Investigational New Drugs: Application, Process, and Trial
Geoffrey Levine and Neil Abel
University of Piusburgh Schools of Medicine and Pharmacy. Pittsburgh. Pennsylvania, and Office of Orphan Products Development. Food and Drug Administration. Rockville. Maryland
updated from time to time in order to make the IND process This is the fourth article in a four-part series of nuclear more effective. This article will additionally call attention to medicine updates. Upon completion of this article, the reader some of the highlights associated with the 1987 IND update, will have: (1) an understanding ofthe various phases involved also known as the IND rewrite (3). in investigational new drugs (IND), (2) a reference for pre But why would anyone want to go to all this trouble to file paring an IND, and (3) an awareness of the common pitfalls an IND if the radiopharmaceutical agent will eventually be associated with preparing and fulfilling the commitment of come available anyway, or might tum out to be of no value an IND. at all? The answer is multidimensional:
I. Certain institutions have a research mission, such as An investigational new drug application (IND) is a request university medical center hospitals. for Food and Drug Administration (FDA) authorization to 2. Certain investigators simply enjoy working with and administer an investigational drug or biological (serums, vac learning about new agents. cines, antitoxins, antigens, etc ... ) to humans. Such authoriza 3. The use of investigational agents can enhance the pres tion must be secured prior to interstate shipment and admin tige of an institution, department, or individual investi istration of any new drug that is not the subject of an approved gator (among peers or with the public). new drug application (NDA) ( 1 ), abbreviated new drug ap 4. Given today's competitive environment, the use ofthese plication (ANDA), or product license application (PLA). IND agents can theoretically provide a competitive edge. Most INDs are filed by two groups: manufacturers (typically 5. The newest agents can possibly bring the most advanced sponsors) and health practitioners (typically investigators). patient care to bear upon a particular medical problem. Individuals may, under certain circumstances, sponsor their own investigations. The commercial manufacturer should It is interesting to observe that until recently new advances have little difficulty in knowing when or if it should file an in nuclear medicine, including new radiopharmaceuticals, IND. The health practitioner, on the other hand, does have have, to a large extent, come from hospital- and university some difficulty in deciding if the study he or she has planned based health practitioners. This is in sharp contrast to tradi (a) requires an IND, (b) falls under the practice of medicine tional pharmaceuticals, which have been developed predom and/or pharmacy, or (c) can be handled by internal commit inantly by pharmaceutical manufactuers ( 4,5 ). tees (2). Whereas it has been argued that radiopharmaceuticals are This article, consequently, focuses on clarifying the role of indeed different from other classes of drugs, and that this the sponsor and/or investigator with regard to the IND process difference has gone unrecognized by the FDA, examination and familiarizing him with some of the nuances involved. At of the guidelines for the clinical evaluation of radiopharma the outset, the reader should be aware that the regulations ceuticals ( 6) compared to the guidelines for the clinical eval and requirements can be exhausting, and the submission, an uation of nonradioactive drugs ( 7) will quickly reveal that exercise in word engineering. This is true for both the appli this difference has been acknowledged, even if this degree of cant and reviewer. To write a simple set of rules/regulations acknowledgement has been subject to controversy (J-7). The or guidelines which would cover every set of circumstances guidelines are clear and relatively comprehensive in deline to protect the public health is no simple task. In fact, the ating expectations; it is the interpretation of these guidelines regulations (Title 21 of the Code of Federal Regulations, Part in specific circumstances that has often caused confusion. 312 [21CFR312] (3) are a living document in that they are The delineation of boundary in practice often gets blurred with the exercising of actual versus perceived authority. The FDA operates from the perspective of public health, its au thority embedded in Federal law. The practice of medicine
For reprints contact: Geoffrey Levine, PhD, Presbyterian-University Hos and pharmacy are geared toward care of the individual patient pital, Nuclear Medicine, DeSoto at O'Hara Streets, Pittsburgh, PA 15213. with authority garnered from State law. Recently, the Nuclear
236 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY Regulatory Commission (NRC) has tread into the arena, but DEPARTMENT OF HEALTH AND HUMAN SERVICES Form"PP'~·OMfNo 0910-0014 hp~rltoon D•tt NOvt'm~r JO. 1987 PUBLIC HEALTH SERVICE ~000 At.IO DRUG AOMINISTRA TIQN NOTE Nodruqmavbell'loppe.dorth"'<•l not without ruffling some feathers (8), in attempting to fill a INVESTIGATIONAL NEW DRUG APPLICATION (I NO) •n~nt•g•I•O" begun ~nt•l•n IND forth.llt ('nTLE 21, CODE OF FEDERAL REGULA nONS (CFRJ Part 312J onvest•9•1oonosonefle('I(21CFRl12&0)
"perceived" void at the interface between FDA regulations 1 NAME OF SPONSOR l OA TE OF SUBMISSION and the practice of medicine and pharmacy as they relate to J AOORESS(Numbt>r. Street. c.ry. St.He ~ndlop Code! 4 HLEP>~ONE NUMBER (lnduchAre•Codt) investigational drugs.
