millions of people ofttimes is more significant than what you can learn before it is placed on the market. So the manufacturer is under the obligation to acquaint us promptly with reports which he receives that have a further bearing on the safety of the drug and which have a further bearing on the efficacy of the drug.

Mr. FOUNTAIN. Thank you very much.

May I interrupt at this point to recognize in the audience a very dear friend and former distinguished colleague, the Honorable Carl Durham, who served North Carolina faithfully, loyally, and wisely for many years here in the Congress of the United States, and who retired just a few years ago. His presence here today I think indicates that he has become active again in this very important field. He was an institution at the University of North Carolina in Chapel Hill before he became a Member of the Congress of the United States, and he always will be, both as a Member of the Congress and in the drug industry in which he has so actively participated.

We are very delighted to have you with us, Congressman Durham. Mr. LARRICK. May I add to that, Mr. Chairman ?

Mr. FOUNTAIN. Yes.

Mr. LARRICK. This gentleman has also been a student of pure food and drug legislation for a great many years, was a distinguished member of the Interstate and Foreign Commerce Committee, and participated very extensively in the law and its amendments. His name is on the Durham-Humphrey amendment to this statute, which is one of the most important amendments we have.

Mr. FOUNTAIN. Thank you for that comment. I noticed that he followed your statement closely all of the way through, so he may have some comments to make on it later.

Mrs. DWYER. Mr. Chairman, I have a question.

Mr. FOUNTAIN. I have a few followup questions and then I will yield.

Dealing further with the 1938 law and amendments, you stated that another deficiency of the 1938 law was that FDA "could not remove a drug from the market unless you could prove it was unsafe" and that "it was not enough to show that new developments had drawn the question of safety sharply into issue." Was this situation corrected by the Drug Amendments of 1962 and if so, how?

Mr. LARRICK. Yes; I think that point is very well illustrated by several drugs that we had to reconsider just before the new law became effective. A review of the data that was then available to us convinced our medical staff that in all probability these newer facts were such as to make it likely that the drug would do more harm than good. In other words, it had gotten out of the category where they would say it was safe. but it was in a category where they could not amass evidence which would stand up, in the opinion of our adıninistrative and legal people, that it was in fact dangerous. The drug had back into an era of uncertainty. And under those circumstances, we could not withdraw the drug from the market.

gone

The Congress, in considering the 1962 amendments, provided that if the safety of the drug is put in serious question, the sale of the drug can then be suspended. So, to answer your question, we do think that was remedied.

Mr. FOUNTAIN. Mr. Gray has a question on this point.

Mr. GRAY. AS I interpret that last answer, Mr. Larrick, the effect of the 1962 amendment was to pass the burden of proof from the agency to the manufacturer? I believe you had the authority to withdraw the drug, even under the 1938 law, if you could prove it was

unsafe. Isn't that the situation?

Mr. LARRICK. You have stated it precisely.

Mr. GRAY. The burden of proof is now on the manufacturer, if there is reasonable question of safety!

Mr. LARRICK. Yes. As it used to be, we assumed the burden of proof and if we couldn't prove it was dangerous, we couldn't take it off the market. Now the burden of proof passes back to the manufacturer and he has the burden of continuing to prove it is safe, if we question it.

Mr. GRAY. One further followup:

In your prepared statement, as the chairman noted, you indicated that the 1962 amendments closed all of the loopholes in the law but you amended it in your oral testimony to say "most" of the possible loopholes. Do you have in mind any particular deficiencies of the law as it now exists that you think should be mentioned?

Mr. LARRICK. I think the consumer message that the President of the United States sent up to the Congress dealt with the need for improving the factory inspection provisions of our law. He didn't mention barbiturates and amphetamines in that message but we have a problem there which the adininistration has indicated it would support. I think that improvements are not necessarily needed in the drug field per se, but that therapeutic devices need greater control. A wide variety of prosthetic appliances that orthopedic surgeons use and quack gadgets such as we showed before Senator Williams' committee the other day should be proved safe and effective before marketing, and I submit that the law is deficient in this respect.

