fact that a compound or preparation failed to produce results or caused undesirable side effects is important information for other investigators. A brief note regarding negative results should be published, so that it will be catalogued in the medical literature. It is very difficult to accept the manufacturer's statements regarding therapeutic effectiveness when the only source of information is personal communication between the manufacturer and the investigator. Acceptance of a new drug should not be expected unless the physician is given an opportunity to read the complete report of studies including the experimental design on which the manufacturer bases his claims.

Conclusions

The development and testing of a new drug is a long and arduous process. The responsibility of the manufacturer for the clinical evaluation of each new drug is continuously increasing. This has necessitated the expansion of facilities and the number of employees. In 1958, at Eli Lilly and Company, approximately 1,300 persons of a total of 8,000 employees in the United States were devoting their full time to research, development, or control. All this effort is destined to give the practicing physician the new therapeutic agents that will enable him to provide the best medical care. Proper use of these additions to his therapeutic armamentarium requires that the physician have complete information about their properties, so that each drug may be used with maximum safety for the patient and in a manner that will give optimum results.

In his opening remarks at a symposium in London (1958) on quantitative methods in human pharmacology and therapeutics, Sir Charles Harington' called attention to the possibility that, in our effort to assess therapeutic effect, the keen and accurate obser

543

vations needed will on occasion yield new insight into the disease process being studied, and thus advance medicine in the general sense. The pharmaceutical industry has come to occupy an important place on the "health team."

References

1. Atchley, D. W.: The Changing Physician, Atlantic Monthly 198:29-31, 1956.

2. Bickerman, J. A., Cohen, B. M., and German, E.: Cough Response of Normal Human Subjects Stimulated Experimentally by Citric Acid Aerosol: Alterations Produced by Antitussive Agents; Methology, Am. J. M. Sc. 232:57-65,

1956.

3. Chernish, S. M., Gruber, C. M., Jr., and Koblstaedt, K. G.: Obtaining Data by Telephone. A Clinical Evaluation of Hypnotic Drugs, Proc. Soc. Exper. Biol. & Med. 93:162-164, 1956. 4. Gardner, M.: Mathematical Games, Scient. Am. 201:181-188, 1959.

5. Gruber, C. M., Jr.: Interpreting Medical Data, A.M.A. Arch. Int. Med. 98:767-773,, 1956.

6. Gruber, C. M., Jr.: Codeine Phosphate, Propoxyphene Hydrochloride, and Placebo, J.A.M.A. 164:966-969, 1957.

7. Harington, C.: Opening remarks in Laurence, D. R., editor: Quantitative Methods in Human Pharmacology and Therapeutics, New York, 1959, Pergamon Press, Inc., p. xvii.

8. Kast, E. C., and Loesch, J.: A Contribution to the Methodology of Clinical Appraisal of Drug Action, Psychosom. Med. 21:228-234, 1959. 9. Modell, W., and Houde, R. W.: Factors I fluencing Clinical Evaluation of Drugs With Special Reference to the Double-Blind Tech nique, J.A.M.A. 167:2190-2199, 1958.

10. Shapiro, A. P.: In Waife, S. O., and Shapiro, A. P., editors: The Clinical Evaluation of New Drugs, New York, 1959, Hoeber-Harper, Inc., P. 114

11. Shipley, R. E.: Symposium on Sitosterol. 1. The Effects of Sitosterol Ingestion on Serum Cholesterol Concentration, Tr. New York Acad. Sc. 18:111-118, 1953.

12. Waife, S. O.: In Waife, S. O., and Shapiro, A. P., editors: The Clinical Evaluation of New Drugs, New York, 1959, Hoeber-Harper, Inc. P. 214.

13. Wolf, S.: In Waife, S. O., and Shapiro, A. P., editors: The Clinical Evaluation of New Drugs, New York, 1959, Hoeber-Harper, Inc., p. 87.

87-272 0-64pt. 313

544

THE

HE INITIAL clinical trial is a crucial matter in the development of a new drug. The risk inherent in its first use in man, and the need to obtain a true evaluation of its action before large sums of money are invested in materials, make it imperative that the initial trial be a well-controlled study. It should be conducted by a physician who is trained in this form of clinical research and the investigation should be performed in an environment that permits accurate observations. Years of effort in research and testing which may have preceded the first clinical trial will have been wasted if the first tests in man are not appraised ac curately.