6 INO NUMBER (lftNevoouV, US19~
CLINICAL TESTING FOR SAFE AND EFFECTIVE 7 INDICA TION(S) (CovE-red by rl'uJ IIJOm,uoon) DRUGS: AN OVERVIEW OF THE PROCESS 8. P!oiASE(S)OFCLI'-'ICAL·NVESfiGAriON'tOBECONOuCTED o~HASE, QP~;A~E1 O~HASEl OOT!iER (Spfi.fy)
9 .,ST NUMBE~S OF ALL INVESTIGATIONAL NEW D~UG APPL,CA T•ONS Ill CFFfPart Jll). NEW DRUG ORANTIBIOTICAP"'LICATIONS Before 1962, the FDA did not require notification of drugs (ll CFRPilrt 314) DRUG MASTER FILES (11 CFR 314 4101, AND ~RODUCT LICENSE APPLICATIONS (ll CFRPitrt601) REFERRED TO IN THIS being tested on humans. The 1962 Kefauver-Harris amend ment to the Federal Food, Drug, and Cosmetic Act greatly strengthened the government's authority over clinical (hu •o liND submtmons should be consecut1vely numb~red. The mttJ.JI /NO should~ nurn~~ SERIAdoju...,SER ~senal Num~r 000 H Th~ ned submiSSIOn (t ~, ilmendment, report. or corttipOndence) man) testing of new drugs. With this regulatory authority, the should be numMred ·senal Number· 001. ~ Subsequent subm1ssions should be numbe~ _ _ _ consecur1vely m the order m whiCh they are submitted
FDA has taken steps to: 11 THIS SUBMISSION CONTAINS THE FOLLOW•NG (C~tkit/1 thiltitpply) 0 lfii PROTOCOLAMENOMENT(SI ''-'FORMATION AMENDMENT($) INOSAFETYREPORT(S) QNEWPROTOCOL 0 CHEMISTRYIMICROSIOLOG Y 01NITIAL WRITHN REPORT 1. Provide added safeguards for those on whom drugs are 0 CHANGE IN PROTOCOL 0 PHARMACOLOGYfTOXICOLOGY 0 FOLLOW·UP TO A WRITHN REPORT tested. 0 NEW INVESTIGATOR OCLINICAL 2. Improve reports by drug investigators. 0 RESr>ONSE TO FOA REQUEST FOR ''-'FORMATION QANNUALIICPORT 0 RESPONSE TO (LINI(AL HOLD 0 GENERAL COIIIIESPONOENCE 0 REQUE5T FOR REINSTAfEMENTOF INO THAT IS WITHDRAWN OOTHER_~{JPi=<>"'IYJ;--- 3. Establish investigative procedures to supply substantial INACTIVATED. TERMINATED OR DISCONTINUED scientific evidence that a drug is safe and effective. Refer torn. de1>9n•tedCFR crtilt•orn b-e few• ch'fodw''9 ilnyofth'f foiiOW•nt;l 0 TREATMENT INO 11 CFR 31l35(b) 0 TREATMtNTf'ROTO(Olll CFR 3121S(a) QCHAR(iE REQUEH,NOTIFICATIONl! CfRJii 7(d) fOR FDA USE ONLY Before a new drug may be tested on humans, the sponsor CORID81NOIOGORECEIPTSTAMP DDRRECEIPT$TAMr> 1ND NUM8ER ASSIGNED (usually a pharmaceutical firm, but sometimes a clinician investigator) must give the FDA information formerly speci DIVISION ASSIGNNIE~T fied as a "Notice of Claimed Investigational Exemption for a FOAM fDA 15 7 1 IM7) PREVIOUS EDITION IS08S0lETO New Drug," but now known as an IND. (As of the 1987 rewrite, FDA forms 1571, 1572, and 1573 have been replaced by new forms FDA 1571 and 1572 (Figs. 1-2). The current CONTENTS OF APPUCAnON IND regulations became effective in June 1987. Copies of the Th1s application contains the follow1ng items: (check all that apply) regulations, further guidance regarding IND procedures, and 0 1.FormFDA1571 (11CFR311.13(a)(J)} additional forms are available from: 0 2.Table of contents (}1 CFR 311.13 (a)(})} 0 3. Introductory statement (11 CFR 311 13 (a) (3)} 0 4. General Investigational plan {11 CFR 312 23 (a) (3)} FDA Legislative, Professional, and 0 5. Investigator's brochure {}I CFR 311l3(i1) (5J/ 6. Protocol(s) {11 CFR 311.13 (a) (6)/ Consumer Affairs Branch (HFN-365) 0 a Study protocol($) (11CFR312.23(a)(6)} 5600 Fishers Lane 0 b. Invest, gator data (}I CFR 311 13 (a) (6)(i11J(b)} or completed Form(s) FDA 1572 0 c. Facilit1es data {11 CFR 312 23 (a)(6J(m)(b)/ or completed Form(s) FDA 1572 Rockville, Maryland 20857 O d. lnst1tut10nal Re111ew Board data {11 CFR 311.23 (a)(6)(m)(b)J or completed Form(s) FDA 1572 Telephone: 301-295-8012. 0 7 Chem1stry, manufactur~ng. and control data [11 CFR 312.13 (a) (7)} O a. Environmental assessment or cla1m for ~xcluswn [11 CFR 311 23(a)(7J(sv)(e}j 0 8 Pharmacology and tOiticology data {21 CFR 31123 (a)(8Jj When a clinical investigator intends to perform a study, for 0 9 Prev1ous human exper~ence [11 CFR 312 23 (a)(9JI 0 10 Addtt1onal mformat1on [21 CFR 311 23(i1)(10)} example, a clinical trial for a radiopharmaceutical manufac turer, he only needs to fill out FDA 1572 (Statement of ~YES, WILL ANY SPONSOR 06LIGA ':'IONS 6€ •RANSI'~RIIED TQ r><€ CONTRACT RESEARCH ORGAN•lATION' 0 YES QNO 'F "ES AT!A(H A ST:O.HME'IIT (QNTAiNIIIIG THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION. IDENTIFICATION OF Investigator) in which one certifies one's qualifications to THE (~INI(Al STUDY AIIIQ A ~!STING 01' THE 08LtGATIONS ~~AIIISFERREQ conduct the study and makes a series of agreements with the '4 NAME AND TITLE OF ·~t PERSON RESPONSIBLE ~OR MONITOR IlliG THE CO,..Du(· AND PIIOGRESi OF •HE (LINICALINVE~TIGATIONS sponsor and the FDA. The simplest way to handle this form IS NAME(S) AND TITLE(SIOF !!iE PfRSON(Sl RES~ON~IBLE 'OR REVIEW ANO EVAL:.JAf•ONOF INFOR...,AT•OIII liE LEVANT fO