Dr. KESSLER. I am aware that there was a withdrawal of an application. Let me look to Ms. Porter. Ms. PORTER. With respect to the first point, maybe Dr. Kessler can say what he knows about the safety and effectiveness of the product. With respect to the withdrawal, we would respectfully submit that the details surrounding any NDA are, as far as I am aware, not a matter of public record, and so we would prefer to discuss those in an executive session. Mr. WEISS. Well, you know, part of the problem is that we have a company that makes a big to-do about the fact that it submitted an NDA application, and the whole world is told about that by them and about their expectation of getting FDA approval. And the physicians out in the field believe that it is true. And then the company silently withdraws it. It seems to me that it is inappropriate for you to tell us that we can't mention the fact that they have gone as far as to withdraw that application, because that is simply balancing the facts, and presenting the truth. Ms. PORTER. Mr. Weiss, I wasn't commenting on what is appropriate for you to mention or not mention. My only point was that with respect to the details of that, if you are asking us to com ment Mr. WEISS. I am not asking for details; I am asking you if it isn't true that they have withdrawn the application? Ms. PORTER. I do not personally know that as a matter of fact. Mr. WEISS. Well, who in the agency knows it? Nobody knows that in fact they have withdrawn the application? Dr. KESSLER. Mr. Chairman, I think I can comment that the use of Retin-A for wrinkles has not been fully evaluated, and at this point consumers should know that. MS. WITT. Perhaps I could also point out, as I said earlier, the labeling very clearly states that its safety and effectiveness have not been established. So physicians who believe that it has are ignoring the labeling. Mr. WEISS. I want somebody whose responsibility this is to check the agency's records and to provide us with information as to whether in fact the application has been withdrawn. Is Dr. Temple here? Would Dr. Temple know? Dr. TEMPLE. Dr. Temple is, but Dr. Temple doesn't know. He's in a different office. Mr. WEISS. Well, that's an indication of Dr. KESSLER. Mr. Chairman, we will be happy to provide Mr. WEISS. That's an indication of what a job you have on your hands. Dr. KESSLER. We will provide that for the record, Mr. Chairman. Mr. WEISS. Who is here at this point-would all the people from FDA who are present in the room just stand and identify yourselves and what bureau, division, or part of the agency you are from? Sir. Mr. TILTON. Yes. My name is Paul Tilton. I'm a biologist within the Center for Devices and Radiological Health. I work within the Office of Device Evaluation. Mr. WEISS. Do you know whether in fact the application has been withdrawn? Mr. TILTON. I do not. Mr. WEISS. Dr. Temple. Dr. TEMPLE. Well, I'm Bob Temple. I'm from the Office of Drug Evaluation I, which does not have as one of its responsibilities dermatological applications, I am pleased to say. Mr. WEISS. Ma'am. MS. PENDERGAST. My name is Mary Pendergast. I am Dr. Kessler's executive assistant. Dr. KESSLER. Mr. Chairman, let me comment. This is-as I understand it-there is a lawyer in me; I am a pediatrician-but, as I understand it, and I would be happy to go back and look further, as I understand it, this is confidential commercial information. And I think the Mr. WEISS. How can that be? Dr. Kessler, think about it. How can it be confidential information that they have withdrawn an application about which they have been bragging and saying that they expect approval from the FDA, so the world out there has one understanding, and then, in fact, they go back and they withdraw the application. The world still believes the application is pending, and you say it's confidential, and can not be made public that they have withdrawn the application? Dr. KESSLER. Mr. Chairman-and, again, I would be happy to go back and check it—but what I have always taught up at Columbia was that the agency was not in a position to comment on pending applications. That's what I've always taught. Mr. WEISS. But this is a nonpending application. This is a withdrawn application. That's what I'm asking. Dr. KESSLER. Again, Mr. Chairman, I would be happy to go back and review and provide you for the record—I mean, again, I just can't answer it at the present time. I just don't want to be in violation of the statute. That's all I request. I can go back; I will look. There is no intent-I have made it very clear to the American public that Retin-A should not be used, OK. I mean, Retin-A has not been fully evaluated, and they know that. Mr. WEISS. I appreciate that. Then my concern is that by not disclosing the information that they have withdrawn the application, in a sense you are allowing the deception about Retin-A to continue. That's my concern. [The FDA acknowledged the withdrawal of the application in a letter that is presented in app. 2, p. 270.] Dr. KESSLER. There is no intent to-we want to get information out. We want the American public to have that information. If there are uses that are unapproved, the American public needs that information, and we have a responsibility to provide it. I just have to make sure that I'm not in