be able to perform the first human trial in a clinical research unit of a large hospital.*

Normal human volunteers may be used in these initial trials. Occasionally, depending on the drug involved, volunteer patients with mild illness are accepted on the program. They are kept under constant observation by trained investigators.2

The selection of the dose in the first human trials is fraught with difficulty. There is no pat formula. Usually the minimum amount expected to produce some result (based on data from dogs and monkeys) is considered, and only a fraction of this is given at the first dose. After experience with several subjects, the small single dose is gradually increased until a therapeutic result is obtained, or toxic effects noted, or a maximum practical dose achieved.

Concomitant with the therapeutic evaluation, careful observation is made of blood, urine, renal, hepatic, and other functions. Metabolic studies, such as sodium balance in the testing of new steroid compounds, are also performed because, in a sense, this phase in the life of a new drug may be considered "clinical pharmacology,"** that is, the study of drug action rather than comparative therapeutic efficacy.

If we assume that our drug "X"

The Lilly Laboratory for Clinical Research at the Marion County General Hospital consists of several wards, outpatient clinics, biochemistry and physiology laboratories, a library, and other facilities in which intensive studies of early clinical trials with new compounds have been performed since 1927.

Carr has recently detailed the organization of a "clinical pharmacology" service.

has shown promise, in that the desired effects are being produced at a known dose level without evidence of toxicity in the small group of subjects of the first phase, we must go on to the next step.

Infancy and Childhood.

In the second phase, the drug is offered to a number of qualified and experienced clinicians, usually in university hospitals, large clinics, and so on, where careful and continuous observation is possible and where excellent laboratory facilities exist. The need for specialized laboratory determinations, for example, measles antibody titer, may limit the distribution of certain drugs.

It is here that the newer methodology in experimental design comes into play. The "double-blind" experiments, the, rigidly controlled series, randomization, the Latin square design, and other technics are involved, because at this stage the investigators are in essence asking the question, "How good is the new drug?" or, rather, "How much better is the new drug than something else?"

That the performing of clinical trials has become a new scientific discipline is becoming well recog

nized.6-11 The methodology is no less rigorous than in traditional experiments with laboratory animals, but the multitude of human factors greatly complicate experiments in man and require even greater care in their performance and the subsequent evaluation of results. The matter of statistical significance, the subjective responses, the role of the placebo, and the ethical considerations are some of the large facets only now being clarified.

The infancy and childhood of a new drug comprise months and often years of meticulous data collecting. Eventually, however, the baby must be exposed to the wide, wide world.

Adolescence.

The third phase of clinical trials with new drugs recognizes that all of the detailed experiences accumulated during infancy and childhood are based on relatively few patients. Now one must ask, "How does it work in the field?" Most new agents will not be used in the rigidly controlled environment of a research ward or university hospital. In the broad clinical trial, the general practitioner or practicing internist or pediatrician plays an essential role.

Advantages of Participation by the General Practitioner.

The advantages that accrue from participation in clinical investigations by the general practitioner are many. Those that come first to mind are:

(1) There is a continuity and uniformity of observation in that

the same person who took the history, conducted the physical examination, and coordinated laboratory data, also follows the patient's subsequent course. His clinical observations are made in the perspective of familiarity with the patient's past experiences, with his social and economic setting, and his mental and emotional reactions. The general practitioner is more likely to know the patient as a thinking and feeling individual with reac tions characteristically his own. Certainly this makes a significant difference if the problem is subjective evaluation of symptomatic relief.

(2) The family physician alone has the opportunity to study a drug in its proper surroundings if the drug is one eventually to be used at the home or office. It may be one thing to study a hypnotic in a hospital setting and quite another thing to see if it will work at home. This is often forgotten in the clinical evaluation of new drugs.

(3) Participation by the family physician in clinical trials may be the best way of developing a critical, objective sense with respect to all drugs. Only one who has actively participated in such a study can readily appreciate the numerous sources of errors or of uncontrolled factors which creep into all clinical investigations.

Disadvantages.

There are certain disadvantages to this phase of the program. In any study involving perhaps hundreds of individuals there will be a considerable variation in the skills of the physician. Patient-groups

will not be comparable, the subjective influences will be especially difficult to control or compare, and there will be considerable differences in the socio-economic and physical settings of the therapy.

It will also be difficult, if not impossible, to study alternate or adequately controlled cases, and for some preparations a "double-blind" technic cannot be used.

A more correctable disadvantage is that there is at present a widespread unfamiliarity with the proper technic of a clinical trial, although more and more articles on methodology are appearing in the literature.

Characteristics of Broad-
Scale Evaluation.

It should be pointed out, however, that by the time an independent clinician obtains the drug, many special studies have been (or should have been) done. This is especially true regarding toxicity, average dose, etc. In short, truly experimental control studies (using double-blind and other technics) are not necessary at all levels of investigations. Instead, what is needed is a study of: (a) the practical uses of the drug in its proper setting; (b) its comparative value; and (c) possible toxic or significant side effects upon chronic administration.

