e.g., why dis-tribution of the drug to test subjectsshould not be considered part of thenormal cost of doing business.

(2) Treatment protocol or treatmentIND. A sponsor or investigator maycharge for an investigational drug for atreatment use under a treatment pro-tocol or treatment IND provided: (i)There is adequate enrollment in theongoing clinical investigations underthe authorized IND; (ii) charging doesnot constitute commercial marketingof a new drug for which a marketingapplication has not been approved; (iii)the drug is not being commerciallypromoted or advertised; and (iv) thesponsor of the drug is actively pursuingmarketing approval with due diligence.FDA must be notified in writing in ad-vance of commencing any suchcharges, in an information amendmentsubmitted under § 312.31. Authorizationfor charging goes into effect automati-cally 30 days after receipt by FDA ofthe information amendment, unless thesponsor is notified to the contrary.

(3) Noncommercialization of investiga-tional drug. Under this section, thesponsor may not commercialize an in-vestigational drug by charging a pricelarger than that necessary to recovercosts of manufacture, research, devel-opment, and handling of the investiga-tional drug.

(4) Withdrawal of authorization. Au-thorization to charge for an investiga-tional drug under this section may bewithdrawn by FDA if the agency findsthat the conditions underlying the au-thorization are no longer satisfied.

(Collection of information requirements ap-proved by the Office of Management andBudget under control number 0910–0014)

[52 FR 8831, Mar. 19, 1987, as amended at 52FR 19476, May 22, 1987]

§ 312.10 Waivers.(a) A sponsor may request FDA to

waive applicable requirement underthis part. A waiver request may be sub-mitted either in an IND or in an infor-mation amendment to an IND. In anemergency, a request may be made bytelephone or other rapid communica-tion means. A waiver request is re-quired to contain at least one of thefollowing:

(1) An explanation why the sponsor’scompliance with the requirement is un-necessary or cannot be achieved;

(2) A description of an alternativesubmission or course of action thatsatisfies the purpose of the require-ment; or

(3) Other information justifying awaiver.

(b) FDA may grant a waiver if itfinds that the sponsor’s noncompliancewould not pose a significant and unrea-sonable risk to human subjects of theinvestigation and that one of the fol-lowing is met:

(1) The sponsor’s compliance with therequirement is unnecessary for theagency to evaluate the application, orcompliance cannot be achieved;

(2) The sponsor’s proposed alter-native satisfies the requirement; or

(3) The applicant’s submission other-wise justifies a waiver.


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

Subpart B—Investigational NewDrug Application (IND)

§ 312.20 Requirement for an IND.(a) A sponsor shall submit an IND to

FDA if the sponsor intends to conducta clinical investigation with an inves-tigational new drug that is subject to§ 312.2(a).

(b) A sponsor shall not begin a clin-ical investigation subject to § 312.2(a)until the investigation is subject to anIND which is in effect in accordancewith § 312.40.

(c) A sponsor shall submit a separateIND for any clinical investigation in-volving an exception from informedconsent under § 50.24 of this chapter.


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Such a clinical investigation is notpermitted to proceed without the priorwritten authorization from FDA. FDAshall provide a written determination30 days after FDA receives the IND orearlier.

[52 FR 8831, Mar. 19, 1987, as amended at 61FR 51529, Oct. 2, 1996; 62 FR 32479, June 16,1997]

§ 312.21 Phases of an investigation.An IND may be submitted for one or

more phases of an investigation. Theclinical investigation of a previouslyuntested drug is generally divided intothree phases. Although in general thephases are conducted sequentially,they may overlap. These three phasesof an investigation are a follows:

(a) Phase 1. (1) Phase 1 includes theinitial introduction of an investiga-tional new drug into humans. Phase 1studies are typically closely monitoredand may be conducted in patients ornormal volunteer subjects. These stud-ies are designed to determine the me-tabolism and pharmacologic actions ofthe drug in humans, the side effects as-sociated with increasing doses, and, ifpossible, to gain early evidence on ef-fectiveness. During Phase 1, sufficientinformation about the drug’s phar-macokinetics and pharmacological ef-fects should be obtained to permit thedesign of well-controlled, scientificallyvalid, Phase 2 studies. The total num-ber of subjects and patients included inPhase 1 studies varies with the drug,but is generally in the range of 20 to 80.

(2) Phase 1 studies also include stud-ies of drug metabolism, structure-ac-tivity relationships, and mechanism ofaction in humans, as well as studies inwhich investigational drugs are used asresearch tools to explore biologicalphenomena or disease processes.

(b) Phase 2. Phase 2 includes the con-trolled clinical studies conducted toevaluate the effectiveness of the drugfor a particular indication or indica-tions in patients with the disease orcondition under study and to deter-mine the common short-term side ef-fects and risks associated with thedrug. Phase 2 studies are typically wellcontrolled, closely monitored, and con-ducted in a relatively small number ofpatients, usually involving no morethan several hundred subjects.

(c) Phase 3. Phase 3 studies are ex-panded controlled and uncontrolledtrials. They are performed after pre-liminary evidence suggesting effective-ness of the drug has been obtained, andare intended to gather the additionalinformation about effectiveness andsafety that is needed to evaluate theoverall benefit-risk relationship of thedrug and to provide an adequate basisfor physician labeling. Phase 3 studiesusually include from several hundredto several thousand subjects.

§ 312.22 General principles of the INDsubmission.

(a) FDA’s primary objectives in re-viewing an IND are, in all phases of theinvestigation, to assure the safety andrights of subjects, and, in Phase 2 and3, to help assure that the quality of thescientific evaluation of drugs is ade-quate to permit an evaluation of thedrug’s effectiveness and safety. There-fore, although FDA’s review of Phase 1submissions will focus on assessing thesafety of Phase 1 investigations, FDA’sreview of Phases 2 and 3 submissionswill also include an assessment of thescientific quality of the clinical inves-tigations and the likelihood that theinvestigations will yield data capableof meeting statutory standards formarketing approval.

(b) The amount of information on aparticular drug that must be submittedin an IND to assure the accomplish-ment of the objectives described inparagraph (a) of this section dependsupon such factors as the novelty of thedrug, the extent to which it has beenstudied previously, the known or sus-pected risks, and the developmentalphase of the drug.

(c) The central focus of the initialIND submission should be on the gen-eral investigational plan and the proto-cols for specific human studies. Subse-quent amendments to the IND thatcontain new or revised protocols shouldbuild logically on previous submissionsand should be supported by additionalinformation, including the results ofanimal toxicology studies or otherhuman studies as appropriate. Annualreports to the IND should serve as thefocus for reporting the status of studiesbeing conducted under the IND and


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21 CFR Ch. I (4–1–99 Edition)§ 312.23

should update the general investiga-tional plan for the coming year.

(d) The IND format set forth in§ 312.23 should be followed routinely bysponsors in the interest of fostering anefficient review of applications. Spon-sors are expected to exercise consider-able discretion, however, regarding thecontent of information submitted ineach section, depending upon the kindof drug being studied and the nature ofthe available information. Section312.23 outlines the information neededfor a commercially sponsored IND for anew molecular entity. A sponsor-inves-tigator who uses, as a research tool, aninvestigational new drug that is al-ready subject to a manufacturer’s INDor marketing application should followthe same general format, but ordi-narily may, if authorized by the manu-facturer, refer to the manufacturer’sIND or marketing application in pro-viding the technical information sup-porting the proposed clinical investiga-tion. A sponsor-investigator who usesan investigational drug not subject toa manufacturer’s IND or marketing ap-plication is ordinarily required to sub-mit all technical information sup-porting the IND, unless such informa-tion may be referenced from the sci-entific literature.

§ 312.23 IND content and format.(a) A sponsor who intends to conduct

a clinical investigation subject to thispart shall submit an ‘‘InvestigationalNew Drug Application’’ (IND) includ-ing, in the following order:

(1) Cover sheet (Form FDA–1571). Acover sheet for the application con-taining the following:

(i) The name, address, and telephonenumber of the sponsor, the date of theapplication, and the name of the inves-tigational new drug.

(ii) Identification of the phase orphases of the clinical investigation tobe conducted.

(iii) A commitment not to begin clin-ical investigations until an IND cov-ering the investigations is in effect.

(iv) A commitment that an Institu-tional Review Board (IRB) that com-plies with the requirements set forth inpart 56 will be responsible for the ini-tial and continuing review and ap-proval of each of the studies in the pro-

posed clinical investigation and thatthe investigator will report to the IRBproposed changes in the research activ-ity in accordance with the require-ments of part 56.

(v) A commitment to conduct the in-vestigation in accordance with allother applicable regulatory require-ments.

(vi) The name and title of the personresponsible for monitoring the conductand progress of the clinical investiga-tions.

(vii) The name(s) and title(s) of theperson(s) responsible under § 312.32 forreview and evaluation of informationrelevant to the safety of the drug.

(viii) If a sponsor has transferred anyobligations for the conduct of any clin-ical study to a contract research orga-nization, a statement containing thename and address of the contract re-search organization, identification ofthe clinical study, and a listing of theobligations transferred. If all obliga-tions governing the conduct of thestudy have been transferred, a generalstatement of this transfer—in lieu of alisting of the specific obligations trans-ferred—may be submitted.

(ix) The signature of the sponsor orthe sponsor’s authorized representa-tive. If the person signing the applica-tion does not reside or have a place ofbusiness within the United States, theIND is required to contain the nameand address of, and be countersignedby, an attorney, agent, or other au-thorized official who resides or main-tains a place of business within theUnited States.

(2) A table of contents.(3) Introductory statement and general

investigational plan. (i) A brief introduc-tory statement giving the name of thedrug and all active ingredients, thedrug’s pharmacological class, thestructural formula of the drug (ifknown), the formulation of the dosageform(s) to be used, the route of admin-istration, and the broad objectives andplanned duration of the proposed clin-ical investigation(s).

(ii) A brief summary of previoushuman experience with the drug, withreference to other IND’s if pertinent,and to investigational or marketing ex-perience in other countries that may


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be relevant to the safety of the pro-posed clinical investigation(s).

(iii) If the drug has been withdrawnfrom investigation or marketing in anycountry for any reason related to safe-ty or effectiveness, identification ofthe country(ies) where the drug waswithdrawn and the reasons for thewithdrawal.

(iv) A brief description of the overallplan for investigating the drug productfor the following year. The plan shouldinclude the following: (a) The rationalefor the drug or the research study; (b)the indication(s) to be studied; (c) thegeneral approach to be followed inevaluating the drug; (d) the kinds ofclinical trials to be conducted in thefirst year following the submission (ifplans are not developed for the entireyear, the sponsor should so indicate);(e) the estimated number of patients tobe given the drug in those studies; and(f) any risks of particular severity orseriousness anticipated on the basis ofthe toxicological data in animals orprior studies in humans with the drugor related drugs.

(4) [Reserved](5) Investigator’s brochure. If required

under § 312.55, a copy of the investiga-tor’s brochure, containing the fol-lowing information:

(i) A brief description of the drugsubstance and the formulation, includ-ing the structural formula, if known.

(ii) A summary of the pharma-cological and toxicological effects ofthe drug in animals and, to the extentknown, in humans.

(iii) A summary of the pharmaco-kinetics and biological disposition ofthe drug in animals and, if known, inhumans.

(iv) A summary of information relat-ing to safety and effectiveness in hu-mans obtained from prior clinical stud-ies. (Reprints of published articles onsuch studies may be appended whenuseful.)

(v) A description of possible risks andside effects to be anticipated on thebasis of prior experience with the drugunder investigation or with relateddrugs, and of precautions or specialmonitoring to be done as part of the in-vestigational use of the drug.

(6) Protocols. (i) A protocol for eachplanned study. (Protocols for studies

not submitted initially in the INDshould be submitted in accordance with§ 312.30(a).) In general, protocols forPhase 1 studies may be less detailedand more flexible than protocols forPhase 2 and 3 studies. Phase 1 protocolsshould be directed primarily at pro-viding an outline of the investigation—an estimate of the number of patientsto be involved, a description of safetyexclusions, and a description of thedosing plan including duration, dose, ormethod to be used in determiningdose—and should specify in detail onlythose elements of the study that arecritical to safety, such as necessarymonitoring of vital signs and bloodchemistries. Modifications of the ex-perimental design of Phase 1 studiesthat do not affect critical safety as-sessments are required to be reportedto FDA only in the annual report.

(ii) In Phases 2 and 3, detailed proto-cols describing all aspects of the studyshould be submitted. A protocol for aPhase 2 or 3 investigation should be de-signed in such a way that, if the spon-sor anticipates that some deviationfrom the study design may become nec-essary as the investigation progresses,alternatives or contingencies to pro-vide for such deviation are built intothe protocols at the outset. For exam-ple, a protocol for a controlled short-term study might include a plan for anearly crossover of nonresponders to analternative therapy.

(iii) A protocol is required to containthe following, with the specific ele-ments and detail of the protocol re-flecting the above distinctions depend-ing on the phase of study:

(a) A statement of the objectives andpurpose of the study.

(b) The name and address and a state-ment of the qualifications (curriculumvitae or other statement of qualifica-tions) of each investigator, and thename of each subinvestigator (e.g., re-search fellow, resident) working underthe supervision of the investigator; thename and address of the research fa-cilities to be used; and the name andaddress of each reviewing InstitutionalReview Board.

(c) The criteria for patient selectionand for exclusion of patients and an es-timate of the number of patients to bestudied.


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21 CFR Ch. I (4–1–99 Edition)§ 312.23

(d) A description of the design of thestudy, including the kind of controlgroup to be used, if any, and a descrip-tion of methods to be used to minimizebias on the part of subjects, investiga-tors, and analysts.

(e) The method for determining thedose(s) to be administered, the plannedmaximum dosage, and the duration ofindividual patient exposure to thedrug.

(f) A description of the observationsand measurements to be made to fulfillthe objectives of the study.

(g) A description of clinical proce-dures, laboratory tests, or other meas-ures to be taken to monitor the effectsof the drug in human subjects and tominimize risk.

(7) Chemistry, manufacturing, and con-trol information. (i) As appropriate forthe particular investigations coveredby the IND, a section describing thecomposition, manufacture, and controlof the drug substance and the drugproduct. Although in each phase of theinvestigation sufficient information isrequired to be submitted to assure theproper identification, quality, purity,and strength of the investigationaldrug, the amount of information need-ed to make that assurance will varywith the phase of the investigation, theproposed duration of the investigation,the dosage form, and the amount of in-formation otherwise available. FDArecognizes that modifications to themethod of preparation of the new drugsubstance and dosage form and changesin the dosage form itself are likely asthe investigation progresses. There-fore, the emphasis in an initial Phase 1submission should generally be placedon the identification and control of theraw materials and the new drug sub-stance. Final specifications for thedrug substance and drug product arenot expected until the end of the inves-tigational process.

