That means that at any particular time there may be more people suffering from iatrogenic disease than from any other one single disease in the ward.

Senator HRUSKA. Doctor, is there any control on this analysis and study? Is there any way of knowing how many of these might not be there at all or might be even more in a more serious position and situation had it not been for those drugs and the use thereof?

Dr. BARR. The Senator's point is well taken. Those who had toxic reactions might have been dead if the drugs had not been used, and these drugs were used presumably of necessity and to control serious situations.

Senator HRUSKA. So that while there is risk in using them, there is also some benefit, is there not?

Dr. BARR. The benefit is enormous, the risk is relatively small. But, nevertheless, the point I am making is that the risk is there from the use of any drug which has any activity at all.

Senator HRUSKA. Is there any law we can pass to eliminate this 5 percent of the ward population where approved drugs employed ethically and conscientiously result in toxic reaction?

Dr. BARR. I don't think you can do anything about the risk that is incurred from the use of necessary drugs.

Senator HRUSKA. That depends on the doctor, doesn't it, Doctor? Dr. BARR. Yes, that is correct.

Senator HRUSKA. When a doctor operates, for example, he always takes a chance?

Dr. BARR. That is right.

Senator HRUSKA. It might not prove out so well.

Dr. BARR. That is right. The way in which the law might help is to prevent the addition of drugs which are unnecessary.

Senator HRUSKA. Do you know of any drugs on the market that are useless, Doctor?

Dr. BARR. Many have been introduced.

Senator HRUSKA. Can you name some for use?

Dr. BARR. No, I am not prepared to do so at the moment. Senator HRUSKA. Would those that you might name be totally useless? Would there be no case in which they could be used?

Dr. BARR. My unwillingness to name them is because I can't answer your question categorecally. I mean I can't say that any one drug that is on the market could not be used in any situation.

Senator HRUSKA. Thank you.

Dr. BARR. But relative uselessness is common among the drugs that are on the market at present, and I repeat that each one of those relatively useless drugs may have toxic reactions.

Senator HRUSKA. What does "relatively useless" mean?

If I have a child in the hospital and that drug happens to help that child and it probably won't help 10 other children in the ward, I wouldn't think that is relatively useless, would you?

Dr. BARR. Expressed in that way, I agree with you.

But I think that the proof that it helps is not available in many instances.

Senator HRUSKA. How can it be obtained?

Dr. BARR. It can be obtained only by experience, and the experience has to be large in order to prove the utility of a drug.

Senator HRUSKA. Would that experience have to be wider than clinical experience?

Dr. BARR. Not in the aggregate, but in the individual, yes.

The fact that one child seemed to be benefited by a drug would not establish its utility.

Senator HRUSKA. And the fact that 50 children were not benefited does not show its uselessness, does it?

Dr. BARR. It doesn't absolutely prove its uselessness.

Senator HRUSKA. It would indicate it until there is a sufficiently wide use to show there is some percentage of cases in which some good has been served that otherwise would not have been served, is that correct?

Dr. BARR. Yes.

The question comes up whether one should admit too freely drugs that need to have so large an experience to prove any utility.

Senator HRUSKA. And, of course, if they were dangerous we wouldn't want them, without any corresponding benefit, we wouldn't want them to begin with, would we?

Dr. BARR. The point about that, Senator, is that it takes a large experience many times to prove that a drug is dangerous. There are so many instances in the literature about this that perhaps it is not necessary to be detailed, but let me give you just two instances. There was a drug called cinchophen

Senator KEFAUVER. Will you spell that for the reporter?

Dr. BARR. C-i-n-c-h-o-p-h-e-n, which was used at first in gout, and then in various forms of arthritis, and then more generally as a symptomatic remedy, and it had utility. It was used for years before enough experience could be assembled to show that on occasion it destroyed the liver.

There was another drug, aminopyrine, which had for a time a use almost as prevelant as the commonest used drug, aspirin. It was an excellent drug for the relief of pain.

Many years elapsed before enough experience accumulated to show without any question that this drug caused toxic destruction of necessary white blood cells in the body.

Senator HRUSKA. In all cases?

