Dr. YOUNG. Bob's concern is, does the language of the rule make it necessary to prove a double negative, and is the preamble language an adequate safeguard? I have had detailed discussions within the agency on this, and we have tried to devise strategies whereby we can address that issue.

Mr. WEISS. And Dr. Paul Leber——

Mr. NORRIS. Before moving on beyond Dr. Temple, I think it would be appropriate to say, and very important to say, having spent the last weeks in very extensive conversation about this, his comments about the regulation are very focused. In fact, he does not oppose in any way the general approach we are taking here to expedite the availability of drugs for the desperately ill. He supports that very strongly.

His concerns are very focused on two particulars related to the methodology being used, and I don't want to

Mr. WEISS. Well, I think that most of the testimony we have heard today generally supports expediting the process, and everyone's criticisms and concerns are basically very focused on the same problems; namely, that the language in the regulation is such that the Commissioner would have little or no authority to deny applications for treatment IND's. That's the concern.

Dr. YOUNG. And that is really, Mr. Chairman, why I wanted to have the reproposal time to really listen to what is said on the outside. I have found in a way regulation writing to be a humbling experience. To try to put down in concise sentences exactly what you mean, and then have it really consistent with law is a tough issue.

Mr. WEISS. Dr. Young, you had no problem; you did a good job. The problem that we have been having is with the people at OMB who are not willing to take scientists' answers as to what is an appropriate way to proceed, and who, instead, decide to override you. So you should not assume the burden. As far as I am concerned, you have done an outstanding job in your proposals and recommendations. It's what they did to those proposals that is the problem. We have a vote on the Gephardt amendment, so we will break for about 10 minutes, after which we will resume.

[Recess.]

Mr. WEISS. The subcommittee is back in session.

Dr. Young, Dr. Paul Leber is an FDA review division director, I understand.

Dr. YOUNG. Yes, he is.

Mr. WEISS. And he has written the following:

I would prefer an arrangement where the Commissioner's intentions do not have to stand against a literal interpretation of the plain text of the regulations. . . . [T]he language of regulations should be simple, clear and understandable. It, for example, would be very difficult to explain to a physician-applicant why the regulations appear to have one meaning while a preamble to them is read to imply

another.

[Dr. Leber's memorandum in which this statement appears is in app. 1, p. 290.]

MR. WEISS. That accurately represents Dr. Leber's position, to the best of your knowledge?

Dr. YOUNG. Yes, it does. And we have had a number of discussions within the center with Dr. Parkman, Dr. Bilstad, Dr. Temple,

and others, and we have gone over this to try to see how we can best deal with the therapeutic benefit issue. Dr. Leber is correctly portraying his concern.

Perhaps if you'd like, Dr. Parkman can further explain or amplify the center's views on that, as well as

Mr. WEISS. It's not necessary, but if Dr. Parkman wants to make an additional comment, we are certainly willing to listen to it.

Dr. PARKMAN. I think today this has demonstrated there is a great deal of controversy concerning this

Mr. WEISS. Could you pull the microphone a little bit closer? It's not at all sensitive.

Dr. PARKMAN. I think today has demonstrated that there is quite a bit of controversy about this reproposal, and I can assure there has been a great deal of discussion within the center itself, and concern about the proposal. I think it is quite clear that the people-although I haven't polled everyone in the center, I believe that generally I can say that we don't object to the principle that treatment IND's can be a good thing, we don't object to the principle that there is a reason to consider the more desperately ill over people who are seriously ill in terms of perhaps their need for availability of experimental therapy. Certainly there is no concern in the center about the Commissioner level appeal which is written into these regulations. I think, in fact, if you look at the treatment IND approach generally, I think they were invented in the thenBureau of Drugs, so we have no reason to be concerned about that.

We did, in preparation for the hearing, look back at a number of actions we'd taken on major treatment protocols, and I have a table here which the committee may or may not

Mr. WEISS. That's the table we have already entered into the record.

Dr. PARKMAN. You already have that table. All right, fine.

I think that it's clear that Dr. Temple and Dr. Bilstad and myself have been concerned about the immediately life-threatening portion-our ability to deal with issues in the section of the regulations that deal with the immediately life-threatening part, particularly the standards by which the Commissioner will be able tomight be able to deny a treatment IND. And so that, quite clearly, I think has been a major issue in the center, and I think Dr. Leber's comments that you read a moment ago fit in with that. Mr. WEISS. Thank you very much.