(ii) It should be emphasized that theamount of information to be submitteddepends upon the scope of the proposedclinical investigation. For example, al-though stability data are required inall phases of the IND to demonstratethat the new drug substance and drugproduct are within acceptable chemicaland physical limits for the planned du-ration of the proposed clinical inves-

tigation, if very short-term tests areproposed, the supporting stability datacan be correspondingly limited.

(iii) As drug development proceedsand as the scale or production ischanged from the pilot-scale produc-tion appropriate for the limited initialclinical investigations to the larger-scale production needed for expandedclinical trials, the sponsor should sub-mit information amendments to sup-plement the initial information sub-mitted on the chemistry, manufac-turing, and control processes with in-formation appropriate to the expandedscope of the investigation.

(iv) Reflecting the distinctions de-scribed in this paragraph (a)(7), andbased on the phase(s) to be studied, thesubmission is required to contain thefollowing:

(a) Drug substance. A description ofthe drug substance, including its phys-ical, chemical, or biological character-istics; the name and address of its man-ufacturer; the general method of prepa-ration of the drug substance; the ac-ceptable limits and analytical methodsused to assure the identity, strength,quality, and purity of the drug sub-stance; and information sufficient tosupport stability of the drug substanceduring the toxicological studies andthe planned clinical studies. Referenceto the current edition of the UnitedStates Pharmacopeia—National For-mulary may satisfy relevant require-ments in this paragraph.

(b) Drug product. A list of all compo-nents, which may include reasonablealternatives for inactive compounds,used in the manufacture of the inves-tigational drug product, including boththose components intended to appearin the drug product and those whichmay not appear but which are used inthe manufacturing process, and, whereapplicable, the quantitative composi-tion of the investigational drug prod-uct, including any reasonable vari-ations that may be expected during theinvestigational stage; the name and ad-dress of the drug product manufac-turer; a brief general description of themanufacturing and packaging proce-dure as appropriate for the product; theacceptable limits and analytical meth-ods used to assure the identity,strength, quality, and purity of the


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drug product; and information suffi-cient to assure the product’s stabilityduring the planned clinical studies.Reference to the current edition of theUnited States Pharmacopeia—NationalFormulary may satisfy certain require-ments in this paragraph.

(c) A brief general description of thecomposition, manufacture, and controlof any placebo used in a controlledclinical trial.

(d) Labeling. A copy of all labels andlabeling to be provided to each investi-gator.

(e) Environmental analysis require-ments. A claim for categorical exclu-sion under § 25.30 or 25.31 or an environ-mental assessment under § 25.40.

(8) Pharmacology and toxicology infor-mation. Adequate information aboutpharmacological and toxicologicalstudies of the drug involving labora-tory animals or in vitro, on the basis ofwhich the sponsor has concluded thatit is reasonably safe to conduct theproposed clinical investigations. Thekind, duration, and scope of animal andother tests required varies with the du-ration and nature of the proposed clin-ical investigations. Guidelines areavailable from FDA that describe waysin which these requirements may bemet. Such information is required toinclude the identification and quali-fications of the individuals who evalu-ated the results of such studies andconcluded that it is reasonably safe tobegin the proposed investigations and astatement of where the investigationswere conducted and where the recordsare available for inspection. As drugdevelopment proceeds, the sponsor isrequired to submit informationalamendments, as appropriate, with addi-tional information pertinent to safety.

(i) Pharmacology and drug disposition.A section describing the pharma-cological effects and mechanism(s) ofaction of the drug in animals, and in-formation on the absorption, distribu-tion, metabolism, and excretion of thedrug, if known.

(ii) Toxicology. (a) An integrated sum-mary of the toxicological effects of thedrug in animals and in vitro. Depend-ing on the nature of the drug and thephase of the investigation, the descrip-tion is to include the results of acute,subacute, and chronic toxicity tests;

tests of the drug’s effects on reproduc-tion and the developing fetus; any spe-cial toxicity test related to the drug’sparticular mode of administration orconditions of use (e.g., inhalation, der-mal, or ocular toxicology); and any invitro studies intended to evaluate drugtoxicity.

(b) For each toxicology study that isintended primarily to support the safe-ty of the proposed clinical investiga-tion, a full tabulation of data suitablefor detailed review.

(iii) For each nonclinical laboratorystudy subject to the good laboratorypractice regulations under part 58, astatement that the study was con-ducted in compliance with the goodlaboratory practice regulations in part58, or, if the study was not conductedin compliance with those regulations, abrief statement of the reason for thenoncompliance.

(9) Previous human experience with theinvestigational drug. A summary of pre-vious human experience known to theapplicant, if any, with the investiga-tional drug. The information is re-quired to include the following:

(i) If the investigational drug hasbeen investigated or marketed pre-viously, either in the United States orother countries, detailed informationabout such experience that is relevantto the safety of the proposed investiga-tion or to the investigation’s rationale.If the durg has been the subject of con-trolled trials, detailed information onsuch trials that is relevant to an as-sessment of the drug’s effectiveness forthe proposed investigational use(s)should also be provided. Any publishedmaterial that is relevant to the safetyof the proposed investigation or to anassessment of the drug’s effectivenessfor its proposed investigational useshould be provided in full. Publishedmaterial that is less directly relevantmay be supplied by a bibliography.

(ii) If the drug is a combination ofdrugs previously investigated or mar-keted, the information required underparagraph (a)(9)(i) of this sectionshould be provided for each active drugcomponent. However, if any componentin such combination is subject to anapproved marketing application or isotherwise lawfully marketed in the


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21 CFR Ch. I (4–1–99 Edition)§ 312.30

United States, the sponsor is not re-quired to submit published materialconcerning that active drug componentunless such material relates directly tothe proposed investigational use (in-cluding publications relevant to com-ponent-component interaction).

(iii) If the drug has been marketedoutside the United States, a list of thecountries in which the drug has beenmarketed and a list of the countries inwhich the drug has been withdrawnfrom marketing for reasons potentiallyrelated to safety or effectiveness.

(10) Additional information. In certainapplications, as described below, infor-mation on special topics may be need-ed. Such information shall be sub-mitted in this section as follows:

(i) Drug dependence and abuse poten-tial. If the drug is a psychotropic sub-stance or otherwise has abuse poten-tial, a section describing relevant clin-ical studies and experience and studiesin test animals.

(ii) Radioactive drugs. If the drug is aradioactive drug, sufficient data fromanimal or human studies to allow areasonable calculation of radiation-ab-sorbed dose to the whole body and crit-ical organs upon administration to ahuman subject. Phase 1 studies of ra-dioactive drugs must include studieswhich will obtain sufficient data fordosimetry calculations.

(iii) Pediatric studies. Plans for assess-ing pediatric safety and effectiveness.

(iv) Other information. A brief state-ment of any other information thatwould aid evaluation of the proposedclinical investigations with respect totheir safety or their design and poten-tial as controlled clinical trials to sup-port marketing of the drug.

(11) Relevant information. If requestedby FDA, any other relevant informa-tion needed for review of the applica-tion.

(b) Information previously submitted.The sponsor ordinarily is not requiredto resubmit information previouslysubmitted, but may incorporate the in-formation by reference. A reference toinformation submitted previously mustidentify the file by name, referencenumber, volume, and page numberwhere the information can be found. Areference to information submitted tothe agency by a person other than the

sponsor is required to contain a writ-ten statement that authorizes the ref-erence and that is signed by the personwho submitted the information.

(c) Material in a foreign language. Thesponsor shall submit an accurate andcomplete English translation of eachpart of the IND that is not in English.The sponsor shall also submit a copy ofeach original literature publication forwhich an English translation is sub-mitted.

(d) Number of copies. The sponsorshall submit an original and two copiesof all submissions to the IND file, in-cluding the original submission and allamendments and reports.

(e) Numbering of IND submissions.Each submission relating to an IND isrequired to be numbered serially usinga single, three-digit serial number. Theinitial IND is required to be numbered000; each subsequent submission (e.g.,amendment, report, or correspondence)is required to be numbered chrono-logically in sequence.

(f) Identification of exception from in-formed consent. If the investigation in-volves an exception from informed con-sent under § 50.24 of this chapter, thesponsor shall prominently identify onthe cover sheet that the investigationis subject to the requirements in § 50.24of this chapter.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599,July 29, 1997; 63 FR 66669, Dec. 2, 1998]

§ 312.30 Protocol amendments.

Once an IND is in effect, a sponsorshall amend it as needed to ensure thatthe clinical investigations are con-ducted according to protocols includedin the application. This section setsforth the provisions under which newprotocols may be submitted andchanges in previously submitted proto-cols may be made. Whenever a sponsorintends to conduct a clinical investiga-tion with an exception from informedconsent for emergency research as setforth in § 50.24 of this chapter, the spon-sor shall submit a separate IND forsuch investigation.


69


(a) New protocol. Whenever a sponsorintends to conduct a study that is notcovered by a protocol already con-tained in the IND, the sponsor shallsubmit to FDA a protocol amendmentcontaining the protocol for the study.Such study may begin provided twoconditions are met: (1) The sponsor hassubmitted the protocol to FDA for itsreview; and (2) the protocol has beenapproved by the Institutional ReviewBoard (IRB) with responsibility for re-view and approval of the study in ac-cordance with the requirements of part56. The sponsor may comply with thesetwo conditions in either order.

(b) Changes in a protocol. (1) A sponsorshall submit a protocol amendment de-scribing any change in a Phase 1 pro-tocol that significantly affects thesafety of subjects or any change in aPhase 2 or 3 protocol that significantlyaffects the safety of subjects, the scopeof the investigation, or the scientificquality of the study. Examples ofchanges requiring an amendment underthis paragraph include:

(i) Any increase in drug dosage or du-ration of exposure of individual sub-jects to the drug beyond that in thecurrent protocol, or any significant in-crease in the number of subjects understudy.

(ii) Any significant change in the de-sign of a protocol (such as the additionor dropping of a control group).

(iii) The addition of a new test orprocedure that is intended to improvemonitoring for, or reduce the risk of, aside effect or adverse event; or thedropping of a test intended to monitorsafety.

(2)(i) A protocol change under para-graph (b)(1) of this section may bemade provided two conditions are met:

(a) The sponsor has submitted thechange to FDA for its review; and

(b) The change has been approved bythe IRB with responsibility for reviewand approval of the study. The sponsormay comply with these two conditionsin either order.

(ii) Notwithstanding paragraph(b)(2)(i) of this section, a protocolchange intended to eliminate an appar-ent immediate hazard to subjects maybe implemented immediately providedFDA is subsequently notified by pro-tocol amendment and the reviewing

IRB is notified in accordance with§ 56.104(c).

(c) New investigator. A sponsor shallsubmit a protocol amendment when anew investigator is added to carry outa previously submitted protocol, exceptthat a protocol amendment is not re-quired when a licensed practitioner isadded in the case of a treatment pro-tocol under § 312.34. Once the investi-gator is added to the study, the inves-tigational drug may be shipped to theinvestigator and the investigator maybegin participating in the study. Thesponsor shall notify FDA of the new in-vestigator within 30 days of the inves-tigator being added.

(d) Content and format. A protocolamendment is required to be promi-nently identified as such (i.e., ‘‘Pro-tocol Amendment: New Protocol’’,‘‘Protocol Amendment: Change in Pro-tocol’’, or ‘‘Protocol Amendment: NewInvestigator’’), and to contain the fol-lowing:

(1)(i) In the case of a new protocol, acopy of the new protocol and a brief de-scription of the most clinically signifi-cant differences between it and pre-vious protocols.

(ii) In the case of a change in pro-tocol, a brief description of the changeand reference (date and number) to thesubmission that contained the pro-tocol.

(iii) In the case of a new investigator,the investigator’s name, the qualifica-tions to conduct the investigation, ref-erence to the previously submitted pro-tocol, and all additional informationabout the investigator’s study as is re-quired under § 312.23(a)(6)(iii)(b).

(2) Reference, if necessary, to specifictechnical information in the IND or ina concurrently submitted informationamendment to the IND that the spon-sor relies on to support any clinicallysignificant change in the new oramended protocol. If the reference ismade to supporting information al-ready in the IND, the sponsor shallidentify by name, reference number,volume, and page number the locationof the information.

(3) If the sponsor desires FDA to com-ment on the submission, a request forsuch comment and the specific ques-tions FDA’s response should address.


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21 CFR Ch. I (4–1–99 Edition)§ 312.31

(e) When submitted. A sponsor shallsubmit a protocol amendment for anew protocol or a change in protocolbefore its implementation. Protocolamendments to add a new investigatoror to provide additional informationabout investigators may be groupedand submitted at 30-day intervals.When several submissions of new proto-cols or protocol changes are antici-pated during a short period, the spon-sor is encouraged, to the extent fea-sible, to include these all in a singlesubmission.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,1988; 61 FR 51530, Oct. 2, 1996]

§ 312.31 Information amendments.

(a) Requirement for information amend-ment. A sponsor shall report in an in-formation amendment essential infor-mation on the IND that is not withinthe scope of a protocol amendment,IND safety reports, or annual report.Examples of information requiring aninformation amendment include:

(1) New toxicology, chemistry, orother technical information; or

(2) A report regarding the discontinu-ance of a clinical investigation.

(b) Content and format of an informa-tion amendment. An information amend-ment is required to bear prominentidentification of its contents (e.g., ‘‘In-formation Amendment: Chemistry,Manufacturing, and Control’’, ‘‘Infor-mation Amendment: Pharmacology-Toxicology’’, ‘‘Information Amend-ment: Clinical’’), and to contain thefollowing:

(1) A statement of the nature andpurpose of the amendment.

(2) An organized submission of thedata in a format appropriate for sci-entific review.

(3) If the sponsor desires FDA to com-ment on an information amendment, arequest for such comment.

(c) When submitted. Informationamendments to the IND should be sub-

mitted as necessary but, to the extentfeasible, not more than every 30 days.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,1988]

§ 312.32 IND safety reports.(a) Definitions. The following defini-

tions of terms apply to this section:–Associated with the use of the drug.

There is a reasonable possibility thatthe experience may have been causedby the drug.

Disability. A substantial disruption ofa person’s ability to conduct normallife functions.

Life-threatening adverse drug experi-ence. Any adverse drug experience thatplaces the patient or subject, in theview of the investigator, at immediaterisk of death from the reaction as it oc-curred, i.e., it does not include a reac-tion that, had it occurred in a more se-vere form, might have caused death.

Serious adverse drug experience: Anyadverse drug experience occurring atany dose that results in any of the fol-lowing outcomes: Death, a life-threat-ening adverse drug experience, inpa-tient hospitalization or prolongation ofexisting hospitalization, a persistent orsignificant disability/incapacity, or acongenital anomaly/birth defect. Im-portant medical events that may notresult in death, be life-threatening, orrequire hospitalization may be consid-ered a serious adverse drug experiencewhen, based upon appropriate medicaljudgment, they may jeopardize the pa-tient or subject and may require med-ical or surgical intervention to preventone of the outcomes listed in this defi-nition. Examples of such medicalevents include allergic bronchospasmrequiring intensive treatment in anemergency room or at home, blooddyscrasias or convulsions that do notresult in inpatient hospitalization, orthe development of drug dependency ordrug abuse.