Dr. BARR. It occurred frequently enough so that it represented a serious risk, and yet it took all that time to accumulate experience enough to say that the drug possessed that toxicity.

Senator HRUSKA. Were those drugs removed from the market?

Dr. BARR. The aminopyrine now is little used but it was not removed from the market.

Senator HRUSKA. But it is not used any more, it is not prescribed any more?

Dr. BARR. Very little, if at all.

Senator HRUSKA. How was that achieved? How did that come about?

Dr. BARR. That was through education, the scandal was so serious that people stopped using it.

Senator HRUSKA. In that first instance was it the liver that was badly impaired?

Dr. BARR. Yes, that is correct.

Senator HRUSKA. Was that in a large percentage of cases?

Dr. BARR. Many, many cases, but not in proportion to the usage of it. I mean it was used in hundreds of cases for one case that had destruction of the liver.

Senator HRUSKA. So it was up to the doctor to make that decision whether to use that drug and take the inherent risk or not use it and probably run a greater risk of improper care?

Dr. BARR. No, I don't think in that instance it was so.

Senator HRUSKA. You don't?

Dr. BARR. No, I think that there were other drugs which did not possess this risk which could accomplish exactly the same result.

Senator HRUSKA. Might there be other doctors who felt that this drug would do it better than any other drug in a given case under certain circumstances?

Dr. BARR. I have no doubt.

Senator HRUSKA. What we are driving at, after all, is that both of those drugs would satisfy the requirements of the bill which is before us. Both of them would be safe and both of them would be useful within the terms of this law, would they not, Doctor, so that this legislation would not reach that kind of situation? We would still have to rely upon the scientific knowledge and the experience and the education which inheres in the practice of medicine?

Dr. BARR. Yes, that is correct, and it is a point which I want to make, that the experience must have been in the end upon the combined experience of doctors in use, and it is true that neither cinchophen nor aminopyrine would have been excluded by any law that I can think of.

Senator HRUSKA. Including the bill which is before us?

Dr. BARR. I think that it would be very difficult for this bill to cover those particular instances. I think the important point, however, is that this bill is so devised as to require information that a new drug possesses advantages which are not apparent in other drugs, I think that one should try to establish the fact that the advantages claimed by the manufacturer are real and that they represent an advance.

Senator HRUSKA. Of course this bill does not require that. It simply says that useless drugs shall not have a permit for manufacture for sale. That is as far as the bill goes.

So within that statutory provision, both of these instances to which you refer would have complied with the law, would they not?

Dr. BARR. That is right, and yet these drugs had they been relatively useless might have possessed the same inherent toxic qualities. Senator HRUSKA. It is a puzzling problem, isn't it, Doctor?

Dr. BARR. It is indeed, and may I repeat that the only point I am trying to make is that toxic qualities are not exclusively the possession of drugs that are therapeutically useful. I mean that you can have toxic reactions from drugs that are ineffective or are so nearly ineffective that they should not be prevalently used.

Senator HRUSKA. Of course a tablespoon of sugar to a certain patient in certain conditions would be highly toxic, would it not? We were given that example yesterday in the case of diabetic patients. Dr. BARR. That is true.

Senator HRUSKA. The administration of a tablespoon of sugar at the wrong time would be very toxic. Is there a law that can deal with that situation other than the judgment of the doctor?

73753-61-pt. 1-17

Dr. BARR. I don't think so.

Senator HRUSKA. And his experience?

Dr. BARR. I am sure not.

Mr. FENSTERWALD. Could I ask one question, Mr. Chairman?
Senator KEFAUVER. All right, Mr. Fensterwald.

Mr. FENSTERWALD. Dr. Barr, could the 5 percent of physiciancaused cases be cut down if the side effect of drugs were more widely brought to the attention of doctors?

That is one of the objectives of this bill, to see that the side effects are brought to the attention of doctors before they prescribe these drugs.

My question is, Could the 5 percent be cut down in that way?

Dr. BARR. I think that in this 5 percent that there were many drugs that might not have been used had the doctors been more cognizant, immediately cognizant, of the possible side effects. In other words, I think that the rule should be that one doesn't use a drug unless he feels that it is necessary, and that it is going to accomplish the specific purpose.