violation of the statute. Mr. WEISS. I assume that the other people who stood up also do not know whether the application has been withdrawn. If any of you three know, please indicate that right now. [No response.] Mr. WEISS. No indication. OK. The potential risks of birth defects associated with vitamin A derivatives used by pregnant women have been examined by FDA in recent years. For example, it is known that the use of Accutane by a pregnant woman can cause serious birth defects. Is there any research indicating whether or not the long-term use of Retin-A or Renova by a woman of child-bearing age can cause birth defects? [A brief description of such research published in the New England Journal of Medicine follows:] 52-16092 - 7 262 Vol 321, No. 4 THE NEW ENGLAND JOURNAL OF MEDICINE 1. Collaborative Study of the Adult Idiopathic Nephrotic Syndrorpe. A controlled study of short-term prednisone treatment in adults with membranous nephropathy. N Engl J Med 1979; 301:1301-6. 2. Black DA, Rose Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J 1970;6:421-6. 3. Ehrenreich T, Porush J Churg J, et al. Treatment of idiopathic membranous nephropathy. N Eng J Med 1976; 295:741-6 4. Bolton WK, Atuk NO, Sturgill BC, Westervelt FB Jr. Therapy of the idiopathic nephrotic syndrome with alternate day steroids. Am J Med 1977; 62:60-70. 5. Tornroth T, Honkanen E, Pettersson E. The evolution of membranous glomerulonephritis reconsidered: new insights from a study on relapsing disease. Clin Nephrol 1987; 28:107-7. 6. Noel LH, Zanetti M, Droz D, Barban C. Long-term prognosis of idiopathic membranous glomerulonephrials: study of 116 untreated patients. Am J Med 1979; 66:82-90. 7. Tu WH, Petitti DB, Biava CG, Tulunay Hopper J Jr. Membranous nephropathy: predictors of terminal renal failure. Nephron 1984; 36:11824. 8. Hopper J Jr. Trew PA, Biaya CG. Membranous nephropathy: its relative benignity in women. Nephron 1981; 29:18-24. 9. Hopper J Jr, Biava CG/Tu WH. Membranous nephropathy: high-dose alternate-day therapy with prednisone. West J Med 1981; 135:1-8. 10. Relman AS. What haye we learned about the treatment of idiopathic membranous nephropathy with steroids? N Engl J Med 1989;20:248-50. 11. Cattran DC, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in parents with idiopathic membranous nephropathy. N Engl J Med 1989; 320/210-5. 12. Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial methylprednisolong and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989; 320:8-13. EMBRYONIC RETINOID CONCENTRATIONS AFTER MATERNAL INTAKE OF ISOTRETINOIN To the Editor: The high risk of major malformation or spontaneous abortion in humans associated with fetal exposure to isotretinoin (Accutane, or 13-cis-retinoic acid) was well documented in 1985 by Lammer et al. in the Journal.' Earlier experiments in mice demonstrated that the all-trans form of retinoic acid (tretinoin, or Retin-A) was highly teratogenic, and the 13-cis form only marginally so.2 Not until 1986, when precise measurements with use of highperformance liquid chromatography detected embryonic retinoid concentrations, was an answer for this discrepancy found. It was shown that in mice, the all-trans form of retinoic acid reached the embryo in large amounts, but the 13-cis form did not. Since alltrans-retinoic acid seemed to be preferably and specifically transported into the mouse embryo, an active transport mechanism was suggested for it. Until now, the only information available in humans involved serum levels of 13-cis-retinoic acid and its metabolite 13-cis-4-oxoretinoic acid. It has been reported that the average elimination halflife for 13-cis-retinoic acid is approximately 10 to 20 hours and that after repetitive dosing, 13-cis-4-oxo-retinoic acid is found in blood at levels three to five times higher than those of the parent compound.* Recently, we studied the disposition of 13-cis-retinoic acid in embryonic tissues obtained when a pregnancy was terminated in a woman who unintentionally took 40 mg of 13-cis-retinoic acid per day from day 8 to 28 of gestation (estimated date of conception, day 0). The pregnancy was terminated on day 31, between 72 and 80 hours after the last dose of 13-cis-retinoic acid. Maternal serum samples were obtained at the time of the abortion; the serum and the tissue samples were quickly frozen. Exposure of the specimens to light was minimized as much as possible to avoid photoisomerization. The specimens were later thawed, and an intact 0.246-g embryo was identified and isolated. Retinoid concentrations were measured by high-performance liquid chromatography in maternal serum, embryonic tissue, and six samples of placental tissue. We measured the levels of 13-cis-retinoic acid, two of its major metabolites all-trans-retinoic acid and 13-cis-4-oxo-retinoic acid — and retinol. The results are shown in Table 1. Plasma measurements showed levels of 13-cis-retinoic acid that were in agreement with its reported serum half-life of 10 to 20 hours, even lower levels for all-trans-retinoic acid, and fairly high levels of the metabolite 13-cis-4-oxo-retinoic acid. Interestingly, in the embryo, concentrations of all-trans-retinoic acid were more than twice July 27, 1989 those of 13-cis-retinoic acid. In contrast to what happened in the mice experiments, 13-cis-retinoic acid was found in the human embryo in high amounts; 13-cis-4-oxo-retinoic acid was likewise present. Placental concentrations of the retinoids were not homogeneous. Morphologic investigation of the tissue was not possible because of the limited amount of sample. Nevertheless, the present measurements show that in humans, the intake of 13-cis-retinoic acid during pregnancy results in high placental and embryonic concentrations of all-trans-retinoic acid, which has been known for years to be extremely teratogenic in almost all species investigated. We propose that the metabolic activation of 13-cis-retinoic acid to the all-trans isomer could be responsible for the teratogenicity of 13cis-retinoic acid. 1. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41. 2. Kochhar DM, Penner JD, Tellone CI. Comparative teratogenic activities of two retinoids: effects on palate and limb development. Teratogenesis Carcinog Mutagen 1984; 4:377-87. 3. Kraft JC, Kochhar DM, Scott WJ, Nau H. Low teratogenicity of 13-cisretinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: comparison to the all-trans isomer. Toxicol Appl Pharmacol 1987; 87:474-82. 4. Brazzell RJ, Vane FM, Ehmann CW, Colburn WA. Pharmacokinetics of isotretinoin during repetitive dosing to patients. Eur J Clin Pharmacol 1983; 24:692-702. ELEVATED SERUM ALPHA-FETOPROTEIN DA PREGNANT WOMAN WITH RHEUMATOID ARTHRITIS To the Editor: We are reporting the finding of an elevated level of serum alpha-fetoproter in a pregnant woman with rheumatoid arthritis, who subsequently gave birth to a normal child, in the hope that studies may be undertaken to establish the frequency of such elevations in other women and ascertain their cause (e.g., placental vasculitis leading to increased diffusion of alpha-fetoprotein in the maternal bloodstream). A 31-year-old primigravida was referred for genetic counseling because of her concern about the potentially teratogenic effects of the medications she was taking for symptomatic control of severe rheumatoid arthritis, which she had had since she was 8 years old. She was counseled that the risk to the fetus was small relative to er maternal age and to the medications she was taking for symptomatic relief of her arthritis (acetaminophen, 2925 mg per day; prednisone, 5 mg per day; ranitidine hydrochloride, 150 mg per day; and hydrochloroquine sulfate, 200 mg per Dr. KESSLER. I am not personally aware of any information. I would have to ask that we provide that information. I don't have it. Mr. WEISS. I would appreciate that. At our subcommittee hearing on silicone breast implants in December, we heard testimony about the well-known dangers of silicone injections. Mr. Sheridan testified that, if physicians advertise or promote the use of silicone for wrinkles or lip enlargement, the FDA would consider any necessary regulatory activity. In your testimony you said that injections of silicone must stop. How do you plan to stop it? Dr. KESSLER. Mr. Chairman, we will bring the full force of the statute to make sure that it stops. I am not going to comment on specific enforcement actions. Mr. WEISS. Over the years, FDA investigators have followed up on leads regarding doctors who were illegally injecting silicone. After one 8-year investigation, FDA considered recommending an injunction against a well-known dermatologist in New York who has been an outspoken advocate of silicone injections. That particular doctor has illegally treated thousands of people with silicone injections. He was an obvious choice for enforcement activities, but FDA decided to do nothing. Why? Dr. KESSLER. Again, Mr. Chairman, I wasn't here at the agency at the time. Such behavior-if I have evidence that such behavior exists, we will bring the full force of the law to make sure that it doesn't continue. Mr. WEISS. According to a 1984 FDA memorandum, investigators believed that the First Lady, this is Mrs. Reagan, had received silicone injections from this doctor. Is it possible that there was pressure from the White House to stop the FDA's enforcement activities? Dr. KESSLER. Mr. Chairman, obviously, I was-1984, I was in the Bronx teaching at Columbia, and I can't comment on that. But it has to be emphasized that I am not going to tolerate the use of liquid silicone. We are not talking about an unapproved use of an approved drug. This is an unapproved drug. It is illegal, and its use must be stopped, and the agency will do whatever it needs to make sure that its use stops. Mr. WEISS. Well, as I said at the outset, obviously, we are not holding you personally responsible for matters which took place before you assumed your office. Dr. KESSLER. I appreciate that, Mr. Chairman. Mr. WEISS. However, the agency can't defend themselves by saying that you have just become the new commissioner. Dr. KESSLER. Absolutely. Mr. WEISS. The agency's actions are what we are exploring at this point. Dr. KESSLER. Absolutely. Mr. WEISS. And, indeed, the memorandum that we have, dated July 26, 1984, specifically states, "So that you will be aware, we have reason to believe that Mrs. Nancy Reagan has been treated by [the doctor]." Are any new enforcement efforts planned against that doctor or any of the dozen or so other doctors that have come to FDA's attention? [The July 26, 1984, memorandum follows:] |