Unexpected adverse drug experience:Any adverse drug experience, the speci-ficity or severity of which is not con-sistent with the current investigator


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brochure; or, if an investigator bro-chure is not required or available, thespecificity or severity of which is notconsistent with the risk informationdescribed in the general investiga-tional plan or elsewhere in the currentapplication, as amended. For example,under this definition, hepatic necrosiswould be unexpected (by virtue ofgreater severity) if the investigatorbrochure only referred to elevated he-patic enzymes or hepatitis. Similarly,cerebral thromboembolism and cere-bral vasculitis would be unexpected (byvirtue of greater specificity) if the in-vestigator brochure only listed cere-bral vascular accidents. ‘‘Unexpected,’’as used in this definition, refers to anadverse drug experience that has notbeen previously observed (e.g., includedin the investigator brochure) ratherthan from the perspective of such expe-rience not being anticipated from thepharmacological properties of thepharmaceutical product.

(b) Review of safety information. Thesponsor shall promptly review all infor-mation relevant to the safety of thedrug obtained or otherwise received bythe sponsor from any source, foreign ordomestic, including information de-rived from any clinical or epidemiolog-ical investigations, animal investiga-tions, commercial marketing experi-ence, reports in the scientific lit-erature, and unpublished scientific pa-pers, as well as reports from foreignregulatory authorities that have notalready been previously reported to theagency by the sponsor.

(c) IND safety reports. (1) Written re-ports—(i) The sponsor shall notify FDAand all participating investigators in awritten IND safety report of:

(A) Any adverse experience associ-ated with the use of the drug that isboth serious and unexpected; or

(B) Any finding from tests in labora-tory animals that suggests a signifi-cant risk for human subjects includingreports of mutagenicity,teratogenicity, or carcinogenicity.Each notification shall be made as soonas possible and in no event later than15 calendar days after the sponsor’s ini-tial receipt of the information. Eachwritten notification may be submittedon FDA Form 3500A or in a narrativeformat (foreign events may be sub-

mitted either on an FDA Form 3500Aor, if preferred, on a CIOMS I form; re-ports from animal or epidemiologicalstudies shall be submitted in a nar-rative format) and shall bear promi-nent identification of its contents, i.e.,‘‘IND Safety Report.’’ Each written no-tification to FDA shall be transmittedto the FDA new drug review division inthe Center for Drug Evaluation and Re-search or the product review divisionin the Center for Biologics Evaluationand Research that has responsibilityfor review of the IND. If FDA deter-mines that additional data are needed,the agency may require further data tobe submitted.

(ii) In each written IND safety re-port, the sponsor shall identify all safe-ty reports previously filed with theIND concerning a similar adverse expe-rience, and shall analyze the signifi-cance of the adverse experience in lightof the previouos, similar reports.

(2) Telephone and facsimile trans-mission safety reports. The sponsor shallalso notify FDA by telephone or by fac-simile transmission of any unexpectedfatal or life-threatening experience as-sociated with the use of the drug assoon as possible but in no event laterthan 7 calendar days after the spon-sor’s initial receipt of the information.Each telephone call or facsimile trans-mission to FDA shall be transmitted tothe FDA new drug review division inthe Center for Drug Evaluation and Re-search or the product review divisionin the Center for Biologics Evaluationand Research that has responsibilityfor review of the IND.

(3) Reporting format or frequency. FDAmay request a sponsor to submit INDsafety reports in a format or at a fre-quency different than that requiredunder this paragraph. The sponsor mayalso propose and adopt a different re-porting format or frequency if thechange is agreed to in advance by thedirector of the new drug review divi-sion in the Center for Drug Evaluationand Research or the director of theproducts review division in the Centerfor Biologics Evaluation and Researchwhich is responsible for review of theIND.

(4) A sponsor of a clinical study of amarketed drug is not required to make


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21 CFR Ch. I (4–1–99 Edition)§ 312.33

a safety report for any adverse experi-ence associated with use of the drugthat is not from the clinical studyitself.

(d) Followup. (1) The sponsor shallpromptly investigate all safety infor-mation received by it.

(2) Followup information to a safetyreport shall be submitted as soon asthe relevant information is available.

(3) If the results of a sponsor’s inves-tigation show that an adverse drug ex-perience not initially determined to bereportable under paragraph (c) of thissection is so reportable, the sponsorshall report such experience in a writ-ten safety report as soon as possible,but in no event later than 15 calendardays after the determination is made.

(4) Results of a sponsor’s investiga-tion of other safety information shallbe submitted, as appropriate, in an in-formation amendment or annual re-port.

(e) Disclaimer. A safety report orother information submitted by a spon-sor under this part (and any release byFDA of that report or information)does not necessarily reflect a conclu-sion by the sponsor or FDA that the re-port or information constitutes an ad-mission that the drug caused or con-tributed to an adverse experience. Asponsor need not admit, and may deny,that the report or information sub-mitted by the sponsor constitutes anadmission that the drug caused or con-tributed to an adverse experience.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 55 FR 11579, Mar. 29,1990; 62 FR 52250, Oct. 7, 1997]

§ 312.33 Annual reports.A sponsor shall within 60 days of the

anniversary date that the IND wentinto effect, submit a brief report of theprogress of the investigation that in-cludes:

(a) Individual study information. Abrief summary of the status of eachstudy in progress and each study com-pleted during the previous year. Thesummary is required to include the fol-lowing information for each study:

(1) The title of the study (with anyappropriate study identifiers such as

protocol number), its purpose, a briefstatement identifying the patient pop-ulation, and a statement as to whetherthe study is completed.

(2) The total number of subjects ini-tially planned for inclusion in thestudy; the number entered into thestudy to date, tabulated by age group,gender, and race; the number whoseparticipation in the study was com-pleted as planned; and the number whodropped out of the study for any rea-son.

(3) If the study has been completed,or if interim results are known, a briefdescription of any available study re-sults.

(b) Summary information. Informationobtained during the previous year’sclinical and nonclinical investigations,including:

(1) A narrative or tabular summaryshowing the most frequent and mostserious adverse experiences by bodysystem.

(2) A summary of all IND safety re-ports submitted during the past year.

(3) A list of subjects who died duringparticipation in the investigation, withthe cause of death for each subject.

(4) A list of subjects who dropped outduring the course of the investigationin association with any adverse experi-ence, whether or not thought to bedrug related.

(5) A brief description of what, if any-thing, was obtained that is pertinent toan understanding of the drug’s actions,including, for example, informationabout dose response, information fromcontrolled trails, and informationabout bioavailability.

(6) A list of the preclinical studies(including animal studies) completedor in progress during the past year anda summary of the major preclinicalfindings.

(7) A summary of any significantmanufacturing or microbiologicalchanges made during the past year.

(c) A description of the general inves-tigational plan for the coming year toreplace that submitted 1 year earlier.The general investigational plan shallcontain the information required under§ 312.23(a)(3)(iv).

(d) If the investigator brochure hasbeen revised, a description of the revi-sion and a copy of the new brochure.


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(e) A description of any significantPhase 1 protocol modifications madeduring the previous year and not pre-viously reported to the IND in a pro-tocol amendment.

(f) A brief summary of significantforeign marketing developments withthe drug during the past year, such asapproval of marketing in any countryor withdrawal or suspension from mar-keting in any country.

(g) If desired by the sponsor, a log ofany outstanding business with respectto the IND for which the sponsor re-quests or expects a reply, comment, ormeeting.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 63 FR 6862, Feb. 11,1998]

§ 312.34 Treatment use of an investiga-tional new drug.

(a) General. A drug that is not ap-proved for marketing may be underclinical investigation for a serious orimmediately life-threatening diseasecondition in patients for whom no com-parable or satisfactory alternativedrug or other therapy is available. Dur-ing the clinical investigation of thedrug, it may be appropriate to use thedrug in the treatment of patients notin the clinical trials, in accordancewith a treatment protocol or treat-ment IND. The purpose of this sectionis to facilitate the availability ofpromising new drugs to desperately illpatients as early in the drug develop-ment process as possible, before gen-eral marketing begins, and to obtainadditional data on the drug’s safetyand effectiveness. In the case of a seri-ous disease, a drug ordinarily may bemade available for treatment use underthis section during Phase 3 investiga-tions or after all clinical trials havebeen completed; however, in appro-priate circumstances, a drug may bemade available for treatment use dur-ing Phase 2. In the case of an imme-diately life-threatening disease, a drugmay be made available for treatmentuse under this section earlier thanPhase 3, but ordinarily not earlier thanPhase 2. For purposes of this section,the ‘‘treatment use’’ of a drug includes

the use of a drug for diagnostic pur-poses. If a protocol for an investiga-tional drug meets the criteria of thissection, the protocol is to be submittedas a treatment protocol under the pro-visions of this section.

(b) Criteria. (1) FDA shall permit aninvestigational drug to be used for atreatment use under a treatment pro-tocol or treatment IND if:

(i) The drug is intended to treat a se-rious or immediately life-threateningdisease;

(ii) There is no comparable or satis-factory alternative drug or other ther-apy available to treat that stage of thedisease in the intended patient popu-lation;

(iii) The drug is under investigationin a controlled clinical trial under anIND in effect for the trial, or all clin-ical trials have been completed; and

(iv) The sponsor of the controlledclinical trial is actively pursuing mar-keting approval of the investigationaldrug with due diligence.

(2) Serious disease. For a drug in-tended to treat a serious disease, theCommissioner may deny a request fortreatment use under a treatment pro-tocol or treatment IND if there is in-sufficient evidence of safety and effec-tiveness to support such use.

(3) Immediately life-threatening disease.(i) For a drug intended to treat an im-mediately life-threatening disease, theCommissioner may deny a request fortreatment use of an investigationaldrug under a treatment protocol ortreatment IND if the available sci-entific evidence, taken as a whole, failsto provide a reasonable basis for con-cluding that the drug:

(A) May be effective for its intendeduse in its intended patient population;or

(B) Would not expose the patients towhom the drug is to be administered toan unreasonable and significant addi-tional risk of illness or injury.

(ii) For the purpose of this section,an ‘‘immediately life-threatening’’ dis-ease means a stage of a disease inwhich there is a reasonable likelihoodthat death will occur within a matterof months or in which premature deathis likely without early treatment.

(c) Safeguards. Treatment use of aninvestigational drug is conditioned on


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21 CFR Ch. I (4–1–99 Edition)§ 312.35

the sponsor and investigators com-plying with the safeguards of the INDprocess, including the regulations gov-erning informed consent (21 CFR part50) and institutional review boards (21CFR part 56) and the applicable provi-sions of part 312, including distributionof the drug through qualified experts,maintenance of adequate manufac-turing facilities, and submission of INDsafety reports.

(d) Clinical hold. FDA may place onclinical hold a proposed or ongoingtreatment protocol or treatment INDin accordance with § 312.42.

[52 FR 19476, May 22, 1987, as amended at 57FR 13248, Apr. 15, 1992]

§ 312.35 Submissions for treatmentuse.

(a) Treatment protocol submitted byIND sponsor. Any sponsor of a clinicalinvestigation of a drug who intends tosponsor a treatment use for the drugshall submit to FDA a treatment pro-tocol under § 312.34 if the sponsor be-lieves the criteria of § 312.34 are satis-fied. If a protocol is not submittedunder § 312.34, but FDA believes thatthe protocol should have been sub-mitted under this section, FDA maydeem the protocol to be submittedunder § 312.34. A treatment use under atreatment protocol may begin 30 daysafter FDA receives the protocol or onearlier notification by FDA that thetreatment use described in the protocolmay begin.

(1) A treatment protocol is requiredto contain the following:

(i) The intended use of the drug.(ii) An explanation of the rationale

for use of the drug, including, as appro-priate, either a list of what availableregimens ordinarily should be tried be-fore using the investigational drug oran explanation of why the use of theinvestigational drug is preferable tothe use of available marketed treat-ments.

(iii) A brief description of the criteriafor patient selection.

(iv) The method of administration ofthe drug and the dosages.

(v) A description of clinical proce-dures, laboratory tests, or other meas-ures to monitor the effects of the drugand to minimize risk.

(2) A treatment protocol is to be sup-ported by the following:

(i) Informational brochure for sup-plying to each treating physician.

(ii) The technical information that isrelevant to safety and effectiveness ofthe drug for the intended treatmentpurpose. Information contained in thesponsor’s IND may be incorporated byreference.

(iii) A commitment by the sponsor toassure compliance of all participatinginvestigators with the informed con-sent requirements of 21 CFR part 50.

(3) A licensed practioner who receivesan investigational drug for treatmentuse under a treatment protocol is an‘‘investigator’’ under the protocol andis responsible for meeting all applica-ble investigator responsibilities underthis part and 21 CFR parts 50 and 56.

(b) Treatment IND submitted by li-censed practitioner. (1) If a licensed med-ical practitioner wants to obtain an in-vestigational drug subject to a con-trolled clinical trial for a treatmentuse, the practitioner should first at-tempt to obtain the drug from thesponsor of the controlled trial under atreatment protocol. If the sponsor ofthe controlled clinical investigation ofthe drug will not establish a treatmentprotocol for the drug under paragraph(a) of this section, the licensed medicalpractitioner may seek to obtain thedrug from the sponsor and submit atreatment IND to FDA requesting au-thorization to use the investigationaldrug for treatment use. A treatmentuse under a treatment IND may begin30 days after FDA receives the IND oron earlier notification by FDA that thetreatment use under the IND maybegin. A treatment IND is required tocontain the following:

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

(ii) Information (when not providedby the sponsor) on the drug’s chem-istry, manufacturing, and controls, andprior clinical and nonclinical experi-ence with the drug submitted in ac-cordance with § 312.23. A sponsor of aclinical investigation subject to an INDwho supplies an investigational drug toa licensed medical practitioner for pur-poses of a separate treatment clinicalinvestigation shall be deemed to au-thorize the incorporation-by-reference


75


of the technical information containedin the sponsor’s IND into the medicalpractitioner’s treatment IND.

(iii) A statement of the steps takenby the practitioner to obtain the drugunder a treatment protocol from thedrug sponsor.

(iv) A treatment protocol containingthe same information listed in para-graph (a)(1) of this section.

(v) A statement of the practitioner’squalifications to use the investiga-tional drug for the intended treatmentuse.

(vi) The practitioner’s statement offamiliarity with information on thedrug’s safety and effectiveness derivedfrom previous clinical and nonclinicalexperience with the drug.

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

(2) A licensed practitioner who sub-mits a treatment IND under this sec-tion is the sponsor-investigator forsuch IND and is responsible for meet-ing all applicable sponsor and investi-gator responsibilities under this partand 21 CFR parts 50 and 56.


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

§ 312.36 Emergency use of an inves-tigational new drug.