The physician who administers a new compound has a responsibility to the patient or volunteer who will be taking the drug. It is necessary, therefore. that all available information be made known to the physician before he undertakes an initial clinical test. Experience in pharmacology is a valuable asset to any physician who wishes to participate in the evaluation of new drugs.

The preclinical data may indicate the nature of any hazards that may exist when the drug is used in man. These must be weighed against the opportunity which the drug offers to benefit the patient directly or by adding to the physician's armamentarium. For example, a drug that may effect relief in a life-threatening disease for which there is no therapeutic agent that is safe or free of serious side reactions might be given to patients with the disease despite the fact that undesirable side effects are likely to occur.

On the other hand, if a new analgesic were being considered, the results of preclinical testing should indicate that the chances of encountering side effects within the expected dosage range would be remote. In other words, the criteria for deciding that a new analgesic merits trial in man are different from those that should be applied in considering a new compound for cancer chemotherapy. Although the difference between the quantity of

From the Laly Research Laboratories.

Proscated as part of the Symponom on the Safety Evaluation of Fire Drugs before the joint meeting of the Section on Experimental Medicine and Therapeutics and the Society of Toxicology during the 112th Annual Morting of the Amenen Medical Association, Atlantic City, NJ, June 17, 1908.

a drug that will kill half the animals (LD) and the amount that will give the desired effect in half of the animals (ED) is important, it is not enough on which to base the decision as to whether or not a new drug should be tried in man.

It is generally accepted that a new drug should have been administered in large amounts (much more than the amount estimated as necessary to obtain the desired response) for at least 30 to 60 days to two or more species of animals before the first dose is given to a human subject. During this time the animals should be carefully observed. A deviation from normal in rate of growth or weight gain or loss, or the occurrence of an abnormality in hepatic or renal function or hematopoiesis, necessitates an additional period of study before the drug can be accepted for the first clinical trial. Half of the animals should be killed, with careful examination of the tissues providing added assur ance of the safety of the drug before the clinical test is undertaken.

In instances in which a new drug appears to afford relief in the treatment of a heretofore incurable disease there is no doubt that a clinical trial is indicated and there should be no difficulty in obtaining the services of a competent investi gator. Furthermore, many important advances in therapy have resulted from the clinical trial of new substances which at the outset did not show great promise of being superior to existing therapeutic agents. If is these compounds that require careful consideration before a decision can be made to test them in man. Frequently it is necessary to conduct a conference between the physicians who will evaluate the drug and the scientists who partici. pated in its preparation and testing in animals. Regardless, the physician has the responsibility for making the final decision as to whether or not the drug is reasonably safe for administration to man and whether there is sufficient evidence to merit a clinical trial.

In March of 1983, new regulations issued by the Food and Drug Administration made it mandatory to submit to this agency a complete report on the nature of the drug, its composition and properties, the method of preparation and tests for quality

control, and the results of all preclinical tests in animals as well as in in vitro studies. The plan for the proposed clinical trial must be outlined and the investigator must sign a form indicating that he is aware of the new regulations and will abide by them. Also, his qualifications as an investigator must be on file with the sponsor of the program.

Rigorous Control Procedures

It is important that all material used for clinical trial be subjected to rigorous control procedures. Capsules are preferred over tablets for the first clinical study because there is less chance of reaction or failure of disintegration. Variations in the composition of the active ingredient or in the pharmaceutical formulation from lot to lot may cause results to vary. Material used for studies of toxicity in animals should equal the purity of that which will be given to human subjects. Variation in clinical material has sometimes been the cause of a difference in results obtained by two investigators.

A recent personal experience illustrates the importance of knowing the exact composition of the substance being tested. The frequency and severity of untoward symptoms that occurred in the course of the preclinical trial of an anticholinergic preparation were found to be related to the ratio of d- and l-isomer in test material. By controlling this ratio it was possible to reduce the occurrence of side effects when an effective dose was given.

Because slight diferences to purity, chemical composition, or pharmaceutical form may have farreaching effects on therapeutic activity, the investigator should not be hasty in reaching a conclusion concerning the inactivity or the unsatisfac tory behavior of a new drug.

