Furthermore, he noted, the risks involved should be thoroughly considered by asking this question: Do the possible benefits of testing the drug outweigh the possible injuries that may result from its use?

The attorney made these suggestions for physicians who are testing drugs for pharmaceutical companies:

Advise the patient, or those who may be legally qualified to act on his behalf, of the nature of his condition and the possible risks involved.

Make sure the drug treatment does not vary too radically from accepted methods.

Obtain consent in writing for use of the drug from the patient or responsible parties.

Be alert for adverse effects of the drug.

Try to obtain a letter in writing from the pharmaceutical firm to the effect that it will stand behind you and indemnify you against any loss which you may sustain.

Is that what you wrote, Mr. Steller?

Mr. STETLER. I am not the attorney that is mentioned in that article. However, it was written by a member of my staff. I agree with it, and I think it is sound legal advice, and I would give it again today. Senator KEFAUVER. Dr. Hussey, are you planning for each individual physician to go out and get these signed statements of consent and an indemnity from the pharmaceutical manufacturer if he is using drugs that may have no beneficial effect and which may actually be harmful because the patient will be deprived perhaps of the use of efficacious or useful drugs?

Dr. HUSSEY. Senator, in the article from which you are quoting, the discussion centers upon drugs that are under experimental use prior to their receiving authorization from the Food and Drug Administration for admission to the market. You are asking me a question about a drug that has already been marketed.

Senator KEFAUVER. The same situation applies to drugs that are of no use, because all the writings here admit that if we are getting drugs that are of no use and indeed your rule 7 says that giving of useless drugs may indeed be harmful first in and of themselves and second because they may be denying the patient a useful drug which might be helpful to him.

Dr. HUSSEY. Let me review the three points.

Senator DIRKSEN. Doctor, before you do, let's just be fair about this. This article states in the first paragraph:

A physician who tests drugs for pharmaceutical firms on his own patients would be wise to use utmost caution from a medical and legal standpoint.

I don't know how you can express it more clearly.

This is testing drugs on a doctor's own patients for a pharmaceutical manufacturer, and I quite agree that it is a perfectly legal statement and I think our distinguished chairman and our distinguished doctor, Dr. Blair, are seeing ghosts under the bed here.

Of course I should point out that Dr. Blair is not a medical doctor. Senator KEFAUVER. Yes.

Senator CARROLL. Mr. Chairman, will you yield at this point? Senator KEFAUVER. Just one matter, and then I will yield.

You will recall, perhaps, Dr. Hussey, that during the course of this hearing last year, Secretary Flemming came before the committee and said there were a lot of things that ought to be done, and that he was appointing a very distinguished committee of physicians, a

committee of the National Research Council-that is a very fine organization, is it not?

Do you say yes?

Dr. HUSSEY. Yes, sir.

Senator KEFAUVER. To review the procedures of the Food and Drug Administration, what they needed in order to do a more effective job, what the medical profession needed. And so Secretary Flemming in the last administration appointed a committee, consisting of Dr. C. Phillip Miller, professor of medicine, University of Chicago; Dr. John H. Dingle, professor of preventive medicine, Western Reserve; Dr. Maxwell Finland, Harvard Medical School; Dr. Colin MacLeod, New York University College of Medicine; Dr. Karl Meyer, George Williams Hooper Foundation, University of California; Dr. John R. Paul, professor of preventive medicine, Yale School of Medicine; Dr. Carl F. Schmidt, professor of pharmacology, University of Pennsylvania; and Dr. Wesley W. Spink, professor of medicine, University of Minnesota. Dr. Miller was the Chairman.

These are very outstanding and knowledgeable men, are they not? Dr. HUSSEY. They are, sir.

Senator KEFAUVER. Are most of them members of the AMA! Dr. HUSSEY. I don't know, sir.

Senator KEFAUVER. Some of them are members of the council on drugs, I believe.

They made their report to Secretary Flemming, and I think the whole report should be made a part of the record as an exhibit. Let's make this exhibit 1.

(Exhibit No. 1 may be found on p. 459.)