Need for an investigational drug mayarise in an emergency situation thatdoes not allow time for submission ofan IND in accordance with § 312.23 or§ 312.34. In such a case, FDA may au-thorize shipment of the drug for a spec-ified use in advance of submission of anIND. A request for such authorizationmay be transmitted to FDA by tele-phone or other rapid communicationmeans. For investigational biologicaldrugs, the request should be directed tothe Division of Biological Investiga-tional New Drugs (HFB–230), Center forBiologics Evaluation and Research,8800 Rockville Pike, Bethesda, MD20892, 301–443–4864. For all other inves-tigational drugs, the request for au-thorization should be directed to theDocument Management and ReportingBranch (HFD–53), Center for Drug Eval-uation and Research, 5600 Fishers Lane,

Rockville, MD 20857, 301–443–4320. Afternormal working hours, eastern stand-ard time, the request should be di-rected to the FDA Division of Emer-gency and Epidemiological Operations,202–857–8400. Except in extraordinarycircumstances, such authorization willbe conditioned on the sponsor makingan appropriate IND submission as soonas practicable after receiving the au-thorization.


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

§ 312.38 Withdrawal of an IND.(a) At any time a sponsor may with-

draw an effective IND without preju-dice.

(b) If an IND is withdrawn, FDA shallbe so notified, all clinical investiga-tions conducted under the IND shall beended, all current investigators noti-fied, and all stocks of the drug re-turned to the sponsor or otherwise dis-posed of at the request of the sponsorin accordance with § 312.59.

(c) If an IND is withdrawn because ofa safety reason, the sponsor shallpromptly so inform FDA, all partici-pating investigators, and all reviewingInstitutional Review Boards, togetherwith the reasons for such withdrawal.



Subpart C—Administrative Actions

§ 312.40 General requirements for useof an investigational new drug in aclinical investigation.

(a) An investigational new drug maybe used in a clinical investigation ifthe following conditions are met:

(1) The sponsor of the investigationsubmits an IND for the drug to FDA;the IND is in effect under paragraph (b)of this section; and the sponsor com-plies with all applicable requirementsin this part and parts 50 and 56 with re-spect to the conduct of the clinical in-vestigations; and


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21 CFR Ch. I (4–1–99 Edition)§ 312.41

(2) Each participating investigatorconducts his or her investigation incompliance with the requirements ofthis part and parts 50 and 56.

(b) An IND goes into effect:(1) Thirty days after FDA receives

the IND, unless FDA notifies the spon-sor that the investigations described inthe IND are subject to a clinical holdunder § 312.42; or

(2) On earlier notification by FDAthat the clinical investigations in theIND may begin. FDA will notify thesponsor in writing of the date it re-ceives the IND.

(c) A sponsor may ship an investiga-tional new drug to investigators namedin the IND:

(1) Thirty days after FDA receivesthe IND; or

(2) On earlier FDA authorization toship the drug.

(d) An investigator may not admin-ister an investigational new drug tohuman subjects until the IND goes intoeffect under paragraph (b) of this sec-tion.

§ 312.41 Comment and advice on anIND.

(a) FDA may at any time during thecourse of the investigation commu-nicate with the sponsor orally or inwriting about deficiencies in the INDor about FDA’s need for more data orinformation.

(b) On the sponsor’s request, FDAwill provide advice on specific mattersrelating to an IND. Examples of suchadvice may include advice on the ade-quacy of technical data to support aninvestigational plan, on the design of aclinical trial, and on whether proposedinvestigations are likely to produce thedata and information that is needed tomeet requirements for a marketing ap-plication.

(c) Unless the communication is ac-companied by a clinical hold orderunder § 312.42, FDA communicationswith a sponsor under this section aresolely advisory and do not require anymodification in the planned or ongoing

clinical investigations or response tothe agency.



§ 312.42 Clinical holds and requests formodification.

(a) General. A clinical hold is an orderissued by FDA to the sponsor to delaya proposed clinical investigation or tosuspend an ongoing investigation. Theclinical hold order may apply to one ormore of the investigations covered byan IND. When a proposed study isplaced on clinical hold, subjects maynot be given the investigational drug.When an ongoing study is placed onclinical hold, no new subjects may berecruited to the study and placed onthe investigational drug; patients al-ready in the study should be taken offtherapy involving the investigationaldrug unless specifically permitted byFDA in the interest of patient safety.

(b) Grounds for imposition of clinicalhold—(1) Clinical hold of a Phase 1 studyunder an IND. FDA may place a pro-posed or ongoing Phase 1 investigationon clinical hold if it finds that:

(i) Human subjects are or would beexposed to an unreasonable and signifi-cant risk of illness or injury;

(ii) The clinical investigators namedin the IND are not qualified by reasonof their scientific training and experi-ence to conduct the investigation de-scribed in the IND;

(iii) The investigator brochure ismisleading, erroneous, or materiallyincomplete; or

(iv) The IND does not contain suffi-cient information required under§ 312.23 to assess the risks to subjects ofthe proposed studies.

(2) Clinical hold of a Phase 2 or 3 studyunder an IND. FDA may place a pro-posed or ongoing Phase 2 or 3 inves-tigation on clinical hold if it findsthat:

(i) Any of the conditions in para-graph (b)(1)(i) through (iv) of this sec-tion apply; or


77


(ii) The plan or protocol for the in-vestigation is clearly deficient in de-sign to meet its stated objectives.

(3) Clinical hold of a treatment INDor treatment protocol.

(i) Proposed use. FDA may place aproposed treatment IND or treatmentprotocol on clinical hold if it is deter-mined that:

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

(B) The treatment protocol or treat-ment IND does not contain the infor-mation required under § 312.35 (a) or (b)to make the specified determinationunder § 312.34(b).

(ii) Ongoing use. FDA may place anongoing treatment protocol or treat-ment IND on clinical hold if it is deter-mined that:

(A) There becomes available a com-parable or satisfactory alternativedrug or other therapy to treat thatstage of the disease in the intended pa-tient population for which the inves-tigational drug is being used;

(B) The investigational drug is notunder investigation in a controlledclinical trial under an IND in effect forthe trial and not all controlled clinicaltrials necessary to support a mar-keting application have been com-pleted, or a clinical study under theIND has been placed on clinical hold:

(C) The sponsor of the controlledclinical trial is not pursuing marketingapproval with due diligence;

(D) If the treatment IND or treat-ment protocol is intended for a seriousdisease, there is insufficient evidenceof safety and effectiveness to supportsuch use; or

(E) If the treatment protocol ortreatment IND was based on an imme-diately life-threatening disease, theavailable scientific evidence, taken asa whole, fails to provide a reasonablebasis for concluding that the drug:

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

(2) Would not expose the patients towhom the drug is to be administered toan unreasonable and significant addi-tional risk of illness or injury.

(iii) FDA may place a proposed or on-going treatment IND or treatment pro-tocol on clinical hold if it finds thatany of the conditions in paragraph

(b)(4)(i) through (b)(4)(viii) of this sec-tion apply.

(4) Clinical hold of any study that isnot designed to be adequate and well-con-trolled. FDA may place a proposed orongoing investigation that is not de-signed to be adequate and well-con-trolled on clinical hold if it finds that:

(i) Any of the conditions in para-graph (b)(1) or (b)(2) of this sectionapply; or

(ii) There is reasonable evidence theinvestigation that is not designed to beadequate and well-controlled is imped-ing enrollment in, or otherwise inter-fering with the conduct or completionof, a study that is designed to be anadequate and well-controlled investiga-tion of the same or another investiga-tional drug; or

(iii) Insufficient quantities of the in-vestigational drug exist to adequatelyconduct both the investigation that isnot designed to be adequate and well-controlled and the investigations thatare designed to be adequate and well-controlled; or

(iv) The drug has been studied in oneor more adequate and well-controlledinvestigations that strongly suggestlack of effectiveness; or

(v) Another drug under investigationor approved for the same indicationand available to the same patient popu-lation has demonstrated a better po-tential benefit/risk balance; or

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

(vii) The sponsor of the study that isdesigned to be an adequate and well-controlled investigation is not activelypursuing marketing approval of the in-vestigational drug with due diligence;or

(viii) The Commissioner determinesthat it would not be in the public inter-est for the study to be conducted orcontinued. FDA ordinarily intends thatclinical holds under paragraphs(b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of thissection would only apply to additionalenrollment in nonconcurrently con-trolled trials rather than eliminatingcontinued access to individuals alreadyreceiving the investigational drug.

(5) Clinical hold of any investigation in-volving an exception from informed con-sent under § 50.24 of this chapter. FDA


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21 CFR Ch. I (4–1–99 Edition)§ 312.42

may place a proposed or ongoing inves-tigation involving an exception frominformed consent under § 50.24 of thischapter on clinical hold if it is deter-mined that:

(i) Any of the conditions in para-graphs (b)(1) or (b)(2) of this sectionapply; or

(ii) The pertinent criteria in § 50.24 ofthis chapter for such an investigationto begin or continue are not submittedor not satisfied.

(c) Discussion of deficiency. WheneverFDA concludes that a deficiency existsin a clinical investigation that may begrounds for the imposition of clinicalhold FDA will, unless patients are ex-posed to immediate and serious risk,attempt to discuss and satisfactorilyresolve the matter with the sponsor be-fore issuing the clinical hold order.

(d) Imposition of clinical hold. Theclinical hold order may be made bytelephone or other means of rapid com-munication or in writing. The clinicalhold order will identify the studiesunder the IND to which the hold ap-plies, and will briefly explain the basisfor the action. The clinical hold orderwill be made by or on behalf of the Di-vision Director with responsibility forreview of the IND. As soon as possible,and no more than 30 days after imposi-tion of the clinical hold, the DivisionDirector will provide the sponsor awritten explanation of the basis for thehold.

(e) Resumption of clinical investiga-tions. An investigation may only re-sume after FDA (usually the DivisionDirector, or the Director’s designee,with responsibility for review of theIND) has notified the sponsor that theinvestigation may proceed. Resump-tion of the affected investigation(s)will be authorized when the sponsorcorrects the deficiency(ies) previouslycited or otherwise satisfies the agencythat the investigation(s) can proceed.FDA may notify a sponsor of its deter-mination regarding the clinical hold bytelephone or other means of rapid com-munication. If a sponsor of an IND thathas been placed on clinical hold re-quests in writing that the clinical holdbe removed and submits a complete re-sponse to the issue(s) identified in theclinical hold order, FDA shall respondin writing to the sponsor within 30-cal-

endar days of receipt of the request andthe complete response. FDA’s responsewill either remove or maintain theclinical hold, and will state the reasonsfor such determination. Notwith-standing the 30-calendar day responsetime, a sponsor may not proceed with aclinical trial on which a clinical holdhas been imposed until the sponsor hasbeen notified by FDA that the hold hasbeen lifted.

(f) Appeal. If the sponsor disagreeswith the reasons cited for the clinicalhold, the sponsor may request recon-sideration of the decision in accord-ance with § 312.48.

(g) Conversion of IND on clinical holdto inactive status. If all investigationscovered by an IND remain on clinicalhold for 1 year or more, the IND maybe placed on inactive status by FDAunder § 312.45.

[52 FR 8831, Mar. 19, 1987, as amended at 52FR 19477, May 22, 1987; 57 FR 13249, Apr. 15,1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678,Dec. 14, 1998]

EFFECTIVE DATE NOTE: At 63 FR 68678, Dec.14, 1998, § 312.42 was amended by revisingparagraph (e), effective Apr. 28, 1999. For theconvenience of the user, the superseded textfollows:

§ 312.42 Clinical holds and requests formodification.

* * * * *

(e) Resumption of clinical investigations. If,by the terms of the clinical hold order, re-sumption of the affected investigation is per-mitted without prior notification by FDAonce a stated correction or modification ismade, the investigation may proceed as soonas the correction or modification is made. Inall other cases, an investigation may onlyresume after the Division Director (or theDirector’s designee) with responsibility forreview of the IND has notified the sponsorthat the investigation may proceed. In thesecases resumption of the affected investiga-tion(s) will be authorized when the sponsorcorrects the deficiency(ies) previously citedor otherwise satisfied the agency that the in-vestigation(s) can proceed. Resumption of astudy may be authorized by telephone orother means of rapid communication.

* * * * *


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§ 312.44 Termination.

(a) General. This section describes theprocedures under which FDA may ter-minate an IND. If an IND is termi-nated, the sponsor shall end all clinicalinvestigations conducted under theIND and recall or otherwise provide forthe disposition of all unused supplies ofthe drug. A termination action may bebased on deficiencies in the IND or inthe conduct of an investigation underan IND. Except as provided in para-graph (d) of this section, a terminationshall be preceded by a proposal to ter-minate by FDA and an opportunity forthe sponsor to respond. FDA will, ingeneral, only initiate an action underthis section after first attempting toresolve differences informally or, whenappropriate, through the clinical holdprocedures described in § 312.42.

(b) Grounds for termination—(1) Phase1. FDA may propose to terminate anIND during Phase 1 if it finds that:

(i) Human subjects would be exposedto an unreasonable and significant riskof illness or unjury.

(ii) The IND does not contain suffi-cient information required under§ 312.23 to assess the safety to subjectsof the clinical investigations.

(iii) The methods, facilities, and con-trols used for the manufacturing, proc-essing, and packing of the investiga-tional drug are inadequate to establishand maintain appropriate standards ofidentity, strength, quality, and purityas needed for subject safety.

(iv) The clinical investigations arebeing conducted in a manner substan-tially different than that described inthe protocols submitted in the IND.

(v) The drug is being promoted or dis-tributed for commercial purposes notjustified by the requirements of the in-vestigation or permitted by § 312.7.

(vi) The IND, or any amendment orreport to the IND, contains an untruestatement of a material fact or omitsmaterial information required by thispart.

(vii) The sponsor fails promptly to in-vestigate and inform the Food andDrug Administration and all investiga-tors of serious and unexpected adverseexperiences in accordance with § 312.32or fails to make any other report re-quired under this part.

(viii) The sponsor fails to submit anaccurate annual report of the inves-tigations in accordance with § 312.33.

(ix) The sponsor fails to comply withany other applicable requirement ofthis part, part 50, or part 56.

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

(xi) The sponsor fails to delay a pro-posed investigation under the IND orto suspend an ongoing investigationthat has been placed on clinical holdunder § 312.42(b)(4).

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

(i) Any of the conditions in para-graphs (b)(1)(i) through (b)(1)(xi) of thissection apply; or

(ii) The investigational plan or pro-tocol(s) is not reasonable as a bona fidescientific plan to determine whether ornot the drug is safe and effective foruse; or

(iii) There is convincing evidencethat the drug is not effective for thepurpose for which it is being inves-tigated.

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

(i) Any of the conditions in para-graphs (b)(1)(i) through (x) of this sec-tion apply; or

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

(c) Opportunity for sponsor response.(1) If FDA proposes to terminate anIND, FDA will notify the sponsor inwriting, and invite correction or expla-nation within a period of 30 days.

