drug evaluation in gastroenterology

Drug Evaluation in Gastroenterology

;~USTIN SMITH, M.D.

o NE OF THE I~,IOST heatedly discussed set of regulations issued by the

Food and Drug Adminis t ra t ion of the Depar tment of Health, Edu- cation, and Welfare in recent years involves new drugs for investigational use. These are known as procedural and interpretat ive regulations and are based on the federal law that existed before it was modified some months ago by the Kefauver-Harris amendments . T h e Commissioner of Food and Drugs (un. der the provisions of the Federal Food, Drug, and Cosmetic Act) has authori ty to issue procedural and interpretat ive regulations; this can be clone with or without hearings. In general, there must be oppor tuni ty for comment by parties who might be adversely affected, a l though this comment may or may not cause subsequent changes in the proposed wording. After the final order has been issued a short period of time, 30 or more days elapse before it becomes effective.

Less than a year ago the Commissioner issued a n u m b e r of regulations the purpose of which was alleged by the Food and Drug Adminis t ra t ion "to eliminate all unnecessary risks to the public that may at tend the de- velopment of new drugs and to impose only necessary restrictions on the conduct of investigational drug research."

The re can be no justifiable quarrel, nor is there, f rom tile drug indus- try with the intended purpose of the regulations. But there is, and should be, with some of the wording of the proposals. T h e wording has caused an avalanche of criticism by investigators as well as others, who feel there has been slowing down of clinical research as a result. This, however, has been commented on repeatedly by others, including researchers, administrators, academicians, clinicians, members of the press (professional and lay), drug manufacturers, and even lawyers. In fact,

some of the problems encountered have been the cause of headlines. Perhaps this is not the place for a review of what has happened since

the introduction of these regulations, but should the reader be interested in facts that have been made public, an inquiry addressed to me will elicit such information. This paper will present a brief summary of the

From the Pharmaceutical Manufacturers Association, Washington, D. C. Presented at a postgraduate course, "Current Therapy in Gastroenterology" (Nov.

16-17, 1963), sponsored by Louisiana State University School of Medicine, New Orleans, ga.

New Series, Vol. 9, No. 8, 1964 545

C U R R E N T T H E R A P Y IN G A S T R O E N T E R O L O G Y

new regulations and a description, in more detail, of those pertaining to the several phases of clinical investigation.

C L E A R A N C E P R O C E I ) U RES

T h e sponsoring finn or other body or individual acting as sponsor for a drug must file with the Food and Drug Adminis t ra t ion certain information before the sponsor and the investigator can proceed with the clinical investigation of a new drug. Even old drugs in a "new dress" or being contemplated for a new nse are subject to such scrutiny, a fact over- looked by some. So far the FDA has not required withholding the investigation until it reviews the submit ted material , a l though later, on review, the FDA may order suspending the clinical trials if in its judgment such action seems indicated.

Inc luded in the submission of material by the sponsor should be the best available descriptive name of the drug, chemical structure, and how it is to be administered; a list of components of the drug; a s tatement of quant i ta t ive composition; the source and prepara t ion of ingredients; a s tatement of methods, facilities, and controls used for the manufacturing, processing, and packing of the new drug; a statement covering all informat ion available to the sponsor derived from preclinical investigations and any clinical studies and experience with the drug; five copies of all informat ional material , including label and labeling supplied to the investigator; a record of the scientific t raining and experience considered appropr ia te by the sponsor to qualify the investigators as suitable experts; the names and a summary of the training and experience of each investigator and of the individual charged with moni tor ing the progress of the investigation and evaluating the evidence of safety and effectiveness of the drug; a s tatement that the sponsor has obtained f rom each investigator certain informat ion concerning his qualifications and expertness; an outl ine of any phase or phases of the p lanned investigations; a statement that the sponsor will notify the FDA if the investigation is discontinued and the reason therefor; and a statement that the sponsor will notify each investigator if a new-drug applicat ion is approved, or if the investigation is discontinued.*

Wha t clearly emerges so far are several points: A desire of the FDA to be notified when it is intended for an investi-

gational drug to be administered to a human being. A desire of the FDA to be informed about the manufac tur ing and con-

trol facilities of the sponsor of the drug.

*Other informat ion is also required but the need for brevity suggests its omission here.

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S M I T H ~ 1)RUG E V A L U A T I O N

A desire by the FDA to ferret out the available laboratory information before a clinical trial is initiated.

A desire on the part of the FDA to gather information on the qualifications of the investigators.

A desire on the part of the FDA to cause sharing of available information among all interested parties.