Mr. FENSTERWALD. There are several provisions in the bill, including approved statements by the Secretary of HEW, with respect to side effects, the fact that package inserts have to go with direct mailings, and so forth.

Would this not make doctors more aware of side effects and make them a little more cautious in their selection of drugs?

Dr. BARR. I believe so. I think that is a very good provision.
Mr. FENSTERWALD. Thank you.

Senator HRUSKA. Of course, Doctor, you did refer to the physician who is busy and he has neither the time nor the experience to explore the true nature of the drug, and so on. If he is given just more material to read, after all, there is quite a little material now in the labeling that is required by present law, would he become less confused and would have more time if he had more material to read and study, to ponder, before he prescribes?

Dr. BARR. I think that the law, as I understand it proposes, or the proposed legislation suggests that such information as is available be presented to him at the same time that the drug is presented to him.

Senator KEFAUVER. You mean the same time as he is presented with the drugs.

Dr. BARR. At the same time that the drug is presented to the physician by the detail man or by advertising.

That is an advantage, because at present the drug is presented often in glowing terms, and the information about any disadvantages is included in the package, but they are not presented in the advertising nor in the presentation.

Senator KEFAUVER. To the physician?

Dr. BARR. That is right.

Senator HRUSKA. And yet that material is available, is it not? It is in the label. It is in the label including safeguards and warnings and so on, that do go on labels, the toxic side effects?

Dr. BARR. The evidence is not adequately presented by the detail man nor in most advertising.

Senator HRUSKA. I am not talking about advertising. I am talking about the label that goes with the package.

Dr. BARR. That is what I think should be more widely spread. Senator HRUSKA. And if that material on the label is expanded and there is more of it, the doctor will be apt to read it, but he doesn't have time to read a lesser amount?

There is something wrong with that logic somehow, Doctor.

Senator KEFAUVER. Senator Hruska, I think the point is that under present law the insert package and the label only go to the pharmacist. They do not go to the physician. That is one of the provisions in the bill, to require that the same things be sent to the physician.

Dr. BARR. That is right.

Senator KEFAUVER. A doctor does not buy large amounts of drugs. It is the pharmacist who buys them.

Dr. BARR. That is right.

Senator HRUSKA. On that score, I would agree.

There would be no objection to that, that I could see.

Senator KEFAUVER. Doctor, while we are interrupted, this came in this morning and I have not had a chance to read very much of it, but there is an article in the J.A.M.A. of July 8, 1961, by Dr. Isaac Starr, of Philadelphia, who is the chairman of the American Council on Drugs of the AMA.

Dr. BARR. Yes.

Senator KEFAUVER. He talks about this very problem you have been mentioning here, about how the good news about a drug precedes the bad-I will read just two paragraphs.

He says:

The "good news" gets a head start because the other doctors concerned are under no such compulsion to tell their story. In their hands, the new treatment was followed by increasing disability; widespread knowledge of this experience would bring no new patients to the doctor's door. Only after they have seen the publications of the first group, attributing an effectiveness to the new drug which is contrary to their experience, are those doctors stimulated to inform others in order to correct what they believe to be an error. Thus, only after some time does the true state of affairs come to light.

This type of happening is so familiar and so in accord with human nature that one might readily formulate a law: "For any new remedy, the favorable reports will appear before the unfavorable." Stated another way: "Whenever a new remedy is introduced, there is likely to be a period when all the reports are favorable."

Does that conform to your experience?

Dr. BARR. Yes. I think that is an admirable statement of what I am talking about, one part of what I am talking about.

Senator KEFAUVER. Since Dr. Starr is the chairman of the council on drugs, I think it might be useful if all of this article, which bears directly on the subject, might be printed as exhibit 39 in the record. (Exhibit 39 may be found on p. 820.)

Senator KEFAUVER. All right, Doctor.

Senator HRUSKA. Would the chairman yield?

Senator KEFAUVER. Yes, sir.

Senator HRUSKA. It is necessary for me to leave here, I am very sorry to say, for a little while to make a quorum of another subcommittee of this committee.

I would at least like to get them started so they can proceed with their hearings. I would like to ask a question or two on statements made by the witness and then I will get back as soon as I can.