THE SAFETY OF is to attach a curriculum vitae (CV) rather than filling in the THEORU(j individual blanks. However, the sponsor or sponsor-investi gator must still deal with FDA 1571 (Investigational New I agree not to begin Clinical Lnvest•gat•ons unt1l 30. days after FDA's rece1pt of the INO or on.earller not1ficat10n by FDA. 1 also agree not to beg1n or cont.nue clm•cal mvestigat•ons covered by the IND 1f th Although much of the basic information requested on the 19 TELEPHONENUM8ER (lncludeAru C VOLUME 18, NUMBER 4, DECEMBER 1990 237 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No.091~14 The IND should include the following specific information: PUBLIC HEALTH SERVICE hP1••t1on O.te: Noftmber JO. 1917 FOOOANO DRUG ADMINISTRATION STATEMENT OF INVESnGA TOR (nTLE 2f, CODE OF FEDERAL REGULAnDNS (CFI) hrt JU} 1. Complete composition of the drug, its source, and man (See instructions on reverse side.) I NAME AND AOOII:ESS OF INVESTIGATOR ufacturing data, to show that there are appropriate stand ards to ensure its safe use. Note: It is not necessary for the sponsor to submit certain information with an IND 2 EDUCATION, TRAINING, AND EXPERIENCE TH.4 T QUAlifiES THE tNVESTIGA TOR AS AN EXPERT IN THE CliNICAL INVESTIGATION OF THE DRUG FOR THE LISE UNDER INVESTIGATION ONE Of THE FOLLOWING 1S A TTA(HED· (such as manufacturing and controls information, phar 0 (URJII(ULUM VITAE 0 OTHER STATEMENT OF QUAli~I(A liONS macology and toxicology data, or data from prior human studies), ifthat information has previously been submit ) NAME AND ADDRESS OF ANY MEDICAL SCHOOL HQSPI~AL. OR OTHER RESEARCH FAC•LITY WHERE THE (i.INI(AL tNVESTIGA TION{S) WILL IE CONDUCTED ted to the FDA, and ifthe sponsor of the file containing that information is willing to provide a letter to the FDA authorizing reference to the information. 4 NAME ANDAOORESSOF ANY CLINICAL LABORATORY FACILITIES TO IE USEOIN THE STUDY 2. Results of all pre-clinical (pre-human) investigations, including animal studies. Initially, these should be di rected toward defining the drug's safety rather than its S NAME ANOADORESS OF THE INSTITUTIONAL REVIEW BOARO(IRB) THAT IS RESPONSIBLE FOR REVIEW ANOAPPROVALOF THE STUOY(IES) efficacy. The data must demonstrate that there will not be unreasonable hazard in initiating studies in humans. Further animal studies may be conducted concurrently with clinical (human) studies. The Center for Drug 6 NAMES Of THE SUBINVESTIGATORS (t!' 9. ••~•rch ,./lows. rt!'SidetiC, .11:$0(',.tt!'s)WI-t0 WILL BE ASSISTING THE INVESTIGATOR IN THE CONDUCT OF THE tNVESTIGA TION(S) Evaluation and Research or the Center for Biologic Evaluation and Research will, on request, comment on the adequacy of the proposed animal studies. Generally, the FDA minimally requires that: (a) there be a phar 7 NAME AND CODE NUMBER, IF ANY,Of THE ~ROTOCOL(S) IN THE INOtOENTIFYING THE STUOY(IESJ TOllE CONDUCTED BY THE INVESTIGATOR macologic profile; (b) acute toxicity be determined in several species of animals and that the route of admin istration will be the same in the animal trials, and (c) there be short-term studies ranging from 2 wk to 3 mo, fOAM FDA 1S7Z IM7) REPLACE\ PREVIOUS EDITIONS OF FDA 1572 AND FDA 157) depending on the proposed use, to evaluate toxicity. Additional animal studies frequently are necessary. 3. A detailed outline (protocol) of the planned investigation 8 ATTACH THE fOlLOWING CLINICAL PROTOCOL INFORMA TI()N: including anticipated or postulated changes to the pro 0FOR PHASE 1 INVESTIGATIONS. A GENERAL OUTLINE OF THE PLANNEDtNVESTIGATlOHINC.LUDING THE ESTIMATED DURATION OF THE STUDY AND THE MA.XIMUM NUMBER OF SUBIECl) THAT WILL8E INVOLVf.D tocols based upon study findings. 0 FOR PHASE 2 OR 3 INVESTIGATIONS. AN OUTLINE Of THE STUDY PROTOCOL INCLUDING AN APPROXIMATION OF THE NUMBER OF 4. Information regarding the training and experience of the SUBJECTS TO BE TREATED WITH THE DRUG AND THE NUMER TO BE EMPLOYED AS CONTROLS, If ANY, THE CLINICAL USES TO BE INVESTIGATI:O: CHARACTERISTICS OF SUBJECTS 8Y AGE, SEX. ANO CONDITION; THE lUND OF CLINICAL OBSERVATIONS AND lABORATORY TESTS TO BE CONDUCTED. THE ESTIMATED DuRATION OF THE STUDY, AND COPIES OR A DESCRIPTION OF CASE investigators. Investigators are responsible for and are REPORT FORMS TO BE USED required to submit to the sponsor (not the FDA) Form 9 COMMITMENTS 1572 for clinical trials. 1 AGRH TO CONDUCT THE STUDY(IES) IN ACCORDANCE W'ITH THE RELE~ANf. CURRENT PROTOCOL($) AND W'Ll ONLY MAKE CHANGES 1N A PROTOCOL AFTER NOTIFYING THE ~PONSOR EXCEPT N>'IEN NECESSARY TO PROTECT THE SAFETY THE RIGHTS. OR WELFARE OF SUBJECTS 5. Copies of all informational material supplied to each 1AGRE£ TO PERSONALLY CONDUCTOR Sc;PE~v·s; ~'"E J€)(q18E:> 1/IIVESrtGAfiON(S) investigator. This type of material is listed in Form FDA I AGREE TO INFORM ANY PAriENTS OR AI\IV PE~SONS uSi'O AS (Q~TIIOLS. THAT TH( DRUGS ARE 9EING \.I~EO FOR INVESTIGATIONAl PURPOSES AND I WIL~ ENSURE THAT T,..E ~EOUIRE._,E~~S RH.l.