Again, there is not, and should not be, any quarrel with the objectives --i.e., the sharing of information about a new drug to be tested by experts and made by those with adequate manufacturing facilities. The quarrels arise essentially over the details of information that are required through paper work; the fear of reprisal if there is unexpected deviation from a filed plan for research for a new drug; the anticipation that sooner or later an administrative agency will attempt to determine who is and who is not qualified.to undertake research in a given area; the annoyance of complying with suggestions, even demands, by a government agency for research work not yet proved desirable let alone necessary; and a host of seemingly contradictory thoughts such as the impossibility of doing a double-blind study under the regulations.

SPECIFIC REGULATIONS

Let me quo te some selected sentences, I shouk l say r equ i r emen t s , in the regu la t ions :

Adequate in format ion ahou t the preclinical iu~estigations, i nc lud ing studies made oll laboratory animals , on the basis of which the sponsor has concluded tha t it is reasonably safe to ini t ia te clinical invest igat ions wi th the drug: Such in fo rmat ion should include identif icat ion of the person who conducted each invest igat ion; identif icat ion and qualif icat ions of the ind iv idua ls who eva lua ted the results and concluded tha t it is reasonably safe to ini t ia te clinical invest igat ions wi th the d rug and a s t a t emen t of where the invest igat ions were conducted and where the records are avai lable for in- spection; and e n o u g h details abou t the invest igat ions to pe rmi t scientific review. T h e preclinical imes t iga t i ons shall no t be considered adeqna te to just i fy clinical test ing maless they gi~e proper a t ten t ion to the condi t ions of the proposed clinical testing. W h e n this in format ion , the ou t l ine of the p lan nf clinical pharmacology, or any progress report on the clinical pharmacology, indicates a need for full r m i e w of the preclinical da ta before a clinical trial is under taken , the D e p a r t m e n t will not ify the sponsor to submi t the comple te preclinical da ta and to w i thho ld clinical trials unt i l the review is comple ted and the sponsor notified. T h e Food and D r u g Admin i s t r a t ion will be prepared to confer with the sponsor concern ing this action . . . .

T h e scientific t ra in ing and exper ience considered appropr ia te hy the sponsor to qual i fy the imes t iga to r s as sui table exper ts to invest igate the safety of the drug, bear- ing in m i n d what is known abou t the pharmacologica l act ion of the d rng and the phase of the invest igat ional p rog ram that is to be unde r t aken .

T h e n a m e s and a s u m m a r y of the t ra in ing and exper ience of each invest igator and of the ind iv idua l charged wi th m o n i t o r i n g the progress of the invest igat ion and evalu-

New Series, Vo[. 9, 14o. 8, 1964 547


at ing the evidence of safety and effectiveness of the d rug as it is received f rom the invest igators?

This, then, is a solid part of the foundat ion on which rests the house of uneasiness now evident in many research circles. T i m e and experience will resolve some of the difficulties. Others, however, will be resolved only by displays of determined, thoughtful effort on the part of all interested parties. Some indications of the problems that have arisen, anticipated by some and unexpected by others, is evident in many of the statements that have been made, and often published, by researchers, business men, administrators, practitioners, and editors. Even medical organizations have voiced concern. Officers of the Pharmaceut ical Manufacturers As- sociation f rom time to t ime have informed members of the PMA anti others about some of the problems, have made suggestions for corrections, and occasionally have flat-footedly had to oppose a specific proposal. For example, in June of this year the PMA office issued a 23-page document for its members on the new FDA regulations and the 1962 drug amendments. T h e Association has even found it necessary to file a statement on the clinical testing regulations with a hear ing clerk, and to initiate a suit in court over one aspect of the new drug amendments .

Incidentally, there are three forms to be completed for drugs under investigation. One, which bears the n u m b e r 1571, is filled out by the sponsor of the research and submit ted to the FDA. T h e other two, which bear the numbers 1572 and 1573, are filled out by the investigator and submit ted to the sponsor.

These, too, bear more discussion than is possible in this short paper. T h e only reason I refer to such activities is to stress what is occurring today and how meaningful it is to so many. In this connection let me refer to the various phases of clinical investigation which could be set forth in simple chronological fashion but which would be less meaningful without some of the preceding associated history.