Senator KEFAUVER. Recommendation No. 1 of this outstanding committee is:

The FDA should be given statutory authority to require proof of the efficacy, as well as the safety, of all new drugs. Treatment of a patient with an ineffective drug in place of an effective one may jeopardize his recovery. This is true even though the drug may not be intrinsically harmful, and even though the specific condition for which the drug is given may not be ordinarily regarded as life threatening.

So the position of the AMA is squarely opposed to the position of this board of eminent men.

Dr. HUSSEY. The position of the AMA is not squarely onroced to this except upon the matter of giving statutory authority to the Food and Drug Administration.

If I might review, there are three barriers to the arrival won the market of a nonefficacious or useless drug. The first of these is the fact that in submitting a new drug application, submitting it to the Food and Drug Administration, a manufacturer must give his indications for use of the drug, his intended indications. He must back up those intended indications with clinical evidence that the drug has been effective in that regard.

This is a part of the present practice.

The Food and Drug Administration, although empowered by statute to look at safety, must perforce look also at efficacy.

The second barrier is within the profession itself. When a new drug arrives on the market and is said to be useful, it is going to be used. If it turns out not to be useful, to be totally inefficacious, that

drug soon will disappear from the market. We hope it will disappear almost immediately under the terms of the new drug information program to which I have alluded in my prepared statement.

The third barrier is in the conscience and in the welfare of the pharmaceutical manufacturer himself. Whether his conscience prescribes it or not, his economic welfare would preclude his putting on the market, intentionally, a useless drug.

Now, if we are talking about totally useless versus some degree of use, everything I have said prevails.

Senator KEFAUVER. Secretary Flemming had all those things in mind when, following the report and findings of this eminent committee, he said.

Recommendation 1: I concur in this recommendation that FDA be given statutory authority to require proof of the efficacy as well as the safety of all new drugs.

And Mr. George P. Larrick, who is with us today, in testifying before this committee on June 3, 1960, said in part :

We would endorse the proposal that the new drug section of the Food, Drug, and Cosmetic Act require a showing of efficacy as well as a showing of safety.

You said that the FDA looked into efficacy to some extent in determining toxicity. If they do look into efficacy, why not give them the direct authority to do so?

Dr. HUSSEY. In my prepared statement I pointed out that our worry concerns the matter of efficacy-using that term not relative to safety or relative to toxicity, but relating drug A to drug B. If the statutory authority to decide about efficacy were granted to the Food and Drug Administration, it is possible that by regulation they would begin to rule on relative efficacy. They would decide that drug A, in view of the tests presented to them, was not as effective relatively as drug B.

Now, this brings us back to the thought that you cannot practice medicine on the average. A drug that is used in the treatment of epilepsy may have wide usefulness and extraordinarily potent effects for the welfare of the patient. It may be without serious side effects in most patients. But patient No. 100 may get serious side effects from the drug because of the way he is constituted. For him, a drug not so potent, not so on the average efficacious, may be the most efficacious drug.

The factor of toxicity may not indeed be necessary. Patients vary in their reactions to drugs. A patient who is benefitted by one anticonvulsant agent for his epilepsy may not be benefitted by another. Senator KEFAUVER. I am not going to quote all of the testimony of Mr. Larrick, who is here with us today.

I will read these two paragraphs from his prepared statement, and then I will yield to Senator Carroll.

This is at page 12120 of part 22 of the hearings:

The safety of a drug cannot be considered as an absolute value to be determined with a computing machine or measuring stick. All potent drugs, old and new, have a potential for harm.

If we were restricted in our decision on whether to clear a new drug for distribution solely to those that are harmless, then we would have none of the lifesaving drugs like the sulpha drugs, corticosteroids, tranquilizers, etc. So the medical officer and the other scientists must evaluate safety in the light of the good inherent in the drug and balance it against the hazards. If the good in

saving lives or alleviating suffering outweighs the hazards, he will permit the NDA to become effective under labeling which clearly sets forth the hazards of the drug, the contraindicated conditions, the side effects, cautions to be observed, warnings and directions for use which reduce to a minimum the danger inherent in the use of the drug.

Then he goes on to say that through the back door method to some extent they do look into efficacy, which you have said they also necessarily have to do but you don't want to give them the direct authority. But, concluding, Mr. Larrick said:

However, the new drug procedures are not adequate to insure the efficacy of drugs which are essentially innocuous. We would endorse a proposal that the new drug section of the Food, Drug, and Cosmetic Act require a showing of efficacy as well as a showing of safety.