One more point needs amplification. If a drug produces annoying side effects in only about one per cent of cases, it is clear that several hundred patients will have to be studied before this finding will be noted. Because it is occa

sionally impractical and unwarranted to withhold certain drugs from the public until hundreds or thousands of cases have been studied for many months, there will of necessity be instances in which rare complications are noted after the drug has been made available for some time.

In the broad clinical trial, careful control over distribution of the drug is maintained. In other words, the pharmaceutical research staff knows who has the drug, how it is being tested, and where. Since the physician must sign the Statement of Investigator form (FD 1573), he is responsible for the use of the compound under his supervision. Therefore, he cannot in turn give it to other clinicians.

In addition, with a point of central communication (the pharmaceutical company acts as the "nerve center"), it is possible to have new information rapidly passed on to all investigators. If a new indication or a contraindication is found, or changes in dosage are indicated, this is related to the drug company which can, in the shortest possible time, notify any or all other investigators throughout the country.

Not all drugs follow the 3-phase program. When rare disorders may be helped, when serious or lifethreatening diseases (treated only in large hospitals) are involved, there may be no typical "third" phase. Obviously, the problems of testing an antileukemia agent are different from those of a cough depressant; an antimeasles vaccine, from a tranquilizer.

Obligations.

There are mutual obligations when the practitioner participates in obtaining data for the pharmaceutical company prior to submission of a new drug application to the Food and Drug Administration. The drug company must supply the investigating clinician with all available data, both in vitro and in vivo, both animal and human. By implication, the drug company should not contact outside investigators (at any stage) until sufficient basic information is available. The manufacturer, through its experienced medical staff, often suggests plans of study, standardizes the data required, and establishes criteria for effectiveness. By use of evaluation forms of one type or another, it is possible to collate data from diverse clinicians in varying situations in a way which makes combining the data meaningful. Often, in largescale studies, electronic data processing machines are useful.

On his part the practitioner participating in such a program has obligations too. He must properly select patients expected to be benefited and to be followed. He must keep full and accurate records— a matter of considerable importance. He must furnish all information promptly to the company, thus enabling it to communicate this promptly in turn to all concerned. He also should consider compiling, collating, interpreting, and publishing his results so that the fruits of his labor will be available to other scientists.

Coming of Age.

At long last, and it often is after years of study, when the data from animals, patients, clinical and laboratory reports are all in, the pharmaceutical company must decide if the new drug adds to the physician's armamentarium. Not every drug is a "breakthrough”—some merely offer alternatives to existing therapy-but to the patient with intolerance or sensitivity to existing drugs the new one is quite important. All the data, together with a mass of material regarding control procedures, assays, manufacturing details, and so on, are forwarded to the Food and Drug Administration. For one preparation recently there were some 8,000 pages of data!

If and when the drug is permitted to be sold, the obligations of the pharmaceutical company do not end at that point. First, in most progressive companies, there is a continuous program of up-grading. Improvements in manufacture have lowered the costs of many essential drugs. Improvements in taste, "pharmaceutical elegance," solubility, stability, etc., are a never-ending project.

The collecting of adverse reports, their prompt investigation and report to the Food and Drug Administration (and, as needed, to the profession), the subsequent (and continual) revision of the product's literature as new information pours in, new dosage schedule, new indications, new side effects and contraindications, are part of this never-ending program of being current, as experience

3. Carr, E. A., Jr.: Proposed Aims, Organization, and Activities of a Division of Clinical Pharmacology, Clin Pharmacol Ther 4:587, 1963.

4. Lasagna, L., and Meier, P.: Experimental Design and Statistical Problems, in Clinical Evaluation of New Drugs. (Edited by S. O. Waife and A. P. Shapiro) New York, Paul B. Hoeber, Inc., 1959, p. 37.

5. Blank, H.: Clinical Trials, A Scientific Discipline, J Invest Derm 37:235, 1961. 6. Modell, W., and Houde, R. W.: Factors Influencing Clinical Evaluation of Drugs: With Special Reference to the Double-Blind Technique, JAMA 167: 2190, 1958.

7. Welt, L. G.: Reflections on the Problems of Human Experimentation, Conn Med 25:75, 1961.

8. Bakke, J. L.: Use of the Placebo in Tests and in Treatment, Northwest Med 59:1134, 1960.

9.

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Clinical Evaluation of New Drugs. (Edited by S. O. Waife and A. P. Shapiro) New York, Paul B. Hoeber, Inc., 1959.

Medical Surveys and Clinical Trials: Some Methods and Applications of Group Research in Medicine. (Edited by L. J. Witts) London, Oxford University Press, 1959.

Beecher, H. K. Experimentation in Man. Springfield. İll., Charles C Thomas, Publisher, 1959.