•1NG TQ OBTAINING 1 N~0RME) CON~ENT •N 1' C~R PART SO AND 1571. Additionally, a letter from the investigator's insti INSTITUTIONAL REVIEW BOARD OR81 qEVIEW .l.NQ APPqQ•JAl N 2' (~~ P.o.RT S6 "-R£ MF 1 AGRH TO REPQil.T •o THE SPONSOR A;>vf~>C- (;H 0 ',l~> n..,' OCCvR ,J>. :-.e COVRSt OF •,.;; •Nv£5T GA ~.OIIj($) 11\j ACCOROA"'CE tutional review board (IRB) stating that it approves of WlfH11CFR)I264 and will monitor the study. I HAVE REAO ,IIID UNOERSTANO T,..f ,r-,FQ~..,.~,' 0 .. ,., '..ti' •llooi:S~ c.:. ~OR S ~RO(,..URE •NC'-O•NG *1-~ ;>Qr!:N~IA, "11S~S AND S•OE EFFECTSmTt- 1 A(iRH TO COMPLY WITH All QTHE~ REOUIREME .. TS REGARO·NG ·.,;: 081.·G"'7•0NS O< (_ "<1(11 .... ~~S',GII.CR$ ll.:ljQ Acl OTHER PERTINENT REQUIREMENTS .N 11 CFR Pli.R7 )11 8. Agreement to submit annual progress reports and com mitments regarding disposal of the drug when studies INSTRUCTIONS FOR COMPLETING FORM FDA 1S72 STATEMENT OF INVESTIGATOR: are discontinued. I Complete all secttons Art.tch a sep.trate p.tge d addJt1on.tl space tS needed 9. Agreement not to initiate any part of a study for 30 days 1 Attach cumculum vtt.te or otherst.ttement of qualdrcattons ,u deScflbed m Section} after submission of the IND in order to allow the FDA J Att.tch protocol outlme .ts desc"bed 1n Sewon 8 to review the submission for safety. 4. Stgn .tnd d.tte below. 5. FORWARD THE COMPLETED FORM AND ATTACHMENTS TO THE SPONSOR SELECTED HIGHLIGHTS AND SHIFTS IN The sponsorwtll mcorpor.tte thts rnformatton along w1th other techmcaldata mto .Jn lnvest1g.ttton.JI New Drug Applte.ttton{INDJ INVESTIGATORS SHOULD NOT SEND THIS FORM OIRECTL Y TO THE FOOD AND DRUG ATTITUDE ASSOCIATED WITH THE IND ADMINISfRA TION 10 SIGNATURE OF INI/EST!GATOII. REWRITE I" DA'E The IND rewrite reflects both a fine-tuning of the regulatory FIG. 2. FDA form 1572, Statement of Investigator. process as well as of a change in attitude on the part the FDA. 238 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY The agency carefully reviewed more than 50 comments re to situations where there is an unreasonable and significant ceived from pharmaceutical manufacturers, trade associa risk to human subjects. Phase II and III studies can be held tions, health professionals, professional societies and con for serious defects in study design. sumer organizations. In addition, agency managers met with Exemption for Certain Studies on Marketed Drugs. This a congressionally-sponsored commission in part responsible exemption is designed to foster research and will most likely for improving the process. Thus, virtually all groups with an be emphatic with respect to academic institutions. Most IND interest in the IND process got to speak their piece. A review requirements would be exempted except for safety reasons. of the comments section in the final ruling (3) suggests that This situation applies to marketed drugs in which dose, route these comments were carefully considered in that two major of administration and patient population with the approved shifts in policy occurred: (a) focusing attention during the labeling are similar to that for which the drug was originally early phase of the IND process(clinical research) on protecting approved. the safety of human test subjects and (b) giving sponsors Dispute Resolution. This process relies on informal com greater freedom to design, revise, and implement clinical munication to resolve differences between the FDA and spon research studies, while providing greater assistance to the sors. An ombudsman's function would be to facilitate timely applicants. and equitable resolutions of administration and managerial disagreements about INDs. Outside consultants can be used Policy Shifts and the informal process supersedes the formal appeals proc Continuing Dialogue. Accordingly, the regulations codify a ess. series of four standard conferences targeted at key stages of Economic Analysis. Additionally, an economic analysis of the drug approval process between FDA staff and sponsor/ clinical trials can result in further savings by the elimination applicants. Another provision provides for conferences on an of poorly designed or unnecessary clinical studies, e.g., avoid as needed basis. Additionally, there is a strong commitment ing the need to redo it. to resolve disputes in a timely manner. Assistance. Whereas the responsibilities of the sponsors and THE PHYSICIAN-SPONSORED IND clinical investigators are substantially the same, the FDA has When a physician and/or a clinical investigator wishes to significantly expanded the use of guidelines on how to fulfill act as a sponsor for the