Dr. Young, would you please describe the language in the preamble that clearly affords the Commissioner the discretion to deny a treatment IND request for an experimental drug to treat an immediately life-threatening condition where he is unable to demonstrate that the drug has "clearly no therapeutic benefit" or would expose patients to "an unreasonable and additional significant risk of illness or injury"?

Dr. YOUNG. Sure. Let me just get this here.

Generally, the drug that is not approved for marketing may be under clinical investigation for an immediately life-threatening-Mr. WEISS. Would you speak into the mike?

Dr. YOUNG. I'm sorry.

In general, a drug that is not approved for marketing may be under clinical investigation for an immediately life-threatening or

serious disease condition, and patients for whom no satisfactory alternative drug or therapy is available. During the clinical investigation of the drug, it may be appropriate to use the drug in the treatment of patients not in clinical trials in accordance with a treatment protocol. I emphasize treatment protocol. And then you see the words on "serious," and I am going to skip over that.

Then on the bottom of the page, that same page, 885-I'm sorry, 8852, in the case of a drug for a life-threatening disease, for example, it is expected that data from controlled clinical trials will ordinarily be made available at the time a treatment IND is requested.

I have been advised by lawyers that "ordinarily" in the legal term means that that is what is expected. The use of "ordinarily❞ is not a casual "ordinarily," but that's what is expected.

Then there is an escape clause. Even so

Mr. WEISS. You might want to get a second opinion from some other lawyers.

Dr. YOUNG. I would appreciate that. If I have been not understanding that correctly-but everyone has told me "ordinarily" means, "that is what is expected." But I will follow your advice.

Then there is the escape clause that says even when there is little data available for the therapeutic benefit of the drug, if phase I studies have just ended or phase II testing has only recently begun-and I emphasize it is not our intent to do that frequently at all-In the case of an immediately life-threatening disease for which there is no adequate therapy, the Commissioner have adequate support for determination that there is an unreasonable and additional risk or clearly no benefit in order for the Commissioner to deny treatment use. That means I have to have the information. Without the information I cannot act. And in making such a determination, the Commissioner obviously——

Mr. WEISS. Will you stop right there.

Look at what information you are requested to have. The Commissioner-the reproposal requires-

Dr. YOUNG. That I have adequate support.

Mr. WEISS [continuing]. That the Commissioner have "adequate support for a determination that there is an unreasonable and additional risk or clearly no therapeutic benefit. You have to have additional information and adequate support for the negative. Dr. YOUNG. Yes.

Mr. WEISS. Not support of safety or efficacy. You have to have proof of the negative. That is the concern we all have.

Dr. YOUNG. Yes, sir. I think that, at least as I understood it, sir, it required me to have adequate support for the determination. And that would mean I would have to have information to make that. And the next sentence goes on in saying that, I think, more clearly, because it is deliberately redundant, in making such a determination, the Commissioner obviously must have sufficient information. This is even stronger than "ordinarily," and requires that I make use of all available information. It follows under the reproposal it is expected that the Commissioner will be provided with sufficient data to make the specified determination. So that I have got to have the data. If I don't have the data, then as I read this, then automatically I say no.

Mr. WEISS. Well, again, this is the preamble language that you are relying on to overcome the very clear and specific language of the regulation. All that it really says is that "it is expected that the Commissioner will be provided" with that information. Let me tell you what Dr. Temple has said about that reading.

He wrote, "I realize the Commissioner believes the preamble does provide authority to require data to support use, even in lifethreatening situations and intends to implement the regulation that way if the final regulation is unchanged from the proposal.... The basis for this interpretation in the preamble still seems weak to me and the words of the regulation itself pose [many] . . . problems:"

[This statement appears at app. 1, p. 289.]

Mr. WEISS. And so again, it is people with a great deal of experience within your shop who are expressing these concerns-never mind the people outside FDA-and that's why I would suggest that a contrary interpretation of a preamble which is not part of the regulation itself, is not going to stand you in very good stead. And I think it's an area you really must pay very strong attention to.