The administration has recommended the food, drug, and cosmetic law be improved, Mrs. Dwyer, to deal particularly with the ladies by having better control over cosmetics. This would be achieved by requiring that cosmetics be proven safe before they are placed on the market.

I

Another aspect which does go to the areas into which you are inquiring more particularly involves the administrative hearings which we must hold under this statute. We now lack subpena power. think virtually all governmental agencies that have the type and kind of responsibilities we have, have the power to subpena the necessary evidence for these hearings.

So those are some of the deficiencies. There are probably others, but those are the most important ones, Mr. Gray.

Mr. FOUNTAIN. Mrs. Dwyer.

Mrs. DWYER. With regard to your investigational use regulations, Mr. Larrick, does FDA have any mechanism by which it reviews the adequacy of reports it receives from drug manufacturers who in turn presumably receive reports of individual doctors using their products? Is there any uniformity to such test reports or any requirements and standard procedures on this!

Mr. LARRICK. All of the data, Mrs. Dwyer, that are submitted to support a new drug application are submitted to the several reviews that I referred to in my testimony, the safety, the effectiveness, the

chemical identity to make sure that each batch is the same as each succeeding batch, and the others to which we referred.

Now on an investigational drug application, you are dealing with a drug before it has reached the stage of administration to people. And there the data that is submitted includes the chemical data to show what the drug is, and that each batch will be the same as each succeeding batch and won't have impurities in it that are harmful, and whether or not there are chemical tests that can be made to make sure of that.

That type of data is routinely sent to a group of very highly skilled chemists to evaluate. Another important part of that application is the animal work, the administration of the drug to rats, dogs, and other animals that in the opinion of the experts involved are the ones best suited to make these preliminary tests.

Thus, quite routinely in accordance with the rules of our administration, these data have to go to pharmacologists who are best skilled in the area of dealing with the results of animal work. Then when the chemists and pharmacologists and perhaps the bacteriologists and others have completed their evaluations, the data goes to the doctor. The doctor is always the one who takes the data from all of these collateral and supporting sciences, and makes the decision as a doctor would in a hospital that this drug has had everything reasonable done to assure that when it is transferred from animal experimentation to people, it will be doing the public a service rather than a disservice. To answer your question, we have tried to simplify, or systemize this procedure, to the extent that the involved scientific work, including the different problems with each product that comes along, will permit systemization. And finally there is a review procedure set up to make sure each one of the drugs considered has been subjected to these procedures. This is the sort of thing we have progressively improved, as the months have gone by and as we have gotten more experienced under the new law.

Mrs. DWYER. Thank you, Mr. Larrick.

Mr. FOUNTAIN. Mr. Roush, do you have any questions!

Mr. ROUSH. No.

Mr. FOUNTAIN. Mr. Stinson!

Mr. STINSON. I wanted to return to a statement Mr. Larrick made previously about the concern back in 1938 as to the possibility that there would be undue restriction on development of new drugs. Has there been undue restriction because of the laws on the development of new drugs?

Mr. LARRICK. Your question is a judgmental question.

I think there would be opportunities for differences of opinion. In my judgment and in the judgment of a great many other people, the mere fact that science had to be introduced increasingly into more and more of the drug operations promoted the development of new drugs and brought science to bear more extensively in all of their operations.

As a matter of fact, a Fortune writer wrote a book for one of the larger drug houses, some few years ago, and in tracing the economic developments of this industry and in giving them credit, as I do, for the tremendous advances they have made in public welfare, he attributed a substantial part of this advance to the influence of this new law.

I think, however, if you were to get an appraisal today across the board in the industry of what the effect of the Kefauver-Harris bill has been in slowing down developments that they think are desirable, I do not think we have yet reached the stage where all of them would be willing to concede that the bill is not going to slow down developments. I personally believe 5 years from now that will be the view.

I could not in all honesty, however, say it is the unanimous view today.

Mr. STINSON. Would you compare the regulations here in the United States with Europe? Are ours more stringent than the European regulations or less stringent!

Mr. LARRICK. Do you mean the total drug regulations or more particularly the investigational drug or new-drug requirements!

Mr. STINSON. In regard to putting a new drug on the market. For instance, are our regulations more restrictive than, say, European regulations?