use of a drug solely as a research tool certain technical requirements in order to provide greater or for early clinical investigation of a drug for its therapeutic guidance to applicants. or diagnostic potential (clinical pharmacology, Phases I and Highlights II), a simpler abbreviated form of submission is acceptable. An example would be the study of a drug that no manufac Selected highlights from the IND rewrite include the follow turer is interested in sponsoring. An outline of such a study ing items. should provide the following information: Regulation ofthe Early Phase of Research. Greater empha sis on safety for human subjects and greater flexibility to I. The identity of the compound or compounds together modify protocols without prior FDA notification. Also, there with facts that satisfy the investigator that the agent is the proposed use of nongovernmental Outside Review maybe justifiably administered to a human as intended. Boards (ORBs). However, this may probably never occur. 2. The purpose of the use and the general protocol. Format for IND Submission. A new organization of the 3. Appropriate background information including a brief form 1571 to facilitate agency review for much of the same statement of the investigator's scientific training and data required, but with a modified time frame for the com experience and the nature of the facilities available to ponents, so that they can be viewed in light of the proposed him/her. The clinical investigator sponsoring this type clinical investigations. of IND deals directly with the FDA. The FDA has no IND Safety Reports. Unexpected or life-threatening reports authority over the practice of medicine and cannot are to be made by telephone in three working days and in require a physician to prescribe or not to prescribe a writing in ten working days. This requires prompt review, drug for a particular illness. Investigator sponsors are evaluating, and reporting on the part of the sponsor. encouraged to submit an IND, when they use a drug for Amendment Procedures. Amendments are divided into purposes other than those approved by the FDA. This three categories with individual reporting intervals: (a) pro enables the FDA to accumulate data on the safety and tocol amendments, (b) information (data) amendments, and efficacy of the drug for that kind of treatment and to (c) safety reports. The annual report provides an overview of share this information with other physicians and health the progress to date and future plans. care professionals. At a recent program session of the Meetings Between FDA and Drug Sponsors. Periodic meet American Pharmaceutical Association, FDA represent ings are codified as a matter of policy to facilitate appropriate atives and program panelists acknowledged that they data submission. recognize the difference between having clinical respon Clinical Hold Procedures. A clinical hold is an order from sibility for a patient's care during an investigational the FDA to the sponsor either not to begin or to discontinue study versus initiating and having responsibility for con a study. The final rule limits clinical holds in Phase I studies ducting and analyzing a particular investigational study. VOLUME 18, NUMBER 4, DECEMBER 1990 239 This is relevant since only a single Principal Investigator is designated on FDA 1571 or 1572 (9). .,_OOOCAL...... , • """""""'OF If the sponsor does not perform the manufacturing and •""'"""""""'" EVAl..UA.TION OF control operations for the new drug substance or final dosage IEWUO AEVEW OF ~ ST\.CIES BY INSTTMlONAt. sor may forward such supporting information or arrange to AEV£W BOAADS. F()A ETHCAL COHSIJEAATIONS APMOVAL FOR have it transmitted directly to the FDA. In practice, the manufacturer usually maintains a Drug Master File (DMF) ...,..,,_.,:j.O:.f!'i"i5.':'. .. I:. .. I APPAOf'AtA TE LA8ELM OF OAUQ containing manufacturing information with the FDA and, on EVIJENCE OF PAOPEA MAN.FACT\R the request of an investigator or sponsor and with permission FIG. 4. Schematic outline showing regulatory monitoring of drug of the DMF holder, this information can be used to satisfy development and evaluation. certain requirements. The sponsor rarely, if ever, reviews the contents of the DMF under these circumstances. It remains his or her responsibility, however, to see that the items in the DMF meet the requirements. obtained in the first two phases demonstrates reasonable assurance of safety and effectiveness or suggests that the drug CLINICAL INVESTIGATION: OBTAINING THE may have a potential value outweighing possible hazards. EVIDENCE Phase III studies are intended to assess the drug's safety, effectiveness, and most desirable dosage in the treatment of a The type and the extent of investigational drug tests are specific