T H R E E PHASES IN CLINICAL TRIALS

Today it is customary to speak of the three phases of clinical trial. Actually, this has come about because of certain wording in the FDA regulations for p lanned investigations, which read in part as follows:

Clinical pharmacology. T h i s is ordinar i ly divided into two phases: Phase 1 starts when the new d r u g is first in t roduced into m a n - - o n l y an imal and in vitro data are ava i l ab l e - -wi th the purpose of d e t e r m i n i n g h u m a n toxicity, metabol i sm, absorpt ion, e l iminat ion , and o the r pharmacologica l action, preferred route of admin is t ra t ion , and safe dosage range; phase 2 covers the ini t ial tr ials o n a l imited n u m b e r of pa t ien ts for specific disease control or p rophy lax i s purposes. A general ou t l ine of these phases shall

548 American Journal of Dicjes~'ive Diseases

S M I T H : DRUG E V A L U A T I O N

be submitted, identifying the investigator or investigators, the hospitals or research facilities where the clinical pharmacology will be under taken, any expert commit tee or panels to be utilized, the max i mu m n u m b e r of subjects to be involved, and the estimated durat ion of these early phases of investigation. Modification of the exper imenta l design on the basis of experience gained need he repor ted only in the progress reports on these early phases, or in the deve lopment of the plan for the clinical trial, phase 3. T h e first two phases may overlap and, when indicated, may require addi t ional animal data before these phases can be completed or phase 3 can be under taken. Such animal tests shall be designed to take into account the expected durat ion of adminis- tration of the drug to h u m a n beings, the age groups and physical status, as for example, infants, p regnant women, premenopausal women, of those h u m a n beings to whom the drug may be administered, unless this has already been done in the original animal studies.

Clinical trial. This phase 3 provides the assessment of the drug's safety and effectiveness and o p t i m u m dosage schedules in the diagnosis, t rea tment , or prophylaxis of groups of subjects involv!ng a given disease or condit ion. A reasonable protocol is developed on the basis of the facts accumulated in the earlier phases, including completed and submit ted animal studies. Th i s phase is conducted by separate groups following the same protocol (with reasonable variations and alternatives permi t ted by the plan) to produce well-controlled clinical data. For this phase, the following data shall be submitted:

i. T h e names and addresses of the investigators. (Additional investigators may be added.)

ii. T h e specific na ture of the investigations to be conducted, together with information or case repor t forms to show the scope and detail of the p lanned clinical observations and the clinical laboratory tests to be made and reported.

iii. T h e approximate n u m b e r of subjects (a reasonable range of subjects is permis- sible and addit ions may be mad e ) , and criteria proposed for subject selection by age,

sex, and condition. iv. T h e estimated durat ion of the clinical trial and the intervals, not exceeding one

year, at which progress reports showing the results of the investigations will be sub-

mit ted to the Food and Drug Adminis t ra t ion. (The notice of claimed investigational exempt ion may be l imited to any one or more

phases, provided the outl ine of the addit ional phase or phases is submit ted before such addit ional phases begin. Th i s does not preclude cont inuing a subject on the drug from phase 2 to phase 3 wi thout in te r rupt ion while the plan for phase 3 is being developed.)

Ordinari ly a plan for clinical trial will not be regarded as reasonable unless, among other things, it provides for more than one independen t competent investigator to mainta in adequate case histories of an adequate n u m b er of subjects, designed to record observations and permi t evaluation of any and all discernible effects a t t r ibutable to the drug in each individual treated, and comparable records on any individuals em- ployed as controls. These records shall be individual records for each subject main- tained to include adequate informat ion per ta in ing to each, including age, sex, condi- tions treated, dosage, frequency of adminis t ra t ion of the drug, results of all relevant clinical observations and laboratory examinat ions made, adequate informat ion concerning any other t rea tment given and a full s ta tement of any adverse effects and use- ftd results observed, together wi th an opinion as to whe the r such effects or results are

at t r ibutable to the drug under investigation?


C U R R E N T T H E R A P Y 1N G A S T R O E N T E R O L O G Y

In brief, this means Phases 1 and 2 embrace clinical pharmacology, the drug being administered to a small number of patients in a closely controlled environment by or under the supervision of specially trained researchers. Phase 3 permits clinical trial to a larger number of patients by different physicians although they follow the same basic investigational procedures.

Phase 1 involves possibly only one, two, or three, or a small number of" investigators, who understand fully the significance of the preclinical (animal) data and are well versed in clinical testing in the area under

study. Dose range and observance of possible side effects or toxic reac- tions rather than efficacy are important in this stage of exploration. On the basis of the findings with a limited number of patients, the advisa- bility of making additional clinical trials will be decided. In Phase 2, the help of a half-dozen to perhaps two dozen or so investigators will be utilized. Each investigator may test the drug or procedure on a half- dozen to a dozen or so patients. These additional studies may reveal the limitations of tlde drug, the need for more animal studies, or the need for digression of originally planned research.

