treatment of a disease for which there was no satisfactory therapeutic agent. It was tested clinically in relatively few patients because of the low incidence of the disease, its serious nature, and the fact that the drug trials were carried out under close supervision in hospitals. The oral antidiabetic agent required a wider margin of safety and, thus, more extensive testing because safe and effective drugs for diabetes were already available-insulin, for example. Its broader clinical trial was indicated because diabetics receiving the drug would not necessarily be hospitalized and because it might be used by diabetics over a long period of time.

Incidentally, the clinical trial of the drug for leukemia, Vincristine, was referred to before the subcommittee by a previous witness, C. Gordon Zubrod, M.D., Director of Intramural Research of the National Cancer Institute, when he testified April 23.

With reference to facilities, unless a subject can be kept under observation by a qualified observer throughout the 24 hours of each day during the first trial of a new substance, he should not be used in the study, in my opinion. He should be under observation until all possible effects of a single dose have disappeared.

In my clinical investigation work, I have been fortunate enough to have available, through Eli Lilly & Co., the facilities of a hospital ward and laboratory at Marion County General Hospital in Îndianapolis. This has made it possible for me to see that the first person to take a new drug has done so under conditions which are as completely controlled as it is possible to make them.

Several important determinations are made from the initial clinical pharmacology on a person or persons who can be observed continuously. The first study establishes the therapeutic activity of the drug in man and a dose range and provides the opportunity to observe the occurrence or lack of side-effects.

One of the important problems we have at this stage is, of course, the selection of this initial dose. We always start with a dose much, much smaller than would be anticipated as the proper dose on the basis of animal work. I can't emphasize too strongly to the subcommittee that, in the initial trial of a clinical drug, there is a cardinal and important principle that you cannot be in a hurry. You must go about this slowly, deliberately, with small increments of the drug. There is no formula which will enable the investigator to translate a dosage found suitable in animals into one which is guaranteed safe for human subjects. A cardinal principle is to select the minimum amount expected to produce some therapeutic effort and then, for safety's sake, to give only a portion of this amount as the first dose to a human being.

After the first dose of an experimental drug is given, the amount is gradually increased, with the clinician keeping a sharp eye for signs of toxic reaction, as well as for evidence of therapeutic effect. Normally, it requires many tests to provide data regarding the effects of a drug on body chemistry or tissues.

Phase 2-Clinical pharmacology (pt. 2)

Now let us presume we are ready to expand our clinical trial programs into what has been called the second phase.

Having demonstrated a therapeutic effect in a very small number of patients, the physician-monitor will present the results to several other experienced investigators. It is desirable that advisory committees or panels be utilized for consultation, and their members should be expert clinicians who are recognized for their knowledge of the disease to be studied.

Also, I would like to emphasize that, by having a conference of the investigators at this time, it is many times possible to avoid unnecessary duplication. In other words, it is not necessary to have four or five competent men performing exactly the same studies. This information can be exchanged.

In Atlantic City, at the present time, there is a meeting of the American Society of Clinical Investigators. When all these men are in Atlantic City, it is frequently possible to set up these meetings and have this sort of a conference.

The studies of these advisory committees or panels will confirm and extend observations made during the initial tests or they will uncover evidence which will lead to the compound's rejection as a new agent in human medicine.

Plans for continued study will, of course, vary with each drug and with the purpose for which it is intended. But in this second stage attention is focused on a limited number of well-controlled studies by outside experts, with emphasis being placed on efforts to find out the mechanisms of action and the metabolic pathway of the new compound. Studies will also be conducted to determine response to administration of larger amounts of drug. This information leads to the development of the details of a dosage schedule.

The physician-monitor continues to be the focal point for the entire program. As coordinator of the investigation, he has the important duty of avoiding the delay and unnecessary costs in duplicating studies. He must keep in touch with investigators and relay to them additional information about the new drug as it becomes available. If one of his clinicians reports an adverse effect, the monitor has the responsibility not only of reporting the observation to FDA but also of alerting other investigators.

When there is sufficient evidence that the drug can be safely administered not only to hospitalized patients but to outpatients in clinics or to persons visiting a physician in his office, the compound is ready for the third stage of the investigation, or "clinical trial." Phase III-Clinical trial

This is one of the areas in which the terminology has been controversial. But this encompasses more than one type of clinical trial. There may be a very broad clinical trial or phase III may be a further extension of phase II. As I mentioned earlier, with an antileukemia drug we went from a phase II study to what might be called a clinical trial, but it was limited to a relatively small number of experts working in the field of hematology in hospitals throughout the country. This was an entirely different sort of clinical trial than we would have for an antidiabetic drug.