Dr. YOUNG. Well, Mr. Chairman, as I said in my testimony, I promise to pay very careful attention to comments, because this seems to be the nub of the issue. And you saw me address this and attempt to develop this in the preamble, and I will consider very strongly whether that is sufficient language in the rule and preamble to deal with that particular point.

Because I do not want, under any circumstance, to violate the information under which a Commissioner must make a decision. That has got to be there, and insufficient evidence does not mean that you go ahead.

Mr. NORRIS. It should be understood, too, the context in which this all arose. The regulation, the proposed regulation, was drafted and then the preamble was crafted over it to interpret it for us and to explain our interpretation of it.

Mr. WEISS. Ultimately anyone who goes to adopted regulations will not even find a preamble. They will only find the regulations. So, even assuming that the preamble did what you think it does, and I don't think it does, it will not be there for people to look at. They are going to be looking at the language of the regulation. Let me yield at this point to Mr. Lightfoot.

Mr. LIGHTFOOT. Thank you, Mr. Chairman.

Thank you, Commissioner Young and the rest of the panelists for being here today. Dr. Young, you are either extremely interested in this topic or a brute for punishment. You have been here since the starting bell.

Dr. YOUNG. Well, I believe really in listening carefully.

Mr. LIGHTFOOT. I noticed you have been taking notes, too, and I'm sure we will see the results of them somewhere down the road. The proposed regulations differentiate between life-threatening and serious when determining if an IND should be used for treatment. What is the definition of life-threatening?

Dr. YOUNG. The definition that I feel, and I believe you will see coming forward, is that the expectation that the patient will succumb to the illness within about a 6-month period of time. That addresses one of the concerns that was raised earlier by Dr. Myer,

and I focused on that issue in my testimony. All of us, once born, have in a sense life-threatening conditions. The ultimate outcome of life is death. But this is crafted to take that very small amount of treatment IND's where the patient has no alternative therapy, is desperately ill, and to focus and narrow it to that condition, and to at least this physician's definition that there is a reasonable expectation that if left alone, the person will be dead in about 6 months. Mr. LIGHTFOOT. So there is basically a 6-month timeframe? Dr. YOUNG. Yes.

Mr. LIGHTFOOT. The reason I ask is that there have been some concerns that the life-threatening definition could be expanded to any disease. Do you think these concerns are legitimate?

Dr. YOUNG. Yes, we do, and that is why I have focused on the 6month period in my testimony today, because as raised earlier, for patients that are HTLV-III, now called HIV-positive, that that exposes severe risk. But, yes, the near positivity would not put one in the category, as I interpret that definition, of immediately life threatening.

Mr. LIGHTFOOT. Is the 6-month time period listed in the regulations?

Dr. YOUNG. No, it is not listed in the regulation, but it's one of the things that I'm going to attend to as I consider the final regulation, because many of the comments that I have heard in my many discussions pointed out the ambiguity of that and we want to define tighter what we mean by immediately life-threatening. I think that is an important thing to address. And I promise you that will be addressed.

Mr. LIGHTFOOT. Thank you.

On the other side of the coin, if you have a specific time period, and someone says this person may die in 7 months, then they wouldn't qualify. This would create a difficult situation.

Dr. YOUNG. Actually it's an advantage for FDA to have discretionary judgment, because a physician's judgments in general are clinical impressions, based on the best scientific evidence, and we would use that discretion. I would not necessarily see that on 6 months, 1 day, that it automatically ends, but it would be an understanding of the timeframe in which we are talking about. Certainly 6 months as contrasted to 6 years or 2 or 3 years-but there has to be a plus or minus figure there.

Mr. LIGHTFOOT. Are you talking more in terms of a guideline than a specific time period?

Dr. YOUNG. Yes. And it would be in that preamble which I have now learned from Mr. Weiss that I have to be very careful of where to put the words, and may have to go in different spots as well.

Mr. LIGHTFOOT. In your estimation, in what stage of the IND process might a treatment protocol be approved?

Dr. YOUNG. I think for immediately life-threatening, I would not anticipate that under ordinary conditions that we would have it earlier than end of phase II, and I would like to illustrate that, because it's a very important point.

Your question actually comes to the heart of this and the gathering of data, but starting this at around the end of phase II, we would have already had a number of clinical trials that take place