And he went into great detail to back it up.

So we have your group, the Council on Drugs, recommending this in 1950, we have this committee, we have the National Research Council, we have Secretary Flemming of the last administration, and we have the Commissioner of the Food and Drug Administration, all saying that they recommend that the addition of the determination of efficacy is important.

Senator Carroll?

Senator CARROLL. Mr. Chairman, this is in response to the questioning of my able and esteemed friend from Illinois, who read: A physician who tests drugs for pharmaceutical firms on his own patients would be wise to use utmost caution from a medical and legal standpoint.

Do you mean to say, and I think I understood you to say that this was prior to clinical approval, so, therefore, is there a practice of the pharmaceutical industry to give its pills to doctors to experiment on patients?

Dr. HUSSEY. Yes, sir, there is.

Senator CARROLL. And this is done prior to any clinical approval? Dr. HUSSEY. That is correct, sir.

Senator CARROLL. Do you approve that?

Dr. HUSSEY. Yes, sir.

Senator CARROLL. Will you tell me why?

Dr. HUSSEY. Yes, because it is by this means that we have the development of effective new agents.

Now, please understand that before any drug would be used in clinical trials with humans, it would have undergone as extensive testing as possible in laboratory animals, and chemically, in order to preclude all possible toxic effects or to foresee toxic effects. Senator CARROLL. Testing by whom, Doctor?

Dr. HUSSEY. This could be done by a pharmacologist working in a university. It could be done by a pharamacologist in a drug manufacturing establishment.

Senator CARROLL. How is it done?

Dr. HUSSEY. By the latter more often.

Senator CARROLL. Is it not done by the industry itself?

Dr. HUSSEY. Sir?

Senator CARROLL. The pharmaceutical industry itself that conducts the research?

Dr. HUSSEY. Mainly.

Senator CARROLL. So, therefore, when we say "prior to clinical approval," this is prior to the council and prior to the AMA giving its approval for marketing?

Dr. HUSSEY. The council and the AMA have no authority to approve for marketing. This is in the jurisdiction of the Food and Drug Administration.

Senator CARROLL. Do you think the Food and Drug Administration ought to have some authority over this type of preclinical observation?

Dr. HUSSEY. I don't know the answer to that, sir. I can't see at the moment why they should have.

Senator CARROLL. What I wanted to make clear for the record, and I thought I was right in this, when you talked about prior clinical approval, this is before it gets to the AMA, or the council, or all the other arguments that you have spoken of in your brief here today. This is really a relationship growing from the pharmaceutical industry through its advertising propaganda to the doctor?

Dr. HUSSEY. No, sir; there would be no advertising at this stage. This is a drug so new that it has not yet reached the market.

Senator CARROLL. Advertising in the sense it is given to the doctor, isn't it? It is not sold. There is no marketing.

Dr. HUSSEY. Let's understand to whom it would be given, please, Senator Carroll.

This drug would be placed by the pharmaceutical manufacturer with someone who would have competence to test its use in patients. He would be expected to report about its use, including side effects as well as desired effects. It is upon the basis of collection of such reports that the pharmaceutical manufacturer may present to the Food and Drug Administration an application for the new drug.

The Food and Drug Administration would review the presentation and make a decision.

Senator CARROLL. And it was, therefore, based upon this procedure, unless this doctor warned his patient that he was being tested, there would be a strong legal liability there, would there not?

Dr. HUSSEY. There is a legal liability, as well as a moral, when a physician gives any drug to a patient.

Senator CARROLL. Do you know what the custom is? Do they warn their patients that this is really a drug that has not been approved; that this is a testing drug?

Dr. HUSSEY. I believe they do; yes, sir.

Senator KEFAUVER. Do you know?

Senator CARROLL. May I ask at this point-Mr. Chairman, go ahead.

Senator KEFAUVER. No; you go ahead.

I just asked, do you know that they have been warned?

Dr. HUSSEY. Only from experiences of my own and from contact with my colleagues who have conducted such trials. I have observed it being done.

Senator CARROLL. Wouldn't it be important to make it mandatory in the law that the patient be informed that he is being tested, used in a sense as a guinea pig?