(2) On such notification, the sponsormay provide a written explanation orcorrection or may request a conferencewith FDA to provide the requested ex-planation or correction. If the sponsordoes not respond to the notificationwithin the allocated time, the INDshall be terminated.

(3) If the sponsor responds but FDAdoes not accept the explanation or cor-rection submitted, FDA shall informthe sponsor in writing of the reason forthe nonacceptance and provide thesponsor with an opportunity for a regu-latory hearing before FDA under part16 on the question of whether the INDshould be terminated. The sponsor’s re-quest for a regulatory hearing must bemade within 10 days of the sponsor’s


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21 CFR Ch. I (4–1–99 Edition)§ 312.45

receipt of FDA’s notification of non-acceptance.

(d) Immediate termination of IND. Not-withstanding paragraphs (a) through(c) of this section, if at any time FDAconcludes that continuation of the in-vestigation presents an immediate andsubstantial danger to the health of in-dividuals, the agency shall imme-diately, by written notice to the spon-sor from the Director of the Center forDrug Evaluation and Research or theDirector of the Center for BiologicsEvaluation and Research, terminatethe IND. An IND so terminated is sub-ject to reinstatement by the Directoron the basis of additional submissionsthat eliminate such danger. If an INDis terminated under this paragraph, theagency will afford the sponsor an op-portunity for a regulatory hearingunder part 16 on the question of wheth-er the IND should be reinstated.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 55 FR 11579, Mar. 29,1990; 57 FR 13249, Apr. 15, 1992]

§ 312.45 Inactive status.

(a) If no subjects are entered intoclinical studies for a period of 2 yearsor more under an IND, or if all inves-tigations under an IND remain on clin-ical hold for 1 year or more, the INDmay be placed by FDA on inactive sta-tus. This action may be taken by FDAeither on request of the sponsor or onFDA’s own initiative. If FDA seeks toact on its own initiative under this sec-tion, it shall first notify the sponsor inwriting of the proposed inactive status.Upon receipt of such notification, thesponsor shall have 30 days to respondas to why the IND should continue toremain active.

(b) If an IND is placed on inactivestatus, all investigators shall be so no-tified and all stocks of the drug shallbe returned or otherwise disposed of inaccordance with § 312.59.

(c) A sponsor is not required to sub-mit annual reports to an IND on inac-tive status. An inactive IND is, how-ever, still in effect for purposes of thepublic disclosure of data and informa-tion under § 312.130.

(d) A sponsor who intends to resumeclinical investigation under an INDplaced on inactive status shall submita protocol amendment under § 312.30containing the proposed general inves-tigational plan for the coming year andappropriate protocols. If the protocolamendment relies on information pre-viously submitted, the plan shall ref-erence such information. Additional in-formation supporting the proposed in-vestigation, if any, shall be submittedin an information amendment. Not-withstanding the provisions of § 312.30,clinical investigations under an IND oninactive status may only resume (1) 30days after FDA receives the protocolamendment, unless FDA notifies thesponsor that the investigations de-scribed in the amendment are subjectto a clinical hold under § 312.42, or (2)on earlier notification by FDA that theclinical investigations described in theprotocol amendment may begin.

(e) An IND that remains on inactivestatus for 5 years or more may be ter-minated under § 312.44.



§ 312.47 Meetings.(a) General. Meetings between a spon-

sor and the agency are frequently use-ful in resolving questions and issuesraised during the course of a clinicalinvestigation. FDA encourages suchmeetings to the extent that they aid inthe evaluation of the drug and in thesolution of scientific problems con-cerning the drug, to the extent thatFDA’s resources permit. The generalprinciple underlying the conduct ofsuch meetings is that there should befree, full, and open communicationabout any scientific or medical ques-tion that may arise during the clinicalinvestigation. These meetings shall beconducted and documented in accord-ance with part 10.

(b) ‘‘End-of-Phase 2’’ meetings andmeetings held before submission of a mar-keting application. At specific timesduring the drug investigation process,meetings between FDA and a sponsorcan be especially helpful in minimizingwasteful expenditures of time and


81


money and thus in speeding the drugdevelopment and evaluation process. Inparticular, FDA has found that meet-ings at the end of Phase 2 of an inves-tigation (end-of-Phase 2 meetings) areof considerable assistance in planninglater studies and that meetings heldnear completion of Phase 3 and beforesubmission of a marketing application(‘‘pre-NDA’’ meetings) are helpful indeveloping methods of presentationand submission of data in the mar-keting application that facilitate re-view and allow timely FDA response.

(1) End-of-Phase 2 meetings—(i) Pur-pose. The purpose of an end-of-phase 2meeting is to determine the safety ofproceeding to Phase 3, to evaluate thePhase 3 plan and protocols and the ade-quacy of current studies and plans toassess pediatric safety and effective-ness, and to identify any additional in-formation necessary to support a mar-keting application for the uses underinvestigation.

(ii) Eligibility for meeting. While theend-of-Phase 2 meeting is designed pri-marily for IND’s involving new molec-ular entities or major new uses of mar-keted drugs, a sponsor of any IND mayrequest and obtain an end-of-Phase 2meeting.

(iii) Timing. To be most useful to thesponsor, end-of-Phase 2 meetingsshould be held before major commit-ments of effort and resources to spe-cific Phase 3 tests are made. The sched-uling of an end-of-Phase 2 meeting isnot, however, intended to delay thetransition of an investigation fromPhase 2 to Phase 3.

(iv) Advance information. At least 1month in advance of an end-of-Phase 2meeting, the sponsor should submitbackground information on the spon-sor’s plan for Phase 3, including sum-maries of the Phase 1 and 2 investiga-tions, the specific protocols for Phase 3clinical studies, plans for any addi-tional nonclinical studies, plans for pe-diatric studies, including a time linefor protocol finalization, enrollment,completion, and data analysis, or infor-mation to support any planned requestfor waiver or deferral of pediatric stud-ies, and, if available, tentative labelingfor the drug. The recommended con-tents of such a submission are de-scribed more fully in FDA Staff Man-

ual Guide 4850.7 that is publicly avail-able under FDA’s public informationregulations in part 20.

(v) Conduct of meeting. Arrangementsfor an end-of-Phase 2 meeting are to bemade with the division in FDA’s Centerfor Drug Evaluation and Research orthe Center for Biologics Evaluationand Research which is responsible forreview of the IND. The meeting will bescheduled by FDA at a time convenientto both FDA and the sponsor. Both thesponsor and FDA may bring consult-ants to the meeting. The meetingshould be directed primarily at estab-lishing agreement between FDA andthe sponsor of the overall plan forPhase 3 and the objectives and designof particular studies. The adequacy ofthe technical information to supportPhase 3 studies and/or a marketing ap-plication may also be discussed. FDAwill also provide its best judgment, atthat time, of the pediatric studies thatwill be required for the drug productand whether their submission will bedeferred until after approval. Agree-ments reached at the meeting on thesematters will be recorded in minutes ofthe conference that will be taken byFDA in accordance with § 10.65 and pro-vided to the sponsor. The minutesalong with any other written materialprovided to the sponsor will serve as apermanent record of any agreementsreached. Barring a significant sci-entific development that requires oth-erwise, studies conducted in accord-ance with the agreement shall be pre-sumed to be sufficient in objective anddesign for the purpose of obtainingmarketing approval for the drug.

(2) ‘‘Pre-NDA’’ and ‘‘pre-BLA’’ meet-ings. FDA has found that delays associ-ated with the initial review of a mar-keting application may be reduced byexchanges of information about a pro-posed marketing application. The pri-mary purpose of this kind of exchangeis to uncover any major unresolvedproblems, to identify those studies thatthe sponsor is relying on as adequateand well-controlled to establish thedrug’s effectiveness, to identify thestatus of ongoing or needed studiesadequate to assess pediatric safety andeffectiveness, to acquaint FDA review-ers with the general information to be


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21 CFR Ch. I (4–1–99 Edition)§ 312.48

submitted in the marketing applica-tion (including technical information),to discuss appropriate methods for sta-tistical analysis of the data, and to dis-cuss the best approach to the presen-tation and formatting of data in themarketing application. Arrangementsfor such a meeting are to be initiatedby the sponsor with the division re-sponsible for review of the IND. To per-mit FDA to provide the sponsor withthe most useful advice on preparing amarketing application, the sponsorshould submit to FDA’s reviewing divi-sion at least 1 month in advance of themeeting the following information:

(i) A brief summary of the clinicalstudies to be submitted in the applica-tion.

(ii) A proposed format for organizingthe submission, including methods forpresenting the data.

(iii) Information on the status ofneeded or ongoing pediatric studies.

(iv) Any other information for discus-sion at the meeting.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,1990; 63 FR 66669, Dec. 2, 1998]

§ 312.48 Dispute resolution.(a) General. The Food and Drug Ad-

ministration is committed to resolvingdifferences between sponsors and FDAreviewing divisions with respect to re-quirements for IND’s as quickly andamicably as possible through the coop-erative exchange of information andviews.

(b) Administrative and proceduralissues. When administrative or proce-dural disputes arise, the sponsor shouldfirst attempt to resolve the matterwith the division in FDA’s Center forDrug Evaluation and Research or Cen-ter for Biologics Evaluation and Re-search which is responsible for reviewof the IND, beginning with the con-sumer safety officer assigned to the ap-plication. If the dispute is not resolved,the sponsor may raise the matter withthe person designated as ombudsman,whose function shall be to investigatewhat has happened and to facilitate atimely and equitable resolution. Appro-priate issues to raise with the ombuds-

man include resolving difficulties inscheduling meetings and obtainingtimely replies to inquiries. Further de-tails on this procedure are contained inFDA Staff Manual Guide 4820.7 that ispublicly available under FDA’s publicinformation regulations in part 20.

(c) Scientific and medical disputes. (1)When scientific or medical disputesarise during the drug investigationprocess, sponsors should discuss thematter directly with the responsiblereviewing officials. If necessary, spon-sors may request a meeting with theappropriate reviewing officials andmanagement representatives in orderto seek a resolution. Requests for suchmeetings shall be directed to the direc-tor of the division in FDA’s Center forDrug Evaluation and Research or Cen-ter for Biologics Evaluation and Re-search which is responsible for reviewof the IND. FDA will make every at-tempt to grant requests for meetingsthat involve important issues and thatcan be scheduled at mutually conven-ient times.

(2) The ‘‘end-of-Phase 2’’ and ‘‘pre-NDA’’ meetings described in § 312.47(b)will also provide a timely forum fordiscussing and resolving scientific andmedical issues on which the sponsordisagrees with the agency.

(3) In requesting a meeting designedto resolve a scientific or medical dis-pute, applicants may suggest that FDAseek the advice of outside experts, inwhich case FDA may, in its discretion,invite to the meeting one or more of itsadvisory committee members or otherconsultants, as designated by the agen-cy. Applicants may rely on, and maybring to any meeting, their own con-sultants. For major scientific and med-ical policy issues not resolved by infor-mal meetings, FDA may refer the mat-ter to one of its standing advisory com-mittees for its consideration and rec-ommendations.

[52 FR 8831, Mar. 19, 1987, as amended at 55FR 11580, Mar. 29, 1990]

Subpart D—Responsibilities ofSponsors and Investigators

§ 312.50 General responsibilities ofsponsors.

Sponsors are responsibile for select-ing qualified investigators, providing


83


them with the information they needto conduct an investigation properly,ensuring proper monitoring of the in-vestigation(s), ensuring that the inves-tigation(s) is conducted in accordancewith the general investigational planand protocols contained in the IND,maintaining an effective IND with re-spect to the investigations, and ensur-ing that FDA and all participating in-vestigators are promptly informed ofsignificant new adverse effects or riskswith respect to the drug. Additionalspecific responsibilities of sponsors aredescribed elsewhere in this part.

§ 312.52 Transfer of obligations to acontract research organization.

(a) A sponsor may transfer responsi-bility for any or all of the obligationsset forth in this part to a contract re-search organization. Any such transfershall be described in writing. If not allobligations are transferred, the writingis required to describe each of the obli-gations being assumed by the contractresearch organization. If all obligationsare transferred, a general statementthat all obligations have been trans-ferred is acceptable. Any obligation notcovered by the written descriptionshall be deemed not to have been trans-ferred.

(b) A contract research organizationthat assumes any obligation of a spon-sor shall comply with the specific regu-lations in this chapter applicable tothis obligation and shall be subject tothe same regulatory action as a spon-sor for failure to comply with any obli-gation assumed under these regula-tions. Thus, all references to ‘‘sponsor’’in this part apply to a contract re-search organization to the extent thatit assumes one or more obligations ofthe sponsor.

§ 312.53 Selecting investigators andmonitors.

(a) Selecting investigators. A sponsorshall select only investigators qualifiedby training and experience as appro-priate experts to investigate the drug.

(b) Control of drug. A sponsor shallship investigational new drugs only toinvestigators participating in the in-vestigation.

(c) Obtaining information from the in-vestigator. Before permitting an investi-

gator to begin participation in an in-vestigation, the sponsor shall obtainthe following:

(1) A signed investigator statement(Form FDA–1572) containing:

(i) The name and address of the in-vestigator;

(ii) The name and code number, ifany, of the protocol(s) in the IND iden-tifying the study(ies) to be conductedby the investigator;

(iii) The name and address of anymedical school, hospital, or other re-search facility where the clinical inves-tigation(s) will be conducted;

(iv) The name and address of anyclinical laboratory facilities to be usedin the study;

(v) The name and address of the IRBthat is responsible for review and ap-proval of the study(ies);

(vi) A commitment by the investi-gator that he or she:

(a) Will conduct the study(ies) in ac-cordance with the relevant, currentprotocol(s) and will only make changesin a protocol after notifying the spon-sor, except when necessary to protectthe safety, the rights, or welfare ofsubjects;

(b) Will comply with all requirementsregarding the obligations of clinical in-vestigators and all other pertinent re-quirements in this part;

(c) Will personally conduct or super-vise the described investigation(s);

(d) Will inform any potential subjectsthat the drugs are being used for inves-tigational purposes and will ensurethat the requirements relating to ob-taining informed consent (21 CFR part50) and institutional review board re-view and approval (21 CFR part 56) aremet;

(e) Will report to the sponsor adverseexperiences that occur in the course ofthe investigation(s) in accordance with§ 312.64;

(f) Has read and understands the in-formation in the investigator’s bro-chure, including the potential risksand side effects of the drug; and

(g) Will ensure that all associates,colleagues, and employees assisting inthe conduct of the study(ies) are in-formed about their obligations inmeeting the above commitments.

(vii) A commitment by the investi-gator that, for an investigation subject


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to an institutional review requirementunder part 56, an IRB that complieswith the requirements of that part willbe responsible for the initial and con-tinuing review and approval of the clin-ical investigation and that the investi-gator will promptly report to the IRBall changes in the research activity andall unanticipated problems involvingrisks to human subjects or others, andwill not make any changes in the re-search without IRB approval, exceptwhere necessary to eliminate apparentimmediate hazards to the human sub-jects.