The requirement that all information about a new drug be fled with the FDA prior to its initial trial in man ofers an opportunity for this agency to be of service to medical research-that is, it will be possible to call to the attention of the sponsor of an investigation the experience of other persons with a similar drug. Because, as stated above, slight changes in chemical composition may alter appreciably the pharmacological activity of a drug the data in the FDA files must be interpreted with caution. Injudicious use of this information could seriously handicap the development of new drugs and thus stiße progress.

The increase in the number of new compounds being synthesized by chemists or being isolated from plants-plus the additional new drugs obtained by the activity of microorganisms, ie antibiotic culture broths-augments the need for clinical trials. Recent legislation and the accompanying regulations of the FDA have served to discour age physicians who were interested in the clinical testing of new drugs. The result has been a rapidly increasing competition for the services of compe

tent investigators who have adequate research facilities. The ordinary ward of a general hospital is usually not a satisfactory location for the first trial of a new drug because the nurses are concerned primarily with patient care. Collection of quantitative urine specimens is difficult, dietary control is often not adequate, and close observation of the patient is not always practicable.

Clinical Research Units

There is a need for research units that provide the proper environment and personnel competent to conduct initial clinical trials. These units could be established in academic centers with large outpatient clinics that would provide a reservoir of patients and normal subjects for tests. Another possible solution is for the pharmaceutical manufacturer to staff and support a clinical research unit, as is currently being done in the field of toxicology. The personal experience of the author in such a research unit at the Marion County General Hospital in Indianapolis has provided proof that this is not only feasible but most satisfactory. Perhaps several manufacturers could pool their interests in support of a single unit.

In addition to a hospital ward, it is essential that the unit include laboratories for chemical and bacteriological tests. It is also requisite that the tests be performed as often as may be indicated during the period of observation. Methods employed may necessarily be more elaborate than those suitable for a hospital clinical laboratory. When these tests add in extra burden to the laboratory, the primary responsibility of which is to provide diagnostic data for patients on regular wards, there may be delays which could create serious problems.

One objection to this type of research is that the physician who is a full-time employee of a pharmaceutical manufacturer would be biased in favor of the drug. This is not true; the employee of the manufacturer is most anxious to obtain the correct information about a drug from his initial clinical trial. If he overlooks a satisfactory response it may mean a serious loss to his company. If he concludes from the first trial that a new drug has the desired activity and this is not confirmed by other investigators, the error may be even more costly because an extensive program may already have been launched. Furthermore, in a clinical research unit supported by the manufacturer it is possible to test several compounds that are closely related and thereby select the one which is most suitable. These physicians should not engage in private practice and they must abide by the rules applying to the staff of the hospital in which the research unit is located. They are privileged to serve in the outpatient clinics and as attending physicians on the regular wards. Such services are essential because they provide contact with patients and, fre

quently, normal controls who may volunteer as subjects for clinical trials. With the cooperation of the visiting staff it is possible to transfer these patients to the research ward during a given study. In this way, many trials can be performed using a small number of hospital beds.

Being full-time employees of a pharmaceutical manufacturer, the physicians can devote more time and perhaps have a greater interest in planning and conducting drug evaluations than if the testing were secondary to private practice or teaching. They are personally required to observe the patients during the period of clinical trial; this duty is not assigned to interns and residents. They should have had training in the methodology of testing drugs and they should have a thorough knowledge of the disease for which the drug is to be used. They are expected to keep abreast of the latest diagnostic procedures and treatment for the disease that is under investigation.

Initial Clinical Trial

If preclinical testing has been thorough and animals have been closely observed, a great deal of useful information will be available for guidance in selecting the amount of the first dose to be given to man. It is important to remember that it is never . safe to extrapolate the dose from animal to man. Although generally the amount that produced the desired effect in a dog weighing 10 kg (22 lb) can be given as the first dose to a human being weighing 50 kg (110 lb). each drug must be considered separately. If the difference between LD and ED is small, then the first dose in man should be very much less than would be estimated from experience in animals. After the quantity to be given is selected, this amount is administered to one patient. If no undesirable effects occur, the same amount is given to a second and then to a third patient. Provided that there have been no untoward symptoms, the first subject then receives a larger dose, but the increment should be small. During an initial trial the cardinal principles for safety are to begin with a small dose, increase it gradually, and keep the patient under constant surveillance. This procedure is continued until the desired effect is obtained, until untoward symptoms occur, or until as much as 1 or 2 gm have been given and no activity is noted. Larger amounts are seldom practical by the oral route of administration. When a drug is given intravenously, it is advisable to give the first doses in very dilute form, injecting slowly into the vein or administering by infusion.