In Phase :4 the drug is tested fairly widely by many so that this condition of medical practice will reveal limitations as well as usefulness. Ob- servations on hundreds to even thousands of patients may be involved in this stage of clinical investigation.

Obviously healthy individuals as well as those who are ill are necessary for the kind of information that finally is necessary to compile on what to expect and what not to expect from any drug. Even then, the unexpected may arise months after all conceivable work is completed. The complex human body is never completely predictable in its responses.

This subject has been discussed in one way or another in a number o[ publications including a symposium published in the official journal of the National Society for Medical Research.'-' Of the ~everal articles that might interest readers of this journal, one discusses the clinical evaluation of pharmacologically active compounds and gives some hint or tlde breadth of research knowledge necessar} today to satisfy researcher and {linician as well as government.

T H E EFFECT ON RESEARCH

What about new drugs and the gastroenterologist? Tide research problems confronting the gastroenterologist in this area are essentially the same as those for other researchers under the new regulations and laws.

Years ago, perhaps close to twenty, several research-oriented individuals from the FDA and I (then acting as Secretary of the A.M.A.'s Council on

550 American Journal of Dicjesfive Diseases

S : \ I I T H : D R U G I ' ; V A I : I ; A T I O N

Pharmacy and Chemistry) prepared a paper on the evah ,a t ion of new drugs.a, 4 I t embraces comments on the need for specific tissue studies; short- term and long- term studies; acute, subacute, and chronic studies; anl,l m a n y other facets of researl,h needs.

T h e r e was no th i ng worll,l-shaking about this paper a l though m u c h of it appeared subsequent ly in tile chapter in a book on the l,levelopment anl,l in t roduc t ion of a new l,lrug, i n fact, many papers appeared on the subject before this one, and p robab ly even more have been wri t ten since then. T h e poin t I want to make is that there is no th ing static about mel,t- ical research; it is about the most fluid th ing since the l,tiscovery of water. Unfor tunate ly , this sometimes is over looked in public, acal, lemic, research, industrial , anl,l gove rnmen t circles.

T h e r e is no such th ing as a stanl,larl,l h u m a n body, or standarl,l h u m a n cell, or final anl,1 foo lproof test, or scientific, social, or legislative crystal ball. Society is conf ron ted almost daily with changing neel,ls. So is research. So is government . Even our ideas concern ing inan imate objects must change with the receipt of new knowlel,lge. So, then, mus t ou r out- look on research, par t icu lar ly as it per ta ins to the use of new drugs.

T h e so-called three phases of clinical research for new l,lrugs should be regarded as guidelines and not as bounl,laries. T h e over lapp ing and the flexibility at times are unanticipatel,l, sometimes even inconceivable. Thus , it is necessary for each researcher tol,lay to be mindfu l of laws and regulations, as well as risks of new exper imenta l technics and theories, as well as accepted practices, and of chang ing publ ic concepts, as welt as medical neel,ls. T o refrain f rom do ing needed research is as ques t ionable as explor ing the u n k n o w n only to satisfy curiosity and no t to advance medical knowlel,lge to benefit man. But unless the researcher is today prepared to speak out on policy issues, inc lud ing research, to defend that which is necessary to preserve and plead for improvemen t where inl,li- l,:atel,l, to provil,le leadership for those who are less in formed and no t be content with fol lowing the more vocal because it is less t roublesome to do this, the researcher may well find himself in the posi t ion of being a technician ra ther than researcher.

Observat ion and in te rpre ta t ion are only par t of research; vision, ex- p lorat ion, and just plain courage are equal ly impor tan t . Research is no t a pure ly physical act. I t is a combina t ion of m i n d and body. Or as T o r a l d Sol lmann described it, "Research is the search for new facts and new factual relations; it is the persistent endeavor to wrest somewhat more of s ign i fcan t knowlel,lge f rom the universe of the u n k n o w n in which we live."

1411 K Street, N.W. Washington 5, D. C.



R E F E R E N C E S

I. Federal Register, J a n u a r y 8, 1963. §130.3. 2. Sympos ium: B i r th of a new drug. Biomedical Pu~,iew 3:1, 1963. 3. VAN WINKLE, W., JR., HERWICK, R. P., CALVERY, H. O., and SMITH, A. Labora tory

and clinical appra isa l of new drugs. Counci l on Pha rmacy and Chemist ry . Repor t of the Council . J. A. M. A. 126:958, 1944.

4. W*N WINKLE, W., JR., HERWlCK, R. P., CALVERV, H. O., and S?alTn, A. Appraisal of new drugs. Letters to the editor. J. A. M. ,'I. 127:353, 1945.

552 American Journal of Digestive Diseases

drug evaluation in gastroenterology

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