(viii) A list of the names of the sub-investigators (e.g., research fellows,residents) who will be assisting the in-vestigator in the conduct of the inves-tigation(s).

(2) Curriculum vitae. A curriculumvitae or other statement of qualifica-tions of the investigator showing theeducation, training, and experiencethat qualifies the investigator as an ex-pert in the clinical investigation of thedrug for the use under investigation.

(3) Clinical protocol. (i) For Phase 1 in-vestigations, a general outline of theplanned investigation including the es-timated duration of the study and themaximum number of subjects that willbe involved.

(ii) For Phase 2 or 3 investigations,an outline of the study protocol includ-ing an approximation of the number ofsubjects to be treated with the drugand the number to be employed as con-trols, if any; the clinical uses to be in-vestigated; characteristics of subjectsby age, sex, and condition; the kind ofclinical observations and laboratorytests to be conducted; the estimatedduration of the study; and copies or adescription of case report forms to beused.

(4) Financial disclosure information.Sufficient accurate financial informa-tion to allow the sponsor to submitcomplete and accurate certification ordisclosure statements required underpart 54 of this chapter. The sponsorshall obtain a commitment from theclinical investigator to promptly up-date this information if any relevantchanges occur during the course of theinvestigation and for 1 year followingthe completion of the study.

(d) Selecting monitors. A sponsor shallselect a monitor qualified by trainingand experience to monitor the progressof the investigation.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 61 FR 57280, Nov. 5,1996; 63 FR 5252, Feb. 2, 1998]

§ 312.54 Emergency research under§ 50.24 of this chapter.

(a) The sponsor shall monitor theprogress of all investigations involvingan exception from informed consentunder § 50.24 of this chapter. When thesponsor receives from the IRB informa-tion concerning the public disclosuresrequired by § 50.24(a)(7)(ii) and (a)(7)(iii)of this chapter, the sponsor promptlyshall submit to the IND file and toDocket Number 95S–0158 in the DocketsManagement Branch (HFA–305), Foodand Drug Administration, 12420 Park-lawn Dr., rm. 1–23, Rockville, MD 20857,copies of the information that was dis-closed, identified by the IND number.

(b) The sponsor also shall monitorsuch investigations to identify when anIRB determines that it cannot approvethe research because it does not meetthe criteria in the exception in§ 50.24(a) of this chapter or because ofother relevant ethical concerns. Thesponsor promptly shall provide this in-formation in writing to FDA, inves-tigators who are asked to participatein this or a substantially equivalentclinical investigation, and other IRB’sthat are asked to review this or a sub-stantially equivalent investigation.

[61 FR 51530, Oct. 2, 1996]

§ 312.55 Informing investigators.(a) Before the investigation begins, a

sponsor (other than a sponsor-investi-gator) shall give each participatingclinical investigator an investigatorbrochure containing the informationdescribed in § 312.23(a)(5).

(b) The sponsor shall, as the overallinvestigation proceeds, keep each par-ticipating investigator informed of newobservations discovered by or reportedto the sponsor on the drug, particu-larly with respect to adverse effectsand safe use. Such information may be


85


distributed to investigators by meansof periodically revised investigatorbrochures, reprints or published stud-ies, reports or letters to clinical inves-tigators, or other appropriate means.Important safety information is re-quired to be relayed to investigators inaccordance with § 312.32.



§ 312.56 Review of ongoing investiga-tions.

(a) The sponsor shall monitor theprogress of all clinical investigationsbeing conducted under its IND.

(b) A sponsor who discovers that aninvestigator is not complying with thesigned agreement (Form FDA–1572), thegeneral investigational plan, or the re-quirements of this part or other appli-cable parts shall promptly either se-cure compliance or discontinue ship-ments of the investigational new drugto the investigator and end the inves-tigator’s participation in the investiga-tion. If the investigator’s participationin the investigation is ended, the spon-sor shall require that the investigatordispose of or return the investigationaldrug in accordance with the require-ments of § 312.59 and shall notify FDA.

(c) The sponsor shall review andevaluate the evidence relating to thesafety and effectiveness of the drug asit is obtained from the investigator.The sponsors shall make such reportsto FDA regarding information relevantto the safety of the drug as are re-quired under § 312.32. The sponsor shallmake annual reports on the progress ofthe investigation in accordance with§ 312.33.

(d) A sponsor who determines that itsinvestigational drug presents an unrea-sonable and significant risk to subjectsshall discontinue those investigationsthat present the risk, notify FDA, allinstitutional review boards, and all in-vestigators who have at any time par-ticipated in the investigation of thediscontinuance, assure the dispositionof all stocks of the drug outstanding asrequired by § 312.59, and furnish FDAwith a full report of the sponsor’s ac-tions. The sponsor shall discontinue

the investigation as soon as possible,and in no event later than 5 workingdays after making the determinationthat the investigation should be dis-continued. Upon request, FDA will con-fer with a sponsor on the need to dis-continue an investigation.



§ 312.57 Recordkeeping and record re-tention.

(a) A sponsor shall maintain ade-quate records showing the receipt,shipment, or other disposition of theinvestigational drug. These records arerequired to include, as appropriate, thename of the investigator to whom thedrug is shipped, and the date, quantity,and batch or code mark of each suchshipment.

(b) A sponsor shall maintain com-plete and accurate records showing anyfinancial interest in § 54.4(a)(3)(i),(a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of thischapter paid to clinical investigatorsby the sponsor of the covered study. Asponsor shall also maintain completeand accurate records concerning allother financial interests of investiga-tors subject to part 54 of this chapter.

(c) A sponsor shall retain the recordsand reports required by this part for 2years after a marketing application isapproved for the drug; or, if an applica-tion is not approved for the drug, until2 years after shipment and delivery ofthe drug for investigational use is dis-continued and FDA has been so noti-fied.

(d) A sponsor shall retain reservesamples of any test article and ref-erence standard identified in, and usedin any of the bioequivalence or bio-availability studies described in,§ 320.38 or § 320.63 of this chapter, andrelease the reserve samples to FDAupon request, in accordance with, andfor the period specified in § 320.38.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 58 FR 25926, Apr. 28,1993; 63 FR 5252, Feb. 2, 1998]


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21 CFR Ch. I (4–1–99 Edition)§ 312.58

§ 312.58 Inspection of sponsor’srecords and reports.

(a) FDA inspection. A sponsor shallupon request from any properly au-thorized officer or employee of theFood and Drug Administration, at rea-sonable times, permit such officer oremployee to have access to and copyand verify any records and reports re-lating to a clinical investigation con-ducted under this part. Upon writtenrequest by FDA, the sponsor shall sub-mit the records or reports (or copies ofthem) to FDA. The sponsor shall dis-continue shipments of the drug to anyinvestigator who has failed to maintainor make available records or reports ofthe investigation as required by thispart.

(b) Controlled substances. If an inves-tigational new drug is a substance list-ed in any schedule of the ControlledSubstances Act (21 U.S.C. 801; 21 CFRpart 1308), records concerning ship-ment, delivery, receipt, and dispositionof the drug, which are required to bekept under this part or other applica-ble parts of this chapter shall, upon therequest of a properly authorized em-ployee of the Drug Enforcement Ad-ministration of the U.S. Department ofJustice, be made available by the in-vestigator or sponsor to whom the re-quest is made, for inspection and copy-ing. In addition, the sponsor shall as-sure that adequate precautions aretaken, including storage of the inves-tigational drug in a securely locked,substantially constructed cabinet, orother securely locked, substantiallyconstructed enclosure, access to whichis limited, to prevent theft or diversionof the substance into illegal channelsof distribution.

§ 312.59 Disposition of unused supplyof investigational drug.

The sponsor shall assure the returnof all unused supplies of the investiga-tional drug from each individual inves-tigator whose participation in the in-vestigation is discontinued or termi-nated. The sponsor may authorize al-ternative disposition of unused suppliesof the investigational drug providedthis alternative disposition does notexpose humans to risks from the drug.The sponsor shall maintain written

records of any disposition of the drugin accordance with § 312.57.



§ 312.60 General responsibilities of in-vestigators.

An investigator is responsible for en-suring that an investigation is con-ducted according to the signed investi-gator statement, the investigationalplan, and applicable regulations; forprotecting the rights, safety, and wel-fare of subjects under the investiga-tor’s care; and for the control of drugsunder investigation. An investigatorshall, in accordance with the provi-sions of part 50 of this chapter, obtainthe informed consent of each humansubject to whom the drug is adminis-tered, except as provided in §§ 50.23 or50.24 of this chapter. Additional spe-cific responsibilities of clinical inves-tigators are set forth in this part andin parts 50 and 56 of this chapter.

[52 FR 8831, Mar. 19, 1987, as amended at 61FR 51530, Oct. 2, 1996]

§ 312.61 Control of the investigationaldrug.

An investigator shall administer thedrug only to subjects under the inves-tigator’s personal supervision or underthe supervision of a subinvestigator re-sponsible to the investigator. The in-vestigator shall not supply the inves-tigational drug to any person not au-thorized under this part to receive it.

§ 312.62 Investigator recordkeepingand record retention.

(a) Disposition of drug. An investi-gator is required to maintain adequaterecords of the disposition of the drug,including dates, quantity, and use bysubjects. If the investigation is termi-nated, suspended, discontinued, orcompleted, the investigator shall re-turn the unused supplies of the drug tothe sponsor, or otherwise provide fordisposition of the unused supplies ofthe drug under § 312.59.

(b) Case histories. An investigator isrequired to prepare and maintain ade-quate and accurate case histories that


87


record all observations and other datapertinent to the investigation on eachindividual administered the investiga-tional drug or employed as a control inthe investigation. Case histories in-clude the case report forms and sup-porting data including, for example,signed and dated consent forms andmedical records including, for example,progress notes of the physician, the in-dividual’s hospital chart(s), and thenurses’ notes. The case history for eachindividual shall document that in-formed consent was obtained prior toparticipation in the study.

(c) Record retention. An investigatorshall retain records required to bemaintained under this part for a periodof 2 years following the date a mar-keting application is approved for thedrug for the indication for which it isbeing investigated; or, if no applicationis to be filed or if the application is notapproved for such indication, until 2years after the investigation is discon-tinued and FDA is notified.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 61 FR 57280, Nov. 5,1996]

§ 312.64 Investigator reports.(a) Progress reports. The investigator

shall furnish all reports to the sponsorof the drug who is responsible for col-lecting and evaluating the results ob-tained. The sponsor is required under§ 312.33 to submit annual reports toFDA on the progress of the clinical in-vestigations.

(b) Safety reports. An investigatorshall promptly report to the sponsorany adverse effect that may reasonablybe regarded as caused by, or probablycaused by, the drug. If the adverse ef-fect is alarming, the investigator shallreport the adverse effect immediately.

(c) Final report. An investigator shallprovide the sponsor with an adequatereport shortly after completion of theinvestigator’s participation in the in-vestigation.

(d) Financial disclosure reports. Theclinical investigator shall provide thesponsor with sufficient accurate finan-cial information to allow an applicantto submit complete and accurate cer-

tification or disclosure statements asrequired under part 54 of this chapter.The clinical investigator shall prompt-ly update this information if any rel-evant changes occur during the courseof the investigation and for 1 year fol-lowing the completion of the study.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 63 FR 5252, Feb. 2,1998]

§ 312.66 Assurance of IRB review.

An investigator shall assure that anIRB that complies with the require-ments set forth in part 56 will be re-sponsible for the initial and continuingreview and approval of the proposedclinical study. The investigator shallalso assure that he or she will prompt-ly report to the IRB all changes in theresearch activity and all unanticipatedproblems involving risk to human sub-jects or others, and that he or she willnot make any changes in the researchwithout IRB approval, except wherenecessary to eliminate apparent imme-diate hazards to human subjects.



§ 312.68 Inspection of investigator’srecords and reports.

An investigator shall upon requestfrom any properly authorized officer oremployee of FDA, at reasonable times,permit such officer or employee tohave access to, and copy and verify anyrecords or reports made by the investi-gator pursuant to § 312.62. The investi-gator is not required to divulge subjectnames unless the records of particularindividuals require a more detailedstudy of the cases, or unless there isreason to believe that the records donot represent actual case studies, or donot represent actual results obtained.

§ 312.69 Handling of controlled sub-stances.

If the investigational drug is subjectto the Controlled Substances Act, the


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21 CFR Ch. I (4–1–99 Edition)§ 312.70

investigator shall take adequate pre-cautions, including storage of the in-vestigational drug in a securely locked,substantially constructed cabinet, orother securely locked, substantiallyconstructed enclosure, access to whichis limited, to prevent theft or diversionof the substance into illegal channelsof distribution.

§ 312.70 Disqualification of a clinicalinvestigator.

(a) If FDA has information indicatingthat an investigator (including a spon-sor-investigator) has repeatedly or de-liberately failed to comply with the re-quirements of this part, part 50, or part56 of this chapter, or has submitted toFDA or to the sponsor false informa-tion in any required report, the Centerfor Drug Evaluation and Research orthe Center for Biologics Evaluationand Research will furnish the investi-gator written notice of the mattercomplained of and offer the investi-gator an opportunity to explain thematter in writing, or, at the option ofthe investigator, in an informal con-ference. If an explanation is offered butnot accepted by the Center for DrugEvaluation and Research or the Centerfor Biologics Evaluation and Research,the investigator will be given an oppor-tunity for a regulatory hearing underpart 16 on the question of whether theinvestigator is entitled to receive in-vestigational new drugs.

(b) After evaluating all available in-formation, including any explanationpresented by the investigator, if theCommissioner determines that the in-vestigator has repeatedly or delib-erately failed to comply with the re-quirements of this part, part 50, or part56 of this chapter, or has deliberatelyor repeatedly submitted false informa-tion to FDA or to the sponsor in anyrequired report, the Commissioner willnotify the investigator and the sponsorof any investigation in which the in-vestigator has been named as a partici-pant that the investigator is not enti-tled to receive investigational drugs.The notification will provide a state-ment of basis for such determination.

(c) Each IND and each approved ap-plication submitted under part 314 con-taining data reported by an investi-gator who has been determined to be

ineligible to receive investigationaldrugs will be examined to determinewhether the investigator has submittedunreliable data that are essential tothe continuation of the investigationor essential to the approval of anymarketing application.

(d) If the Commissioner determines,after the unreliable data submitted bythe investigator are eliminated fromconsideration, that the data remainingare inadequate to support a conclusionthat it is reasonably safe to continuethe investigation, the Commissionerwill notify the sponsor who shall havean opportunity for a regulatory hear-ing under part 16. If a danger to thepublic health exists, however, the Com-missioner shall terminate the IND im-mediately and notify the sponsor of thedetermination. In such case, the spon-sor shall have an opportunity for a reg-ulatory hearing before FDA under part16 on the question of whether the INDshould be reinstated.