Mr. LARRICK. I would say in general they are. They differ tremendously. England has a system quite different from ours. Rocently, for example, thalidomide

Mr. STINSON. That is what I was leading up to.

Mr. LARRICK. It was not permitted on the market in France. It was permitted on the market in England, Germany, and in other countries.

Of course, our laws have been strengthened even more since then. I know there is a great interest in stricter drug regulations aroused throughout the world. I participated some years ago in a meeting with a dozen or so drug controllers from various countries. A study of drug controls in Japan, Egypt, England, and France, among others, was going on back at that time.

We are having increasing contacts with South American countries and other countries throughout the world. I think there is a trend to tighten up. But to answer your question, I think probably we have the strictest controls throughout the world."

Mr. STINSON. If a drug is developed in a European country and put into use over there, is it given the same inspection and testing when it arrives in this country as a brand new American drug that hasn't been put on the market previously?

Mr. LARRICK. In general, yes. What I mean by that is this: It has to go through precisely the same review as any other drug, whether it is originated in Arizona or in France.

Now, if there has been a drug originated in France and the work has been done by people who are international authorities in their field, and our medical staff knows them and knows the quality of their work, their work is accepted. But we do require that some work that we can take a look it, if necessary, be done in this country. We try, however, to keep abreast of what is going on throughout the world.

Dr. Smith was not able to prepare very well for this hearing, because he just got back Monday morning from an international conference where people from all over the world were considering the same type and kinds of problems that we are considering here today. But I think the United States, sir, ever since I have been in this work, has been the leader in pure food and drug legislation.

I think the purity of our food supply surpasses that of almost any place in the world. There are very few places where you can go into a restaurant and eat without worrying about what you are going to get. I think our regulations are superior.

Now there are some other countries, the Scandinavian countries, for example, that have good food control. But considering food, drugs, and cosmetics as a whole, I think the United States has led the world.

Mr. FOUNTAIN. Mr. Larrick, another deficiency of the 1938 law, which you indicate has been corrected, was a lack of adequate controls over the distribution and the use of investigational drugs, as shown by the thalidomide episode.

However, was this correction not achieved largely through the issuance of administrative regulations rather than through legislation! Mr. LARRICK. Yes, Mr. Chairman. That point was made repeatedly when the bills were on the floor of the House and Senate.

Mr. FOUNTAIN. If that is true, why could this action not have been initiated long before the thalidomide episode occurred!

Mr. LARRICK. It could have. There are many things, Mr. Chairman, that in retrospect all of us could have done 5 or 10 years ago to great advantage. But as I tried to point out in my testimony, there are some things that you cannot do until you have the right public attitude and public interest and congressional interest to accomplish them.

In retrospect, I wish we had and could have put into effect that type of control much sooner. I do not think that we could have successfully put it into effect and had it prevail very many years ahead of when we did.

Mr. FOUNTAIN. I think you have alluded to it, but in this connection, I noted in your statement that your agency announced proposed revisions of FDA's investigational new drug regulations 2 months before the new law was passed in 1962.

Mr. LARRICK. Right. Mr. Kefauver made the point repeatedly that he was putting a sound legal foundation under our regulations and removing any doubt about the validity of our action.

Mr. FOUNTAIN. You also stated that under the 1938 act, FDA's factory inspection authority was so limited as to seriously handicap your operations. Did this situation hamper your activities with respect to drug safety and, if so, I wonder if you would explain how.

Mr. LARRICK. I think I will ask Mr. Goodrich to give you an answer on the legal view about that, as to where we do have the authority and where we still don't have it.

Mr. GOODRICH. The original factory inspection authority was to enter and inspect any establishment, all labeling, raw materials, and a number of enumerated things in the factory.

In about 1951 or 1952, the Supreme Court knocked down the original factory inspection law, because there was a conflict between the authority to inspect and the penal provisions. The Court held there was an unconstitutional conflict making the law vague. We went back to Congress for improvement of that situation and came out with a new legislative authority, back in 1952, or 1953, which was handicapped by expressions of the sponsors, when the bill was going through, over the extent of our authority. There was much contro