When single doses have been shown to produce satisfactory responses in several subjects and the duration of effect has been determined, the same dose of the drug may then be given at regular intervals. The efficiency of observations during clinical trial will be improved if equipment for

continuous monitoring of vital signs-blood pres sure, pulse, respiratory rate, etc-is available.

During the initial trial, observations in the realn of pharmacology are made. Sometimes this formation can be best obtained by tests on normal persons rather than on the patients. For example, before an antibiotic is used in the treatment of disease, the absorption from the intestinal tract, the duration of an effective concentration in the blood after a single dose, and the percentage of the administered dose which appears in the urine are determined. Were the trial of an agent for the control of malignant disease to be conducted, however, very little could be accomplished by giving the drug to normal subjects. As has been mentioned previously, rather serious side effects might be acceptable if the drug shows promise in the contral of an incurable disease.

The Problem of Bias

The elimination of bias is essential in all stages of clinical trial, but it is especially important in the early stages of evaluation. Gruber states, "A bias, experimentally, is any uncontrolled and/or unrecognized factor which by acting in a single direction may alter the results of the study." Bias may be either in favor of the desired result or against it. When the action of a drug can be measured by objective tests, ie determination of a change in blood sugar or blood pressure, or activ ity or serum against bacteria, testing is relatively easy. When the evaluation must depend upon the relief of subjective symptoms, the design of the experiment becomes of great importance.

Every precaution must be taken to eliminate bias, not only of the physician and nurse, but of the patient or subject as well. The attitude of the physician toward his task of evaluating a new drug can be transferred to the patient. The manner in which questions are asked can reveal the answer the investigator would like to hear. This form of bias can be eliminated by having questions printed so that the phraseology will always be the same and inflections in the voice of the physician or nurse will be eliminated, avoiding any clue to the answer the observer expects. We have also used a peg board with questions in printed form. The subject merely inserts the peg in a hole labeled "yes" or "no" opposite each question.

An example of bias is illustrated by the experi ence of one of my colleagues who investigate the effect produced by increasing the number of placeho tablets prescribed. No side effects were reported when a group of subjects received one placebo. Several individuals described untoward symptoms when they were given two placebos and others noted nausea and headache when they received three tablets. These subjects assumed that the dose of a medication had been increased. This bias can be eliminated by using three tablets as the

initial dose-one containing the active agent and two placebos identical in appearance. Thus the dosage can be increased or decreased without the patient being aware that a change has been made. Similar variations can be accomplished by placing more, or less, of the drug in capsules of identical size.

Nurses assisting with a study should be instructed never to discuss the nature of the drug, the anticipated results, or the side effects with the patients and never to permit discussion of these or similar subjects among the patients or their visitors. Dose Response

When sufficient data have been collected to establish that a drug is active in man, it is necessary to increase the amount given so that a "dose response" can be developed. The next step is a comparison with a known drug. Again, experimental design becomes very important. The patient will serve as his own control in the "crossover" type of study. Randomization must be planned. Such devices as the "Latin Square" are employed to be sure that the new drug is given prior to the control drug as many times as it is administered after the control substance. When patients with disease are used as subjects, a known drug is usually used for control, but when normal subjects are partici

pating, the use of a placebo and double-blind techniques are essential.

It is always desirable to perform a battery of hepatic and renal function tests before beginning the initial clinical trial. These tests should be repeated at intervals after a dosage schedule has been established. The initial clinical trial is considered complete when dose response has been es tablished and definite activity has been demonstrated. The entire procedure is usually finished within 30 days. At this point it is customary to discontinue the use of the drug in man until it has been administered in large amounts for at least 90 days to more than one species of animal. When sufficient evidence of its safety has been accumulated from the toxicity testing, the second phase of the trial is undertaken. At this time the drug is placed with several competent investigators for indefinite trial periods. The results from the initial clinical trial are presented to the investigators and plans are made for future studies on the basis of the data that have been collected during the first phase.

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Reference

1. Gruber, C.M., Jr.: Interpreting Medical Data, Arch Intern Med (Chicago) 98:767, 1958.