(e) If the Commissioner determines,after the unreliable data submitted bythe investigator are eliminated fromconsideration, that the continued ap-proval of the drug product for whichthe data were submitted cannot be jus-tified, the Commissioner will proceedto withdraw approval of the drug prod-uct in accordance with the applicableprovisions of the act.

(f) An investigator who has been de-termined to be ineligible to receive in-vestigational drugs may be reinstatedas eligible when the Commissioner de-termines that the investigator has pre-sented adequate assurances that the in-vestigator will employ investigatioaldrugs solely in compliance with theprovisions of this part and of parts 50and 56.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,1990; 62 FR 46876, Sept. 5, 1997]

Subpart E—Drugs Intended toTreat Life-threatening and Se-verely-debilitating Illnesses

AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371;42 U.S.C. 262.


89


SOURCE: 53 FR 41523, Oct. 21, 1988, unlessotherwise noted.

§ 312.80 Purpose.The purpose of this section is to es-

tablish procedures designed to expeditethe development, evaluation, and mar-keting of new therapies intended totreat persons with life-threatening andseverely-debilitating illnesses, espe-cially where no satisfactory alter-native therapy exists. As stated§ 314.105(c) of this chapter, while thestatutory standards of safety and effec-tiveness apply to all drugs, the manykinds of drugs that are subject tothem, and the wide range of uses forthose drugs, demand flexibility in ap-plying the standards. The Food andDrug Administration (FDA) has deter-mined that it is appropriate to exercisethe broadest flexibility in applying thestatutory standards, while preservingappropriate guarantees for safety andeffectiveness. These procedures reflectthe recognition that physicians and pa-tients are generally willing to acceptgreater risks or side effects from prod-ucts that treat life-threatening and se-verely-debilitating illnesses, than theywould accept from products that treatless serious illnesses. These proceduresalso reflect the recognition that thebenefits of the drug need to be evalu-ated in light of the severity of the dis-ease being treated. The procedure out-lined in this section should be inter-preted consistent with that purpose.

§ 312.81 Scope.This section applies to new drug and

biological products that are being stud-ied for their safety and effectiveness intreating life-threatening or severely-debilitating diseases.

(a) For purposes of this section, theterm ‘‘life-threatening’’ means:

(1) Diseases or conditions where thelikelihood of death is high unless thecourse of the disease is interrupted;and

(2) Diseases or conditions with poten-tially fatal outcomes, where the endpoint of clinical trial analysis is sur-vival.

(b) For purposes of this section, theterm ‘‘severely debilitating’’ meansdiseases or conditions that cause majorirreversible morbidity.

(c) Sponsors are encouraged to con-sult with FDA on the applicability ofthese procedures to specific products.

[53 FR 41523, Oct. 21, 1988, as amended at 64FR 401, Jan. 5, 1999]

EFFECTIVE DATE NOTE: At 64 FR 401, Jan.5, 1999, § 312.81 was amended by removing ‘‘,antibiotic,’’ from the introductory text, ef-fective May 20, 1999.

§ 312.82 Early consultation.

For products intended to treat life-threatening or severely-debilitating ill-nesses, sponsors may request to meetwith FDA-reviewing officials early inthe drug development process to reviewand reach agreement on the design ofnecessary preclinical and clinical stud-ies. Where appropriate, FDA will inviteto such meetings one or more outsideexpert scientific consultants or advi-sory committee members. To the ex-tent FDA resources permit, agency re-viewing officials will honor requestsfor such meetings

(a) Pre-investigational new drug (IND)meetings. Prior to the submission of theinitial IND, the sponsor may request ameeting with FDA-reviewing officials.The primary purpose of this meeting isto review and reach agreement on thedesign of animal studies needed to ini-tiate human testing. The meeting mayalso provide an opportunity for dis-cussing the scope and design of phase 1testing, plans for studying the drugproduct in pediatric populations, andthe best approach for presentation andformatting of data in the IND.

(b) End-of-phase 1 meetings. When datafrom phase 1 clinical testing are avail-able, the sponsor may again request ameeting with FDA-reviewing officials.The primary purpose of this meeting isto review and reach agreement on thedesign of phase 2 controlled clinicaltrials, with the goal that such testingwill be adequate to provide sufficientdata on the drug’s safety and effective-ness to support a decision on its ap-provability for marketing, and to dis-cuss the need for, as well as the designand timing of, studies of the drug in pe-diatric patients. For drugs for life-threatening diseases, FDA will provideits best judgment, at that time, wheth-er pediatric studies will be requiredand whether their submission will be


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21 CFR Ch. I (4–1–99 Edition)§ 312.83

deferred until after approval. The pro-cedures outlined in § 312.47(b)(1) withrespect to end-of-phase 2 conferences,including documentation of agree-ments reached, would also be used forend-of-phase 1 meetings.

[53 FR 41523, Oct. 21, 1988, as amended at 63FR 66669, Dec. 2, 1998]

§ 312.83 Treatment protocols.If the preliminary analysis of phase 2

test results appears promising, FDAmay ask the sponsor to submit a treat-ment protocol to be reviewed under theprocedures and criteria listed in§§ 312.34 and 312.35. Such a treatmentprotocol, if requested and granted,would normally remain in effect whilethe complete data necessary for a mar-keting application are being assembledby the sponsor and reviewed by FDA(unless grounds exist for clinical holdof ongoing protocols, as provided in§ 312.42(b)(3)(ii)).

§ 312.84 Risk-benefit analysis in reviewof marketing applications for drugsto treat life-threatening and se-verely-debilitating illnesses.

(a) FDA’s application of the statu-tory standards for marketing approvalshall recognize the need for a medicalrisk-benefit judgment in making thefinal decision on approvability. As partof this evaluation, consistent with thestatement of purpose in § 312.80, FDAwill consider whether the benefits ofthe drug outweigh the known and po-tential risks of the drug and the needto answer remaining questions aboutrisks and benefits of the drug, takinginto consideration the severity of thedisease and the absence of satisfactoryalternative therapy.

(b) In making decisions on whetherto grant marketing approval for prod-ucts that have been the subject of anend-of-phase 1 meeting under § 312.82,FDA will usually seek the advice ofoutside expert scientific consultants oradvisory committees. Upon the filingof such a marketing application under§ 314.101 or part 601 of this chapter, FDAwill notify the members of the relevantstanding advisory committee of the ap-plication’s filing and its availabilityfor review.

(c) If FDA concludes that the datapresented are not sufficient for mar-

keting approval, FDA will issue (for adrug) a not approvable letter pursuantto § 314.120 of this chapter, or (for a bio-logic) a deficiencies letter consistentwith the biological product licensingprocedures. Such letter, in describingthe deficiencies in the application, willaddress why the results of the researchdesign agreed to under § 312.82, or insubsequent meetings, have not pro-vided sufficient evidence for marketingapproval. Such letter will also describeany recommendations made by the ad-visory committee regarding the appli-cation.

(d) Marketing applications submittedunder the procedures contained in thissection will be subject to the require-ments and procedures contained in part314 or part 600 of this chapter, as wellas those in this subpart.

§ 312.85 Phase 4 studies.Concurrent with marketing approval,

FDA may seek agreement from thesponsor to conduct certain post-marketing (phase 4) studies to delin-eate additional information about thedrug’s risks, benefits, and optimal use.These studies could include, but wouldnot be limited to, studying differentdoses or schedules of administrationthan were used in phase 2 studies, useof the drug in other patient popu-lations or other stages of the disease,or use of the drug over a longer periodof time.

§ 312.86 Focused FDA regulatory re-search.

At the discretion of the agency, FDAmay undertake focused regulatory re-search on critical rate-limiting aspectsof the preclinical, chemical/manufac-turing, and clinical phases of drug de-velopment and evaluation. When initi-ated, FDA will undertake such re-search efforts as a means for meeting apublic health need in facilitating thedevelopment of therapies to treat life-threatening or severely debilitating ill-nesses.

§ 312.87 Active monitoring of conductand evaluation of clinical trials.

For drugs covered under this section,the Commissioner and other agency of-ficials will monitor the progress of theconduct and evaluation of clinical


91


trials and be involved in facilitatingtheir appropriate progress.

§ 312.88 Safeguards for patient safety.All of the safeguards incorporated

within parts 50, 56, 312, 314, and 600 ofthis chapter designed to ensure thesafety of clinical testing and the safetyof products following marketing ap-proval apply to drugs covered by thissection. This includes the requirementsfor informed consent (part 50 of thischapter) and institutional reviewboards (part 56 of this chapter). Thesesafeguards further include the reviewof animal studies prior to initialhuman testing (§ 312.23), and the moni-toring of adverse drug experiencesthrough the requirements of IND safe-ty reports (§ 312.32), safety update re-ports during agency review of a mar-keting application (§ 314.50 of this chap-ter), and postmarketing adverse reac-tion reporting (§ 314.80 of this chapter).

Subpart F—Miscellaneous§ 312.110 Import and export require-

ments.(a) Imports. An investigational new

drug offered for import into the UnitedStates complies with the requirementsof this part if it is subject to an INDthat is in effect for it under § 312.40 and:(1) The consignee in the United Statesis the sponsor of the IND; (2) the con-signee is a qualified investigatornamed in the IND; or (3) the consigneeis the domestic agent of a foreign spon-sor, is responsible for the control anddistribution of the investigationaldrug, and the IND identifies the con-signee and describes what, if any, ac-tions the consignee will take with re-spect to the investigational drug.

(b) Exports. An investigational newdrug intended for export from theUnited States complies with the re-quirements of this part as follows:

(1) If an IND is in effect for the drugunder § 312.40 and each person who re-ceives the drug is an investigatornamed in the application; or

(2) If FDA authorizes shipment of thedrug for use in a clinical investigation.Authorization may be obtained as fol-lows:

(i) Through submission to the Inter-national Affairs Staff (HFY–50), Asso-

ciate Commissioner for Health Affairs,Food and Drug Administration, 5600Fishers Lane, Rockville, MD 20857, of awritten request from the person thatseeks to export the drug. A requestmust provide adequate informationabout the drug to satisfy FDA that thedrug is appropriate for the proposed in-vestigational use in humans, that thedrug will be used for investigationalpurposes only, and that the drug maybe legally used by that consignee in theimporting country for the proposed in-vestigational use. The request shallspecify the quantity of the drug to beshipped per shipment and the fre-quency of expected shipments. If FDAauthorizes exportation under this para-graph, the agency shall concurrentlynotify the government of the importingcountry of such authorization.

(ii) Through submission to the Inter-national Affairs Staff (HFY–50), Asso-ciate Commissioner for Health Affairs,Food and Drug Administration, 5600Fishers Lane, Rockville, MD 20857, of aformal request from an authorized offi-cial of the government of the countryto which the drug is proposed to beshipped. A request must specify thatthe foreign government has adequateinformation about the drug and theproposed investigational use, that thedrug will be used for investigationalpurposes only, and that the foreigngovernment is satisfied that the drugmay legally be used by the intendedconsignee in that country. Such a re-quest shall specify the quantity of drugto be shipped per shipment and the fre-quency of expected shipments.

(iii) Authorization to export an in-vestigational drug under paragraph(b)(2)(i) or (ii) of this section may berevoked by FDA if the agency findsthat the conditions underlying its au-thorization are not longer met.

(3) This paragraph applies only wherethe drug is to be used for the purpose ofclinical investigation.

(4) This paragraph does not apply tothe export of new drugs (including bio-logical products, antibiotic drugs, andinsulin) approved or authorized for ex-port under section 802 of the act (21U.S.C. 382) or section 351(h)(1)(A) of the


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21 CFR Ch. I (4–1–99 Edition)§ 312.120

Public Health Service Act (42 U.S.C.262(h)(1)(A)).


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999]

EFFECTIVE DATE NOTE: At 64 FR 401, Jan.5, 1999, § 312.110 was amended by revisingparagraph (b)(4) and by removing paragraph(b)(5), effective May 20, 1999. For the conven-ience of the user, the superseded text fol-lows:

§ 312.110 Import and export requirements.

* * * * *

(b) * * *(4) This paragraph does not apply to the

export of an antibiotic drug product shippedin accordance with the provisions of section801(d) of the act.

(5) This paragraph does not apply to theexport of new drugs (including biologicalproducts) approved for export under section802 of the act or section 351(h)(1)(A) of thePublic Health Service Act.

* * * * *

§ 312.120 Foreign clinical studies notconducted under an IND.

(a) Introduction. This section de-scribes the criteria for acceptance byFDA of foreign clinical studies not con-ducted under an IND. In general, FDAaccepts such studies provided they arewell designed, well conducted, per-formed by qualified investigators, andconducted in accordance with ethicalprinciples acceptable to the world com-munity. Studies meeting these criteriamay be utilized to support clinical in-vestigations in the United States and/or marketing approval. Marketing ap-proval of a new drug based solely onforeign clinical data is governed by§ 314.106.

(b) Data submissions. A sponsor whowishes to rely on a foreign clinicalstudy to support an IND or to supportan application for marketing approvalshall submit to FDA the following in-formation:

(1) A description of the investigator’squalifications;

(2) A description of the research fa-cilities;

(3) A detailed summary of the pro-tocol and results of the study, and,

should FDA request, case records main-tained by the investigator or addi-tional background data such as hos-pital or other institutional records;

(4) A description of the drug sub-stance and drug product used in thestudy, including a description of com-ponents, formulation, specifications,and bioavailability of the specific drugproduct used in the clinical study, ifavailable; and

(5) If the study is intended to supportthe effectiveness of a drug product, in-formation showing that the study isadequate and well controlled under§ 314.126.

(c) Conformance with ethical principles.(1) Foreign clinical research is requiredto have been conducted in accordancewith the ethical principles stated inthe ‘‘Declaration of Helsinki’’ (seeparagraph (c)(4) of this section) or thelaws and regulations of the country inwhich the research was conducted,whichever represents the greater pro-tection of the individual.

(2) For each foreign clinical studysubmitted under this section, the spon-sor shall explain how the research con-formed to the ethical principles con-tained in the ‘‘Declaration of Helsinki’’or the foreign country’s standards,whichever were used. If the foreigncountry’s standards were used, thesponsor shall explain in detail howthose standards differ from the ‘‘Dec-laration of Helsinki’’ and how theyoffer greater protection.

(3) When the research has been ap-proved by an independent review com-mittee, the sponsor shall submit toFDA documentation of such review andapproval, including the names andqualifications of the members of thecommittee. In this regard, a ‘‘reviewcommittee’’ means a committee com-posed of scientists and, where prac-ticable, individuals who are otherwisequalified (e.g., other health profes-sionals or laymen). The investigatormay not vote on any aspect of the re-view of his or her protocol by a reviewcommittee.

(4) The ‘‘Declaration of Helsinki’’states as follows:


93


RECOMMENDATIONS GUIDING PHYSICIANS INBIOMEDICAL RESEARCH INVOLVING HUMANSUBJECTS

Introduction

It is the mission of the physician to safe-guard the health of the people. His or herknowledge and conscience are dedicated tothe fulfillment of this mission.