disease in a large group of subjects. The studies, no crucial for producing the substantive scientific evidence of matter how extensive, should be carefully monitored. safety and effectiveness needed to approve the drug for mar The FDA continually receives reports on the progress of keting. This evidence is obtained in three phases. each phase. If the continuation of the studies appears to Phase I present an unwarranted hazard to the patients, the sponsor Pharmacology studies are used to determine toxicity, me may be requested to modify or discontinue clinical testing tabolism, absorption, elimination and other pharmacologic until further preclinical work has been completed (2,10). actions, preferred route of administration, and safe dosage A schematic outline of the new drug development process range. These studies involve a small number of subjects and is presented in Figure 3. In Figure 4, the development and are conducted under carefully controlled circumstances by regulation of drugs, including radiopharmaceuticals, are fur people trained in clinical pharmacology. ther described. Phase II INSURANCE AGAINST UNNECESSARY DELAYS: Initial trials are conducted on a limited number of patients TIPS FOR SPONSORS AND INVESTIGATORS OF for a specific disease treatment or prevention. Additional INDS pharmacologic studies performed concurrently on animals may be necessary to indicate safety. Instructions for the preparation and submission of FDA- 1571 are available from the FDA (1 ), yet, we have reviewed Phase Ill or assisted in the preparation of INDs in which the directions Proposals for Phase III of the clinical investigation, which had never been consulted. Thus, just as with income tax involve extensive clinical trials, are in order if the information forms or any unfamiliar application, the individual clinical investigator has a choice between a relatively painless exercise or one fraught with futility. 30-llAY WAIT NVESTIGATIONAI.. It is important to understand that the FDA is made up of r~:T~ PERIOD STATUS r""• - ·-~=-- IDEA FOR individuals, with numerous responsibilities. They are few in NEWDAUG D number when compared to the vast variety of products and l procedures being investigated. Your submission must clearly ----- STIDES ·~. ---1 L~ I state the goal of the study as well as the sponsor/investigator's - ..,., ...... _.._,.... ,._..,..,. R£VEW --, competency in carrying out the task. "" """"""'AN>AEVEW I ...... 1 I Another important point is that the FDA is the only game Sn.<>ES I PHASES H II· I •I in town when it comes to utilizing investigative products. ..,. !LI'I'UIEN'I.. They may not always be as expert as you presume. The ...... ,. =.-: IIEPOATS sponsor should present information in a form that the FDA USE OF OAUG ) BY CON&.NERS can understand. Although the investigator fully understands FIG. 3. Schematic rendering of the new drug development process. what he is trying to accomplish, it is often not presented in 240 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY such a fashion to the FDA. It is your task to ensure that the administratively handle the IND function. The CV of study's principal contact communicates well (in writing and the person(s) preparing the radiopharmaceutical is also orally). Frequently, an investigator lets his/her temper or important (pharmacist, technologist). The IND must frustration cause a study either to be placed on hold or delayed state whether the preparation of the radiopharmaceu from having to answer questions that may have been unnec tical will be under the supervision of a physician or essary if one had just been tactful. One can be stubborn but pharmacist (practice of medicine or pharmacy) or be it will not pay off in the long run. Persuasion is far more prepared by a drug manufacturing firm (and, thus, be effective. regulated by Good Manufacturing Practices). A number of simple, common sense, administrative prob 9. The 30-day safety period can be waived on request, lems immediately evident to the reviewer can, if not handled i.e., on an IND for an already-approved drug (because properly, result in unnecessary delays. Paying close attention there would probably be no safety problem). When an to detail and to instructions for filling out the IND is impor IND is filed for what is really the practice of medicine tant. These obvious oversights are mentioned here because and pharmacy, the FDA does not really find it neces they occur so often. Information about how the IND is sary to review the study, nor does it want to. It will, processed inside the FDA is presented to aid the sponsor and/ however, do so as a courtesy at the present time. or investigator. I 0. There are no FDA-required limits on dosage. Each case is examined on its own merit, but consider the