I might use an analogy somewhat similar to Dr. Zbinden's about an airplane. When a new type of aircraft is designed-say, a jet

transport for commercial use-it is, of course, put through many laboratory tests to determine the power of its engines and its aerodynamic qualities. But after all of the simulated flight studies, in order to establish its airworthiness, it is then necessary actually to test-fly it under the conditions of everyday use. So it is with a new drug. Reports on its use in groups of people who are seen in the everyday practice of medicine by competent physicians with clinical experience supplement the laboratory and clinical pharmacology findings. This is an exceedingly important part of most new drug evaluations.

Regulations of the FDA require that each physician who is to take part in the clinical trial file with the drug manufacturer a form entitled: "Statement of Investigator," form FD-1573. This form requires detailed information about the investigator's education and experience; pertinent medical or other scientific publications which he has authored; identification of any hospital, institutional, or clinical laboratory facilities which will be employed in connection with the investigation; the plan of investigation which he will follow; and a certification that he will obtain the consent of any subjects or their representatives before using investigational drugs.

I wish to emphasize that under the regulations this information is kept in the file of the drug manufacturer. Therefore, if we have the man's curriculum vitae, or biographical data, on file in the investigation of one drug, this can be applied to another drug, but we must have a complete file.

In my opinion, this form is more complicated than is necessary and I fear that the legalistic phraseology in which it was made available and published has a tendency to discourage many physicians. If you actually read the form, it sounds very formidable and rather confusing. Perhaps this is one area in which the Food and Drug Administration can make a contribution-making it less onerous for clinicians to participate in drug evaluation studies without lessening any of the protection afforded the public.

On the other hand, the FDA shows desirable flexibility in connection with emergency needs for a new investigational drug. It will permit immediate shipment of the drug to a physician needing it for a patient in critical condition. If the benefit versus risk ratio is always allowed to be the determining factor, the interests of the public will be best served.

We had an example of this recently. A very prominent citizen of this country needed an antibiotic which has not yet been cleared by the Food and Drug Administration but which has some very important properties that were very much needed for the treatment of this individual. Within 2 hours we had this drug available for this man, without any delay-and the paperwork came afterward.

I think this is good, the way it should be, for these emergencies, so that in a life-threatening situation an individual need not be deprived of a drug that is important to save his life while somebody is filling out a lot of papers and going through a lot of formalities.

We have tried to devise some report forms. They are in the exhibits that the subcommittee has, but perhaps you would like to see them.

The Early Life History of a New Drug

S. O. Waife, M.D.-Assistant Director, Medical Research Division, The Lilly Research Laboratories, Indianapolis,

Indiana.

Every time a physician writes a prescription, he is saying to himself, "I have learned that drug 'X' is useful in my patient's condition. Therefore, I will use it in the dose and manner recommended."

Where did that information come from? How was it shown that drug "X" was useful in certain disorders, and how were the dose and manner of administration determined? These are some of the data that the pharmaceutical manufacturer compiles with the help of numerous investigators working independently. In the following article a brief survey will be presented of the life history of a new drug as seen by the "parent"-the manufacturer.

Conception.

A new therapeutic agent is often conceived in the mind of a clinician, chemist, microbiologist, or other scientist who wonders if a certain compound or extract might be useful in one of man's innumerable disabilities. Sometimes the agent is found in the "routine" screening of thousands of soil samples, plant leaves, or related synthetic chemicals. Sometimes, as with other conceptions, it is accidental-the chance that the prepared mind favors.

Gestation.

The drug (if we may call it that in this embryonic stage) is first administered to animals. To the pharmaceutical industry this is a stage of tremendous complexity and cost. An antibiotic may show valuable antimicrobial properties on the

Petri dish, but this does not mean that it will be effective (and safe) in man. It will have to be given to several species of animals with experimental infections of all types. Different doses will have to be used; different routes of administration and time schedules must be tried.

With some drugs, special animals will need to be used (e.g., adrenalectomized, or pancreatectomized, or thyroidectomized) in order to show the possible action of the drug being tested. In some instances abnormalities, such as hypertension or hypercholesteremia, are produced in several species of animals to mimic, in a general way, the clinical situation at which the therapy is aimed. In other instances elaborate physiologic studies are performed so that renal blood flow or cardiac output, for example, will

Reprinted from the Southern Medical Bulletin, Bulletin of the Southern Medical Association, Volume 51, Number 4, December 1963, Pages 6-12, Copyright 1963 by Southern Medical Association, Birmingham, Alabama