The Declaration of Geneva of the WorldMedical Association binds the physician withthe words, ‘‘The health of my patient will bemy first consideration,’’ and the Inter-national Code of Medical Ethics declaresthat, ‘‘A physician shall act only in the pa-tient’s interest when providing medical carewhich might have the effect of weakeningthe physical and mental condition of the pa-tient.’’

The purpose of biomedical research involv-ing human subjects must be to improve diag-nostic, therapeutic and prophylactic proce-dures and the understanding of the aetiologyand pathogenesis of disease.

In current medical practice most diag-nostic, therapeutic or prophylactic proce-dures involve hazards. This applies espe-cially to biomedical research.

Medical progress is based on researchwhich ultimately must rest in part on ex-perimentation involving human subjects.

In the field of biomedical research a funda-mental distinction must be recognized be-tween medical research in which the aim isessentially diagnostic or therapeutic for apatient, and medical research, the essentialobject of which is purely scientific and with-out implying direct diagnostic or thera-peutic value to the person subjected to theresearch.

Special caution must be exercised in theconduct of research which may affect the en-vironment, and the welfare of animals usedfor research must be respected.

Because it is essential that the results oflaboratory experiments be applied to humanbeings to further scientific knowledge and tohelp suffering humanity, the World MedicalAssociation has prepared the following rec-ommendations as a guide to every physicianin biomedical research involving human sub-jects. They should be kept under review inthe future. It must be stressed that thestandards as drafted are only a guide to phy-sicians all over the world. Physicians are notrelieved from criminal, civil and ethical re-sponsibilities under the laws of their owncountries.

I. Basic Principles

1. Biomedical research involving humansubjects must conform to generally acceptedscientific principles and should be based onadequately performed laboratory and animalexperimentation and on a thorough knowl-edge of the scientific literature.

2. The design and performance of each ex-perimental procedure involving human sub-jects should be clearly formulated in an ex-perimental protocol which should be trans-mitted for consideration, comment and guid-ance to a specially appointed committeeindependent of the investigator and thesponsor provided that this independent com-mittee is in conformity with the laws andregulations of the country in which the re-search experiment is performed.

3. Biomedical research involving humansubjects should be conducted only by sci-entifically qualified persons and under thesupervision of a clinically competent med-ical person. The responsibility for the humansubject must always rest with a medicallyqualified person and never rest on the sub-ject of the research, even though the subjecthas given his or her consent.

4. Biomedical research involving humansubjects cannot legitimately be carried outunless the importance of the objective is inproportion to the inherent risk to the sub-ject.

5. Every biomedical research project in-volving human subjects should be precededby careful assessment of predictable risks incomparison with foreseeable benefits to thesubject or to others. Concern for the inter-ests of the subject must always prevail overthe interests of science and society.

6. The right of the research subject to safe-guard his or her integrity must always be re-spected. Every precaution should be taken torespect the privacy of the subject and tominimize the impact of the study on the sub-ject’s physical and mental integrity and onthe personality of the subject.

7. Physicians should abstain from engagingin research projects involving human sub-jects unless they are satisfied that the haz-ards involved are believed to be predictable.Physicians should cease any investigation ifthe hazards are found to outweigh the poten-tial benefits.

8. In publication of the results of his or herresearch, the physician is obliged to preservethe accuracy of the results. Reports of ex-perimentation not in accordance with theprinciples laid down in this Declarationshould not be accepted for publication.

9. In any research on human beings, eachpotential subject must be adequately in-formed of the aims, methods, anticipatedbenefits and potential hazards of the studyand the discomfort it may entail. He or sheshould be informed that he or she is at lib-erty to abstain from participation in thestudy and that he or she is free to withdrawhis or her consent to participation at anytime. The physician should then obtain thesubject’s freely-given informed consent, pref-erably in writing.

10. When obtaining informed consent forthe research project the physician should beparticularly cautious if the subject is in a


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21 CFR Ch. I (4–1–99 Edition)§ 312.130

dependent relationship to him or her or mayconsent under duress. In that case the in-formed consent should be obtained by a phy-sician who is not engaged in the investiga-tion and who is completely independent ofthis official relationship.

11. In case of legal incompetence, informedconsent should be obtained from the legalguardian in accordance with national legis-lation. Where physical or mental incapacitymakes it impossible to obtain informed con-sent, or when the subject is a minor, permis-sion from the responsible relative replacesthat of the subject in accordance with na-tional legislation.

Whenever the minor child is in fact able togive a consent, the minor’s consent must beobtained in addition to the consent of theminor’s legal guardian.

12. The research protocol should alwayscontain a statement of the ethical consider-ations involved and should indicate that theprinciples enunciated in the present Declara-tion are complied with.

II. Medical Research Combined withProfessional Care (Clinical Research)

1. In the treatment of the sick person, thephysician must be free to use a new diag-nostic and therapeutic measure, if in his orher judgment it offers hope of saving life, re-establishing health or alleviating suffering.

2. The potential benefits, hazards and dis-comfort of a new method should be weighedagainst the advantages of the best currentdiagnostic and therapeutic methods.

3. In any medical study, every patient—in-cluding those of a control group, if any—should be assured of the best proven diag-nostic and therapeutic method.

4. The refusal of the patient to participatein a study must never interfere with the phy-sician-patient relationship.

5. If the physician considers it essentialnot to obtain informed consent, the specificreasons for this proposal should be stated inthe experimental protocol for transmissionto the independent committee (I, 2).

6. The physician can combine medical re-search with professional care, the objectivebeing the acquisition of new medical knowl-edge, only to the extent that medical re-search is justified by its potential diagnosticor therapeutic value for the patient.

III. Non-Therapeutic Biomedical Research In-volving Human Subjects (Non-Clinical Bio-medical Research)

1. In the purely scientific application ofmedical research carried out on a humanbeing, it is the duty of the physician to re-main the protector of the life and health ofthat person on whom biomedical research isbeing carried out.

2. The subjects should be volunteers—ei-ther healthy persons or patients for whom

the experimental design is not related to thepatient’s illness.

3. The investigator or the investigatingteam should discontinue the research if inhis/her or their judgment it may, if contin-ued, be harmful to the individual.

4. In research on man, the interest ofscience and society should never take prece-dence over considerations related to thewell-being of the subject.(Collection of information requirements ap-proved by the Office of Management andBudget under control number 0910–0014)

[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 56 FR 22113, May 14,1991; 64 FR 401, Jan. 5, 1999]

EFFECTIVE DATE NOTE: At 64 FR 401, Jan.5, 1999, § 312.120 was amended by removing‘‘or antibiotic drug’’ from the last sentenceof paragraph (a), effective May 20, 1999.

§ 312.130 Availability for public disclo-sure of data and information in anIND.

(a) The existence of an investiga-tional new drug application will not bedisclosed by FDA unless it has pre-viously been publicly disclosed or ac-knowledged.

(b) The availability for public disclo-sure of all data and information in aninvestigational new drug applicationfor a new drug will be handled in ac-cordance with the provisions estab-lished in § 314.430 for the confidentialityof data and information in applicationssubmitted in part 314. The availabilityfor public disclosure of all data and in-formation in an investigational newdrug application for a biological prod-uct will be governed by the provisionsof §§ 601.50 and 601.51.

(c) Notwithstanding the provisions of§ 314.430, FDA shall disclose upon re-quest to an individual to whom an in-vestigational new drug has been givena copy of any IND safety report relat-ing to the use in the individual.

(d) The availability of informationrequired to be publicly disclosed for in-vestigations involving an exceptionfrom informed consent under § 50.24 ofthis chapter will be handled as follows:Persons wishing to request the publiclydisclosable information in the IND thatwas required to be filed in DocketNumber 95S–0158 in the Dockets Man-agement Branch (HFA–305), Food andDrug Administration, 12420 ParklawnDr., rm. 1–23, Rockville, MD 20857, shall


95


submit a request under the Freedom ofInformation Act.

[52 FR 8831, Mar. 19, 1987. Redesignated at 53FR 41523, Oct. 21, 1988, as amended at 61 FR51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999]

EFFECTIVE DATE NOTE: At 64 FR 401, Jan.5, 1999, § 312.130 was amended by removing‘‘or antibiotic drug’’ from paragraph (b), ef-fective May 20, 1999.

§ 312.140 Address for correspondence.

(a) Except as provided in paragraph(b) of this section, a sponsor shall sendan initial IND submission to the Cen-tral Document Room, Center for DrugEvaluation and Research, Food andDrug Administration, Park Bldg., Rm.214, 12420 Parklawn Dr., Rockville, MD20852. On receiving the IND, FDA willinform the sponsor which one of the di-visions in the Center for Drug Evalua-tion and Research or the Center forBiologics Evaluation and Research isresponsible for the IND. Amendments,reports, and other correspondence re-lating to matters covered by the INDshould be directed to the appropriatedivision. The outside wrapper of eachsubmission shall state what is con-tained in the submission, for example,‘‘IND Application’’, ‘‘Protocol Amend-ment’’, etc.

(b) Applications for the products list-ed below should be submitted to the Di-vision of Biological InvestigationalNew Drugs (HFB-230), Center for Bio-logics Evaluation and Research, Foodand Drug Administration, 8800 Rock-ville Pike, Bethesda, MD 20892. (1)Products subject to the licensing provi-sions of the Public Health Service Actof July 1, 1944 (58 Stat. 682, as amended(42 U.S.C. 201 et seq.)) or subject to part600; (2) ingredients packaged togetherwith containers intended for the collec-tion, processing, or storage of blood orblood components; (3) urokinase prod-ucts; (4) plasma volume expanders andhydroxyethyl starch for leukapheresis;and (5) coupled antibodies, i.e., prod-ucts that consist of an antibody com-ponent coupled with a drug or radio-nuclide component in which both com-ponents provide a pharmacological ef-fect but the biological component de-termines the site of action.

(c) All correspondence relating to bi-ological products for human use whichare also radioactive drugs shall be sub-mitted to the Division of Oncology andRadiopharmaceutical Drug Products(HFD–150), Center for Drug Evaluationand Research, Food and Drug Adminis-tration, 5600 Fishers Lane, Rockville,MD 20857, except that applications forcoupled antibodies shall be submittedin accordance with paragraph (b) ofthis section.

(d) All correspondence relating to ex-port of an investigational drug under§ 312.110(b)(2) shall be submitted to theInternational Affairs Staff (HFY–50),Office of Health Affairs, Food and DrugAdministration, 5600 Fishers Lane,Rockville, MD 20857.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,1990]

§ 312.145 Guidelines.

(a) FDA has made available guide-lines under § 10.90(b) to help persons tocomply with certain requirements ofthis part.

(b) The Center for Drug Evaluationand Research and the Center for Bio-logics Evaluation and Research main-tain lists of guidelines that apply tothe Centers’ regulations. The listsstate how a person can obtain a copy ofeach guideline. A request for a copy ofthe lists should be directed to theCDER Executive Secretariat Staff(HFD–8), Center for Drug Evaluationand Research, Food and Drug Adminis-tration, 5600 Fishers Lane, Rockville,MD 20857, for drug products, and theCongressional, Consumer, and Inter-national Affairs Staff (HFB–142), Cen-ter for Biologics Evaluation and Re-search, Food and Drug Administration,8800 Rockville Pike, Bethesda, MD20892, for biological products.

[52 FR 8831, Mar. 19, 1987, as amended at 55FR 11580, Mar. 29, 1990; 56 FR 3776, Jan. 31,1991; 57 FR 10814, Mar. 31, 1992]


96

21 CFR Ch. I (4–1–99 Edition)§ 312.160

Subpart G—Drugs for Investiga-tional Use in Laboratory Re-search Animals or In VitroTests

§ 312.160 Drugs for investigational usein laboratory research animals orin vitro tests.

(a) Authorization to ship. (1)(i) A per-son may ship a drug intended solely fortests in vitro or in animals used onlyfor laboratory research purposes if it islabeled as follows:

CAUTION: Contains a new drug for inves-tigational use only in laboratory researchanimals, or for tests in vitro. Not for use inhumans.

(ii) A person may ship a biologicalproduct for investigational in vitro di-agnostic use that is listed in§ 312.2(b)(2)(ii) if it is labeled as follows:

CAUTION: Contains a biological productfor investigational in vitro diagnostic testsonly.

(2) A person shipping a drug underparagraph (a) of this section shall usedue diligence to assure that the con-signee is regularly engaged in con-ducting such tests and that the ship-ment of the new drug will actually beused for tests in vitro or in animalsused only for laboratory research.

(3) A person who ships a drug underparagraph (a) of this section shallmaintain adequate records showing thename and post office address of the ex-pert to whom the drug is shipped andthe date, quantity, and batch or codemark of each shipment and delivery.Records of shipments under paragraph(a)(1)(i) of this section are to be main-tained for a period of 2 years after theshipment. Records and reports of dataand shipments under paragraph(a)(1)(ii) of this section are to be main-tained in accordance with § 312.57(b).The person who ships the drug shallupon request from any properly au-thorized officer or employee of theFood and Drug Administration, at rea-sonable times, permit such officer oremployee to have access to and copyand verify records required to be main-tained under this section.

(b) Termination of authorization toship. FDA may terminate authoriza-tion to ship a drug under this section ifit finds that:

(1) The sponsor of the investigationhas failed to comply with any of theconditions for shipment establishedunder this section; or

(2) The continuance of the investiga-tion is unsafe or otherwise contrary tothe public interest or the drug is usedfor purposes other than bona fide sci-entific investigation. FDA will notifythe person shipping the drug of its find-ing and invite immediate correction. Ifcorrection is not immediately made,the person shall have an opportunityfor a regulatory hearing before FDApursuant to part 16.

(c) Disposition of unused drug. Theperson who ships the drug under para-graph (a) of this section shall assurethe return of all unused supplies of thedrug from individual investigatorswhenever the investigation discon-tinues or the investigation is termi-nated. The person who ships the drugmay authorize in writing alternativedisposition of unused supplies of thedrug provided this alternative disposi-tion does not expose humans to risksfrom the drug, either directly or indi-rectly (e.g., through food-producinganimals). The shipper shall maintainrecords of any alternative disposition.


[52 FR 8831, Mar. 19, 1987, as amended at 52FR 23031, June 17, 1987. Redesignated at 53FR 41523, Oct. 21, 1988]

PART 314—APPLICATIONS FOR FDAAPPROVAL TO MARKET A NEWDRUG


Sec.314.1 Scope of this part.314.2 Purpose.314.3 Definitions.

Subpart B—Applications

314.50 Content and format of an application.314.52 Notice of certification of invalidity

or noninfringement of a patent.314.53 Submission of patent information.314.54 Procedure for submission of an appli-

cation requiring investigations for ap-proval of a new indication for, or otherchange from, a listed drug.

314.55 Pediatric use information.


21 cfr 312 – investigational new drug (ind) · pdf filethe safety of quinine drug...

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