follow I. IND Form FDA-1571 must be signed. ing when submitting an IND: Is the risk to be taken 2. The application must be submitted in triplicate. Many worthwhile for the information to be gained? Does the of the applications are held up for this reason. INDs patient benefit or will the information more likely be are initially sent to a Central Record Room where they of benefit to mankind? Clearly, the FDA wants the user are given a number as they are received (INDs are not to administer the smallest dose possible to obtain the numbered by category). The IND is then reviewed by desired effect. three disciplines (pharmacology, chemistry, clinical medicine) and others as required. One final point. Do not hesistate to phone the FDA. This 3. On receipt, the FDA has 30 days to evaluate the IND agency will do its best to help. The answer to your question for safety (safety only, not effectiveness). It is valuable may not always be the one you want, but at least you will not to send the IND by certified or registered mail so that have spent time and resources needlessly. you have proof that the IND was received in order to validate the 30-day safety period. ON-SITE OVERSIGHT AND RESPONSIBILITY 4. Be sure to answer each question and do so in the proper sequence. It is a tedious job to search through piles of Given a process that can be complex in terms of its com paper to find the answer to a question. ponents, establishing a protocol once an investigation is un 5. If the IND document contains many pages, paginate. derway is relevant so that "the ball, so to speak, doesn't get 6. Recognize that INDs are of two major types: (a) com dropped between the cracks." For example, at our institution, mercially-sponsored INDs in which a large population we are performing clinical trials using radiolabeled mono will be put at risk, and (b) individually-sponsored I NOs, clonal antibodies (MAbs) for imaging. The MAb is supplied in which a smaller population will be placed at risk. (manufactured) by a commercial pharmaceutical firm (spon The IND will address two primary situations: (a) one sor). The final dosage form is prepared in the nuclear phar in which the drug has already been approved, perhaps macy and the dose is administered by a nudear medicine for another indication, and (b) one in which there is a technologist in the out-patient facility under oncology nursing new clinical entity, i.e., a new drug. In the former and physician supervision. The technologist later images the situation, the safety may have already been established patient. The nuclear medicine physician interprets the study and literature can be cited. A photocopy of a few and a protocol nurse-data manger collates the data. All the articles attached to the back of the IND as an appendix personnel involved fill out the case report forms. Who then aids the process. If nothing else, it saves duplicate trips is responsible for what? to the library. 7. When calculations of dosimetry are indicated, (a) 21CFR 50.25 Requires an Informed Consent. It is the "walk" the reviewer through the calculations, since he responsibility of the IRB to officially approve the informed or she cannot make assumptions, and (b) include the consent document. The sponsor of the IND need only say total radiation dose to the patient from all modalities. that an informed consent will be obtained. A copy of the 8. The CV of the primary investigator and co-investiga informed consent need not be submitted with the applica tors (if any) is used to ascertain whether their training tion. However, if submitted, reviewers can be quite helpful in the handling and administration of radioactive drugs in pointing out deficiencies in the investigator-prepared is adequate. If the sponsor of the IND is not one of the informed consent forms; this clearly being to the investi investigators, his CV is important to submit, too, since gator's advantage. The investigator often relies heavily upon it is necessary to demonstrate that this person can the sponsor in preparing the informed consent. VOLUME 18, NUMBER 4, DECEMBER 1990 241 The Radiation Safety Committee Oversees Radiation What if this is the first time this treatment has performed Safety. If the trial is a Phase I (a metabolism and kinetic on a patient? The treatment is still the practice of medicine study), then the Radioactive Drug Research Subcommittee and pharmacy. The patient (or his parents acting for him) (RDRC) is responsible; if it is a Phase II or III study, then can choose whether or not to receive the prescribed treat the Human Use Subcommittee is responsible. In any event, ment. the radiation dose to the patient from all facets of the study Example2 is considered, not just the drug in question, e.g., preliminary A nuclear medicine physician and a pediatrician decide to and confirmatory computed tomography scans. collaborate and compare 111 In-oxine labeled lymphocyte scans Scientific Merit. At our institution, the scientific merit in one group of patients with lymphoma to iodine-123- C23I) of cancer-related projects is reviewed by the Scientific Re labeled lymphocyte scans in another group of patients with view Committee. This may also be done at the school lymphoma. The 123I radiolabeling methodology has not been department (Radiology) or hospital level research commit approved. tee and at other levels. Is an IND required before the administration of 111 ln Funding. At our institution, funding is handled by the lymphocytes under these circumstances? This apparently is a Protocol Development Committee. It also may be done at bona fide research study in which the findings from two the school department (Radiology) and hospital department groups of patients are compared. The patient has no choice (Nuclear Medicine) levels. as to which group he or she is entered into. Reference 2 Patient Care. This is the responsibility of the physician; provides a large series of illustrative examples of this type. in our case, nuclear medicine or oncologist, in the event of an adverse reaction, since the physician is best qualified to ACKNOWLEDGMENT treat a patient. Sponsor Liasion. It is the responsibility of the principal The authors wish to thank Judy Holden for her assistance investigator to coordinate and integrate the program as well in the preparation of this manuscript. as to serve as the liasion with the sponsor. NOTE Peer Review. It should be noted that other areas of clinical investigation could be examined by other nuclear The views expressed in this article do not officially represent medicine professionals. These areas include: (a) new indi the views of the FDA. cations for an existing radiopharmaceutical; (b) new routes REFERENCES of administration for existing radiopharmaceuticals; (c) new I. Food and Drug Administration: Information for sponsor-investigators dosage forms; (d) evaluating new salts of existing agents; (e) submitting investigational new drug applications (IND's), FDA. Central Doc animal studies using new or existing agents; and (0 new ument Room. Center for Drug Evaluation and Research. HFN-100/HFN-800. ways of processing imaging data using computer programs. Rockville. MD .• Bureau of Drugs, December 10. 1987. 2. Levine G. Abel N. Considerations in the assembly and submission of the physician-sponsored investigational new drug application. In: Hladik WB. EXAMPLES OF WHEN AN IND IS (AND IS NOT) Saha GB. Study KT. eds. Essentials of nuclear medicine science. Baltimore. REQUIRED MD: Williams and Wilkins. 1987: 357-386. 3. Department of Health and Human Services. FDA, 21CFR Parts Example1 312,341.511. and 514. New Drug, Antibiotic. and Biologic Product Regulations: A hospital-based nuclear medicine physician is consulted Final Rule, Washington, D.C.. U.S. Government Printing Office. Thursday, by a pediatrician, whose patient is depleted of lymphocytes. March 19, 1987, pp. 8798-8849. The pediatrician suspects that the lymphoma in the patient's 4. Siegel BA. Radiopharmaceuticals and FDA: A clinician's perspective. Med lnstrum 1981;15:355-360. cheek is trapping the lymphocytes. The nuclear medicine 5. Siegel BA. Radiopharmaceuticals and FDA: A clinician's perspective. J 11 physician suggests an indium-Ill- C In) labeled lymphocyte Nucl Med Technoll983;ll:l77-l86. scan. 6. Department of Health and Human Services: Guidelines for the Clinical Is an IND required? No, it is not. A specific patient is Evaluation of Radiopharmaceutical Drugs (revised), HHS (FDA)81-3120. being treated (diagnosed) under the practice of medicine Washington, D.C., United States Government Printing Office, 1981. 7. Department of Health and Human Services: General Considerations for and pharmacy. The lymphocytes are a component of an the Clinical Evaluation of Drugs. HHS (FDA) 77-3040. Washington, D.C.. 111 already approved radiopharmaceutical, autologous In United States Government Printing Office, 1977. radiolabeled leukocytes. 8. APhA Supports Change in NRC Rule. Pharmacy Today 1990;29( I ):2. Is informed consent required? No, not from the FDA's 9. The Pharmacist as Principal Investigator. Program Session 104. Amer point of view. If an IND is not required, neither is informed ican Pharmaceutical Association !37th Annual Meeting, Washington, D.C., March 10, 1990. consent. 10. Department of Health and Human Services: Clinical Testing for Safe Is it necessary to have the approval of RDRC if there is and Effective Drugs (revised), HHS(FDA) 74-3015, Washington. D.C.. United one? No. States Government Printing Office, 1981. 242 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY