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Transcripts of the US Congressional Hearings 15th Dec '00

ACCUTANE ? IS THIS ACNE DRUG TREATMENT LINKED TO DEPRESSION AND SUICIDE?

Good afternoon. A quorum being present, the Committee on Government Reform will come to order. I ask unanimous consent that all Members' and witnesses' written opening statements be included in the record. Without objection, so ordered. I ask unanimous consent that all articles, exhibits, and extraneous or tabular material referred to be included in the record. Without objection, so ordered.


Opening Statements

[CHAIRMAN BURTON] We are here today to talk about the acne medication Accutane and concerns that the drug is linked to depression and suicide. Accutane was licensed by the Food and Drug Administration (FDA) in 1982 as an oral prescription drug for the treatment of severe acne. Current recommendations indicate that the drug should only be used when a patient has not responded to other treatments including antibiotics. During the course of our investigation, we were told by dermatologists that while the drug has many severe side effects, that there is no other treatment available; however, we also learned that many individuals have been prescribed this drug for less severe forms of acne. I am attaching for the record an article outlining natural treatments for acne. The most well known adverse effect attributed to Accutane is birth defects of the children born to women who take the drug during pregnancy, However, we will focus today's hearing on the mental health issues. Did the Department of Health and Human Services fulfilled its public safety obligation in making the public aware of the potential for depression and suicide related to this drug? A significant number of psychiatric events, mostly severe depression, have been reported through post-marketing surveillance. The FDA has received reports of sixty-six suicides and one thousand three hundred seventy three psychiatric adverse events other than suicide related to Accutane. According to Roche Pharmaceuticals, the manufacturer of Accutane, the number of domestic and foreign reports of serious adverse events in the post-marketing adverse events database for Accutane as of April 30 was five thousand six hundred sixty-five. The largest percentage of these reports were psychiatric problems. Almost nineteen percent of the adverse events reported to Roche were psychiatric. Also, the most recent Periodic Adverse Drug Event Report for Accutane includes, for a twelve-month period, over seven hundred fifty new psychiatric adverse event reports (foreign and domestic), including two hundred that were coded as serious events, nine reports of suicide attempts, and six reports of completed suicides. Four questions arose during the course of this investigation:

  1. When did the issue of depression and suicide first arise regarding Accutane?
  2. What actions did Roche and the FDA take to determine if there was a causal link?
  3. When and how was the public notified? And
  4. Was that public notification adequate?

According to Roche, there is no evidence of increased risk ofdepression or suicide related to Accutane. Instead, they believe that the events reflect the multiple risk factors in the population of adolescents and young adults afflicted with the disfiguring disease of acne. While the package insert for Accutane contains language that warns of depression and suicide, this information is not typically provided to patients by either the physician or the pharmacist. Extensive patient education is required regarding pregnancy prevention while on Accutane because of the risk of birth defects. However, there is no system in place to educate patients and families about depression and suicide. We learned through our investigation that reports of depression and suicide are not new. The first report of depression in patients taking Accutane occurred in September 1982. Two patients in a clinical trial with 523 patients reported depression. Roche received five adverse experience reports of depression in 1983. November 1983, Roche received its first report of attempted suicide. November 1984, Roche received its first report of suicide. In May 1986 Roche received reports of five or six positive rechallenges in patients who experienced depression during Accutane therapy. In these patients, the depression went away when they stopped taking Accutane and began again after starting Accutane therapy again. Positive rechallenge is a significant indicator of a causal link between a drug and the adverse event.

As early as November 1984, Roche began including information on the package insert about reports of depression. Even thought French authorities required a label change to include "suicide attempt" in March 1997, the FDA did not require Roche to make a label change until February 1998. FDA also required that Roche notify physicians who were likely to prescribe Accutane. In February 1998, the FDA issued a "Talk Paper" advising consumers of and health care providers of new safety information regarding Accutane. The paper states: "Although the Accutane label already included information regarding depression as a possible adverse reaction, the agency felt health care providers and others needed additional information as a result of adverse events the agency has received. FDA and the drug manufacturer are strengthening this label warning, even though it is difficult to identify the exact cause of these problems…patients who reported depression also reported that the depression subsided when they stopped taking the drug and came back when they resumed taking it." What is disturbing to me is that the FDA published an article in their own Consumer Magazine entitled, "On the Teen Scene: Acne Agony" in July 1999. Thirty percent of the article focuses on Accutane. It goes into great detail about the pregnancy prevention because of birth defects, but fails to make any mention of depression and suicide. This article appeared 16 months after FDA's advisory. Why did the FDA not use its own Consumer magazine to notify the public of this concern? Today we will hear from three families: Amanda Callais was prescribed Accutane as a 14 year-old in September 1997. By November she was seriously depressed and attempted suicide. The psychiatrist treating her for depression was not aware of the connection between Accutane and depression and did not suspend her use of the drug after her suicide attempt. She remained seriously depressed. In February 1998, Amanda's mother, Lori learned of the FDA's warning and stopped Amanda's treatment. Amanda quickly made a full recovery. Mother and daughter are here today to share their experience. Stacy and Mike Baumann of Mundelein Illinois lost their son Daniel to suicide in December 1999. Daniel began Accutane treatment in July 1999. He suffered many adverse effects - chapped lips, dry skin and itching, joint and muscle pain, headaches, nausea, loss of appetite, mood swings, and insomnia. The physician thought his depression was school-related and never mentioned the FDA warning. Mr. Charles Jackson of Lubbock, Texas lost his 17 year-old son, Clay, in January 2000. Clay had been on Accutane for about three months. The family was provided no information by the physician regarding the FDA warning. Accutane is only supposed to be prescribed for severe recalcitrant nodular acne after every other treatment option has faiiled. Dr. David Pariser of Norfolk, Virginia, will be testifying on the behalf of the American Academy of Dermatology and providing an overview of the types of acne and when Accutane is recommended. Dr. Douglas Jacobs, on faculty at Harvard, and a Roche consultant, will present his evaluation of the adverse drug events regarding psychosis, depression, and suicide and Accutane. Dr. James O'Donnel, Assistant Professor of Pharmacology, Rush Medical School will present information regarding the connection between Accutane and other vitamin A derivatives and depression and suicide. Dr. Jonca Bull will testify on behalf of the Food and Drug Administration. I realize that this issue will be difficult for some of you to discuss. My heart goes out to each of you and to every family member dealing with the tragedy of suicide. I hope that this hearing can help resolve some of the unanswered questions so that maybe future tragedies can be avoided. The hearing record will remain open until December 18.

And of course we have one of our colleagues in the Congress who lost his son, Bart Stupak's son was lost to suicide not too long ago, and he believes it was Accutane related a well.

To those families who have lost loved ones because of this, or because we believe that is what caused it, our heart goes out to each and every one of you, and I know it's going to be a difficult time for you today, and we really appreciate your being here.

-o0o-

I now recognise my colleague from California, Mr. Waxman.

MR. WAXMAN: Thank you very much, Mr. Chairman. Today's hearing address an issue of great importance, and I want to begin by commending the work of Congressman Bart Stupak in this area. His tireless efforts to raise public awareness about the risks of Accutane have, I'm sure, already helped many families. His efforts have also been instrumental in encouraging Hoffman?La Roche and FDA to do more to learn about the risks of Accutane, and to inform patients and families about those risks. Accutane is a powerful and effective drug for the treatment of severe, recalcitrant acne. For many acne sufferers, it is the only drug that cure them of an otherwise scouring disease. Because of this drug's benefits, it is imperative that we understand all of its risks, and fully inform patients and their families. We already know a great deal about Accutane's risks of severe birth defects. That knowledge has provided the basis for patient education, targeting women of childbearing age. But the same is not true of the risk of psychiatric disorders, and that must be changed. I am troubled by how little we know about the link between Accutane and psychiatric disorders. No study has proven conclusively that Accutane causes psychiatric disorders, but a great deal of evidence suggests that there may be a link. A recent FDA analysis of voluntary reports, so called "adverse event reports" found that 147 cases of suicide and hospitalised depression had been associated with Accutane since it was first introduced in 1982. Even more disturbing, evidence shows that many patients feel depressed while taking Accutane, stop feeling depressed after treatment ceases, and then feel depressed again when treatment is resumed. Officials at FDA state that such cases, "provide the best evidence to support a relationship between Accutane and psychiatric disorders." But this is not conclusive proof, and it is unacceptable that such an important question has gone unanswered for so long. I am also troubled by the lack of information provided to patients and their families. As we will hear today, and as was the case for Congressman Stupak, many families are completely unaware that depression and suicide have been associated with Accutane. While the risk of depression has been a part of the label since 1985, the risk of suicide was not added to the label until 1998. Patients and their families simply did not have reliable and valuable access to this information until Hoffman?La Roche changed the Accutane box in only May of this year. But this new warning is still not reaching all users, because many old boxes without the warning remain in circulation. With the risk as detrimental and tragic as suicide, it is unacceptable that patients, including many minors and their families are not informed about it. A box warning is insufficient. Until a pamphlet specifically geared for patients is issued under the Med Guide program, they will not be fully informed. I am heartened by some positive developments. Hoffman?La Roche has agreed to work with FDA on a Patient Informed Consent Form, and a Med Guide pamphlet to warn of the risk of psychiatric disorders. Both will clearly discuss the risk of depression and suicide, and will do a great deal to inform patients and their families of these grave risks. I call on FDA and Roche to implement the Med Guide and Patient Consent Forms quickly. Most important of all, Roche has finally agreed to fund research into the link between Accutane and psychiatric disorders. Roche will be working with both NIH and FDA on the design of this research. I want to emphasize that this research must be independent, comprehensive, and extensive enough to answer the very serious questions about the psychiatric risks of this drug. This research is crucial and long overdue. I look forward to hearing from our witnesses, and to exploring how to improve the information and understanding about Accutane. Mr. Chairman, should there be further hearings on this subject, I would like to work with you. I think we ought to hear from the Hoffman?La Roche Company representatives themselves, because there are questions that I think they ought to answer. I am pleased you called this hearing. I think you have witnesses who can help us understand the problem, and give us a good guide as to what public policy recommendations we need to make as representatives of the people. Thank you very much.

CHAIRMAN BURTON: Thank you, Mr. Waxman. Ms. Mirella.

MS. MIRELLA: Thank you, Mr. Chairman. Just briefly, I want to thank you for holding this hearing on this issue. There is nothing we can do in this Committee that's more important than insuring that the medication given to individuals, particularly children, is safe and effective. I can't imagine any pain that is more grievous than finding that the medication prescribed to your child or family member actually caused them significant pain, or in some instances, even led to their death. Today's hearing will hopefully enlighten all of us on the efficacy of Accutane, whether its side effects lead to depression and suicide. I know the witnesses that come before us will elucidate both the positive and the negative outcomes of Accutane. I do want to thank the first panel for their courage in coming before us. This drug, Accutane, which has helped thousands of individuals who have serious acne problems, may also have dangerous psychological side effects. It's essential that we look at all facets of the issue before any decision is rendered. Preventing others from benefiting from Accutane without ample evidence to the contrary could be considered pernicious, just as continuing to prescribe the drug if we know that it is dangerous. In the end, our objective today must be to insure that all available information is passed on to families and patients about all possible side effects. I look forward to hearing the testimony today, and then discerning an appropriate role for our Committee. I yield the balance of my time.

CHAIRMAN BURTON: Thank you, Ms. Mirella. Mr. Horne.

MR. HORNE: Thank you, Mr. Chairman. This is a very important hearing, when you look at what seems to be an absolute flood of suicides in many of the high schools of America, I would hope someone in these two panels will tell us if there is any medical data as to whether Accutane has resulted in a type of suicide that haven't been with other types of suicide. That's the question I'd like to know. What else besides Accutane.

CHAIRMAN BURTON: Thank you, Mr. Horne. We will now turn to our witnesses. Will all please rise. (Witnesses sworn.) Please be seated. I think we will start right down here at the left with Mrs. Callais, and we'll have both you and your daughter both make your statements. If you could try to confine your statements to five minutes, that would be fine. If you go a little bit over we'll be lenient, but we'd like you to be as close to it as possible. Ms. Callais.


Testimonies

 

MS. CALLAIS: Good morning. In August 1997 my 14 year?old daughter Amanda was a normal teenager. She liked ??

CHAIRMAN BURTON: Would you pull the mike a little bit closer to you so that we make sure we pick it up. Thank you.

MS. CALLAIS: In August 1997 my 14 year?old daughter Amanda was a normal teenager. She liked school and she made straight A's. She liked talking on the phone for hours. She had a new boyfriend, and she liked life, but that quickly changed. On September 23rd, 1997, Amanda started taking the new acne medication, Accutane. She was excited about taking Accutane because the dermatologist said that the acne Amanda had been undergoing treatment for since the 6th grade would be cleared up. During the visit to the dermatologist, Amanda and her father, who accompanied her, were given an explanation about the physical side effects, a warning about pregnancy, and a pamphlet to read at home. So together Amanda and I carefully read that pamphlet and the release form her father had signed. I remember the warning about pregnancy and the many physical side effects, but I do not remember seeing the word "depression" in that pamphlet. It definitely wasn't on the release form, and I know the word "suicide" was never mentioned anywhere. However, by November Amanda had fallen into such a depression that she wanted to die, and on November 15th, my daughter took 40 pills in an attempt to kill herself, and she came within hours of succeeding. After her suicide attempt we continued to follow the doctor's orders, only now psychiatrists and therapists were involved. On the advice of those doctors, we admitted her to an adolescent facility, and she started taking anti?depressant medication along with the Accutane. By the way, the Accutane was continued with the psychiatrist's approval. As Amanda's depression worsened despite the therapy and medication, the only thing we could visibly see working was the Accutane. Her lips dried out, cracked and bled; her joints ached, and she was always thirsty. But the dermatologist told us that that was just the effect of Accutane, nothing to be worried about, just don't get pregnant. Finally after three months of treatment, in February 1998, even the psychiatrists could not understand why Amanda was getting worse. By now she had lost 15 pounds, she slept through her classes, she never talked on the phone, she wouldn't take a bath, she cut her hands with razor blades and she generally hated the world, and my daughter hated herself. My husband and I watched our daughter die before our eyes. Now even the experts were telling us they couldn't help Amanda, and they didn't understand why she was so depressed. I cannot begin to describe the hopelessness and the terror we felt as parents. We didn't know how to help our own child, and we were trying. Then on February 26th, 1998, I found out from a friend about the FDA's warning about the possible depressive effects of Accutane. She happened to see it on television. You know, I never did see that information. I had to get a copy of the warning from the internet. As a matter of fact, I gave that information to both the psychiatrists and the dermatologist, because you see, they knew nothing about the new warning. I threw the pills away, and within days I watched my daughter make a miraculous recovery. Within one month her psychiatrist, who knew and had approved of Amanda taking Accutane all those months before, could not believe the change in my daughter. Thank God, we have gotten our normal, at times aggravating, but definitely normal teenage daughter back. Yes, she still talks for hours on the phone. Amanda stopped taking the drug, but we've not stopped telling people about the effects of this drug. And I have not stopped hearing about the devastating effect it has on teenagers. We've done news articles in our local paper; we've appeared on news shows; we've done whatever it takes to get the word out. But should I have to do this? Is it my job to tell the world that this drug is dangerous and needs to be studied and controlled? I know that Roche Pharmaceuticals will tell you that Accutane does not affect teens, that teenagers are depressed anyway, especially teens with acne. After 16 years of teaching teenagers every day ?? and I am an English teacher ?? I can tell you that while teens emotions are very volatile, very few are clinically depressed, and even fewer are suicidal. Shame on Roche for not giving our children a fair chance, and just casually dismissing their lives as a trivial matter. It is time to find out the truth about this drug. Therefore I demand that the FDA take action. The FDA must require Roche to produce their worldwide data base of adverse psychiatric reactions to this drug. The FDA must hold Roche Pharmaceuticals accountable. The FDA must also require Roche to explain why the French learned ?? the French changed their warning in March of 1998, but the FDA wasn't aware of the change until a year later. Claiming ignorance about the warning in France is not an excuse or an explanation, it's a cover?up. Because you see, Roche's parent company is in Europe. Finally I demand, ask, plead and beg as a mother that the FDA require an independent study to be conducted on Accutane, to look into and determine if and how Accutane in the United States, and Roaccutane in the rest of the world causes depression. We need to see an unbiased study done to investigate this matter. I know that recently Roche issued a stronger warning label, but at this point warning labels are not enough. Our children are dying because a drug company makes lots of money from this drug. This is the same company, cited for once advertising that Accutane helped depression, this just one month after the FDA required the warning about suicide. Is the almighty dollar and corporate bottom line worth more than our children? We would never allow our children to play Russian roulette with a gun, but we allow that to happen every time a prescription for Accutane is given. If you do not act, and act promptly, you have just pulled the trigger. I just hope it's not your child, and I hope and pray that the chamber of that gun isn't loaded. Thank you.

CHAIRMAN BURTON: Thank you, Ms. Callais. Amanda, would you like to make a couple of comments? (Testimony of Amanda Callais.)

CHAIRMAN BURTON: Thank you very much, Amanda. Mr. Baumann.

MR. BAUMANN: Can I take 7 minutes?

CHAIRMAN BURTON: Sure.

MR. BAUMANN: May I say that listening to Amanda for the first time, I can see exactly what happened to my son. It was the same thing. I am coming to Washington today, not in anger, but with some hope. I am not angry at the school system that called us in unexpectedly, and with no previous communication, to sit down in a small room in front of two administrators and three armed police officers, to be told our son Dan was to come home, and be home schooled because of the result of the Columbine tragedy, simply because he wore black. They were afraid, and I understand that. I am not angry at the dermatologist who diagnosed the cause of Daniel's acne as being stress related, and even pinpointed the day of the meeting as its beginning, but then prescribed Accutane as an initial remedy rather than a last resort, with no patient/parent counseling as to the possible consequences. I am not sure if he was not aware, or just thought that the worst was not worth mentioning in light of the great results that could be obtained. I am not angry at the pharmacy that distributed this expensive drug for now counseling us in any way as to the potential side effects. Recently we went to the same pharmacist for a prescription for antibiotics, and he spent five minutes talking with me, including talking to me about the side effects, which included nothing at that time more serious than a possible stomach ache if not taken with a meal. I know he cares. I am not angry with the company that labels the drug, even though the labeling did not include the dangerous potential side effect of suicide, although I am not sure why it did not. I am not angry with the drug company that makes Accutane, because I believe that for many it is a God send. I am not angry at the therapist in Lincoln, Nebraska, last Thanksgiving, who when told that Dan had scored high on a suicide risk inventory test, elected to interview him over the phone from home, and clear him from all risk. Dan committed suicide two weeks later. Mostly I am not angry with myself or my wife Stacy for thinking that our son's behavior was just that of a normal, healthy, independent thinking teenager who was going through a phase in life. I do not know if our dermatologist giving up his practice had anything to do with our son's death or not, but I do know he is now teaching at Loyola University. I can only hope that he teaches his students that the use of these drugs, even for dermatology, should not be taken lightly. I met a friend from high school not long ago in a Sam's Club, it turns out she was there to pick up a prescription for her son of Accutane. When I asked if she was aware of the potential risk, she looked at me like I was crazy. I asked her if she was counseled by her dermatologist, who was different from ours, and she said she was not. I asked her if this drug was prescribed when other remedies had failed, and found that it had been prescribed first, before any other remedies had been tried. I then asked to look at the labeling and letter that came with her prescription, and found that it made no mention of depression or suicide, and the pharmacy ?? well, he made no mention of the suicide for sure. The pharmacist said nothing about these potential dangers to her. The pharmacy and the labeling company were both different than ours. I then tried to reiterate my concern, and I was dismissed with, "My son is very well liked, outgoing and happy," much like my Dan, as though nothing could happen to her son. I don't think hearing the potential risk from me meant anything to her. I believe people do have the right to determine the amount of risk they are willing to assume for themselves, but they do not have the right to impose that risk on others unbeknownst to them. I fly small airplanes for a living, and occasionally take people from one place to another in bad weather. If there's a thunderstorm in my path, I let them know the possible consequences, and that it will be safe, however it may be very uncomfortable. Even if the situation changes, we may have to divert and delay, or possibly not be able to get to the intended destination. I believe the choice is theirs, and if I lose a few trips as a result, so be it. I find that this drug can be very dangerous for pregnant women, as associated with various birth defects. There is no circumstances under which it should be prescribed. Put into the Physician's Desk Reference that women should sign a form saying they will not get pregnant while on Accutane. I have seen a television commercial which is animated, with kids sitting around a computer, and then the computer screen shows ?? is shown with a picture of a boy's face with dots on it, representing acne. The child at the computer presses a button and the dots disappear. Call Roche for more info. I don't think it's as easy as pressing a button on a computer, getting rid of your acne. I saw a doctor on TV saying that there is no link between this drug and suicide, but later found that the drug company itself funded his research. In my mind this is a conflict of interest, and at the very least gives the appearance of impropriety. In the PDR, Roche itself lists "depression and suicide involved," which means highlighted as possible adverse reactions. I believe that this is a powerful drug, and have no doubt that it can clear up, or at least include even the most severe acne, which my son did have. I realise that the drug company is in the business to make money, and I am sure that a widely prescribed, expensive drug like Accutane does just that. But my question would be: At what cost? My suggestion is that I do not necessarily think that this drug should be pulled from the market, but I think its distribution should be handled differently, and additional research conducted by an independent source as to potential hazards. I wonder if my son's suicide was ever reported to the FDA, and how many others there might be out there. Wouldn't it be okay if we let people know that there may be a danger and let them decide for themselves if it is an acceptable risk? So what if the drug company makes a little less money. After all, I believe most people think that smoking is harmful, but many still do it, and the cigarette companies are still in business. None of us as individuals have the time or resources to fight for all the causes that are important in life. But if by coming here today we are able to find a stronger, more powerful voice to carry on this investigation and education, we've done our job. In conclusion I would like to thank you for letting me come here and speak my piece. If my experience helps even one person, the trip will have been worth it, and I believe that life should also be held with a higher regard than money, fear, greed and ignorance. All things, I think, can be overcome with compassion, understanding and education, quite apart from my son's death. Lastly, my greatest hope is that by coming here in some small way, my son's life will be given meaning, and his death dignity. Thank you.

CHAIRMAN BURTON: Thank you, Mr. Baumann. Mrs. Baumann.

MRS. BAUMANN: Daniel began Accutane therapy on June 25, 1999, three days after his first visit to the dermatologist. On June 22nd, Daniel's dermatologist told us that the breakout was a result of high school stress, and even pointed to the week the stress may have begun. The dermatologist sent Daniel home with a prescription of prednizone, erythromycin, a shopping list that included Purpose Bar, Coliderm Fluid Gel, Presun Ultragel, and Vitamin B5. In addition we received two brochures that we were to read before starting Accutane therapy, "Important Information Concerning Your Treatment with Accutane," and "What Young Men Need to Know about Acne and its Treatment with Accutane." Daniel and I read both brochures and felt that it was something that we needed to do, and was looking forward to the promising results. This was a very big decision for us, considering we didn't have insurance, and it was going to be self paid throughout the Accutane therapy, monthly dermatologist visits and blood tests. It wasn't long before the side effects started. Chapped lips, drying skin and itching, joint and muscle pains, headaches, nausea, loss of appetite, mood swings and insomnia. This was a very difficult summer for Daniel. He didn't even want to leave the house anymore, and just wanted to stay in his room all day. On the first day of school Daniel cried as we were driving there. He was 15 at the time, going to be a sophomore. He didn't know why he was crying. He said he just felt weird. School was very difficult for Daniel this term, and he had a very hard time concentrating. Daniel and I went to the dermatologist every month, and we were told that this was all very normal and to be expected. He assured us that the mood swings were normal, and would be going away as soon as the Accutane therapy ended. On December 11th, 1999, Daniel committed suicide. I called the dermatologist two days after Daniel's death and talked to him directly, and let him know what had happened, and that we wouldn't be making our next appointment. He offered his deepest condolences. At the time of Daniel's death we knew nothing about Accutane and its adverse reactions linked to depression and suicide. It wasn't until two months later, on February 9th, that I discovered that Accutane might have played a role in Daniel's suicide. I was having lunch with some friends, and a concerned friend mentioned that she had heard that prednizone might be linked to depression, and she knew Daniel was taking this for his acne. As soon as I came home that afternoon I looked for Daniel's entire prescription receipts and started reading everything I could. I got online and used the two key words, Accutane and suicide, and found FDA's Newswatch dated February 26th, 1998, "Important New Safety Information about Accutane." I was home alone at the time, and just couldn't believe what I was hearing; learning for the very first time. In addition, I also discovered that the brochures Daniel's dermatologists gave us were copyrighted in 1996 and 1997 respectively. The brochures had no adverse reactions reporting depression, psychosis, suicidal ideation, suicide attempts and suicide. I was finding it very hard to believe that Daniel's dermatologist had no idea or updated information to hand out to his patients. I have since visited the pharmacy where Daniel's prescriptions were filled, and asked the pharmacist if she knew of any of the adverse reactions associated with Accutane. She was not aware of depression and suicide. She immediately grabbed a 40 milligram package from the shelf and was surprised that the depression and suicide warning was not present on the packaging. I find it interesting that five months after Daniel's death his dermatologist unexpectedly announces to his patients by way of postcard that he was closing down his practice to teach at Loyola University. In addition to everything that continues to point that Accutane played a role in Daniel's suicide is a picture that I received from a friend on the day after Thanksgiving this year. Looking at the picture brought tears to my eyes. His beautiful smile, hopes, dreams and promises have been taken away by Accutane therapy. I realise that we have pictures of Daniel before Accutane, all smiling, and pictures of Daniel on Accutane, no smiles. As you can imagine, this past year has been very painful for our family, and the more we research, the more we realise that somehow or another our precious son's life fell through the cracks. I am not looking for an out. I do know this for a fact: that dermatologists provided us with outdated information; the pharmacist didn't provide any patient counseling. Grandmar Systems (phonetic) and First Databank's package insert did not include the most current adverse reaction, suicide. Roche's labeling did not include in the warning depression and rarely suicidal thoughts, suicide attempts and suicide. The FDA has allowed Roche to continue to profit from this drug for far too long without taking any responsibility for the damage that it continues to do to our children. Mistakes were made by many, and now we are all suffering because this could have all been prevented if everybody did their jobs. I hope that this limited information that I have provided today will somehow make a positive difference in our children's future. Thank you for giving me an opportunity to share Daniel's story with you.

CHAIRMAN BURTON: Mr. Jackson.

MR. JACKSON: Mr. Chairman, thank you for inviting me to come and testify before this Committee today. This is going to be extremely difficult for me to talk about; however it's extremely important for me to be here, if we can prevent just one parent to have to experience the pain and grief that my family's had to endure, then all this will be worthwhile. On January 13th, 2000, my 17 year?old son, and my best friend, Clay, died from a self?inflicted gunshot in my home. Around 4:00 o'clock in the afternoon that day, imagine my wife and my 10 year?old son coming home to find his lifeless body dead in his bedroom. I will never be able to remove what they saw that day from their memory. This is going to stay with them for the rest of their lives. Clay began going to a dermatologist at the age of 14, for normal teenage acne. In October of '99, at the age of 16, his treating physician decided to put Clay on Accutane for his mild acne. There was never any mention of suicide as a side effect. The information that Clay brought home from the dermatologist was a brochure dated 1994, and it made no mention of suicide. The only thing that concerned the dermatologist was our ability to pay for the drug. The package insert that came with the prescription made no mention of suicide as a side effect. The pharmacist where we had all of Clay's prescriptions filled never mentioned suicide as a side effect. The first time that we were ever made aware of any relationship between Accutane and suicide was when we heard the news stories about Congressman Stupak's loss of his son, and the information that he uncovered. Looking back, I have to assume that neither the dermatologist or the pharmacist knew anything about the link between Accutane and suicide. We are given so much freedom in this country to make choices for ourselves, because we have so many checks and balances built into the system to protect the citizens. Sometimes we make those choices blindly. That trust has been violated. I am not sure who is to blame. I don't have those answers. I just know that that trust and faith that I once had has been greatly diminished. Also, looking back, I wish I had taken seriously that young investigating officer to investigated Clay's death, when he asked me the question back in January, was Clay taking Accutane, and did I think that this attributed to his death. Oh, I wish I had taken him seriously then, maybe Congressman Stupak's son would be here today. I will be happy to answer any questions that you might have, Mr. Chairman.


Questions for families

CHAIRMAN BURTON: First of all, on behalf of the Committee, I want to thank you all for being here, and I want to once again express our condolences for the tragedies that you've had to encounter, and will continue to live with. Let me start with you, Mr. and Mrs. Baumann. You found out after your son was gone that prior to his death, that on the internet there was information that showed that there was depression and possible suicide if they took Accutane.

MS. BAUMANN: That is correct.

CHAIRMAN BURTON: So this information was on the internet before this tragedy occurred, but you had never been told that by a pharmacist or a dermatologist, or by the company itself?

MS. BAUMANN: That's correct. The information that the dermatologist gave me were brochures that are made by La Roche that were copyrighted in 1996 and 1997.

CHAIRMAN BURTON: The point I want to make is, had you been made aware of the problem when it was first put on the internet, if it had been properly given to you by the company or by the pharmacist or the dermatologist, this whole tragedy very well might have been avoided.

MS. BAUMANN: I agree.

CHAIRMAN BURTON: How about you, Mr. Jackson?

MR. JACKSON: Yes, sir, the same situation. This was nine, ten months after Clay died before we even suspected anything like this. We saw the news story and went to Congressman Stupak's website and saw what information he had. I think what got our attention was that even though it was nine, ten months later, we heard the little news story on the 10:00 o'clock local news, and we saw like the last three seconds, and my wife and I both reacted because there was something about Accutane, something about suicide, but we didn't catch the whole story. And that put us back to January when the investigating officer asked us this. At the time we thought it to be absolutely ridiculous. Now we hear the story, we find Congressman Stupak's website, we see this mountain of information that has obviously been available for as much as two years prior to Clay's death.

CHAIRMAN BURTON: And so had you been able to have that information before you, you would have seen the signs, and you might very well have avoided the tragedy.

MR. JACKSON: There would have been absolutely no way that that young man would have ever been on that drug. Because the other thing that we learned was that it was a drug of last resort, and for the most severe cases of acne. Clay did not have those traits. It was, in my opinion ?? he had no reason to be on this drug. He had a normal, 16?year?old face, and it was not the severe case that this drug is licensed to be prescribed for.

CHAIRMAN BURTON: Ms. Callais and Amanda, had you known what was available prior to Amanda going on Accutane, you probably wouldn't have had her on that, or at least you would have noticed the signs?

MS. CALLAIS: We probably would have started it. You don't know until you're on this drug how you're going to react, but I know, had we had the information, I can only tell you what happened when we walked in the emergency room, and my husband looked at the emergency room physician, and he said, "Do you think Accutane could cause this?" Because it was the only drug she was taking, and his response was, "No, that's an acne drug." So had we known, we would have taken it away from her immediately. But we didn't have that option, and so she continued it.

CHAIRMAN BURTON: But the point is, the physician at the hospital when you went in had no knowledge whatsoever about the side effects of the Accutane, even though it had been reported much earlier, and it was on the internet.

MS. CALLAIS: I don't know at that time, because this was back in 1997 that it was on the internet.

CHAIRMAN BURTON: Uh?huh.

MS. CALLAIS: Apparently it was in the PDR, buried, possible depression, but we didn't know that, and apparently neither did the physicians. Because had we known any of that, and had it been available to us, we definitely would have taken her off Accutane.

CHAIRMAN BURTON: Mr. Waxman.

MR. WAXMAN: Thank you, Mr. Chairman. Thank you all for your testimony. I know how difficult it must be to come before a Committee of the Congress and share your pain, and we certainly want to extend our sympathies to you. I think your being here is very important as we explore this issue and we learn what we can. You have all said, as I understand it, that if you had known about this risk, if there was some information about a risk of suicide versus clearing up some acne, none of you would have put your children in that kind of risk. Is that a fair statement from all of you? And you didn't know until very late that the problem, in the case of suicides, might have been related to Accutane. Once you learned, or at any point, did you ever let the company know that there was a problem related to the drug, or let the FDA or your doctor know about it?

MR. JACKSON: We notified the FDA. We filled out an adverse incident report form and sent it to the FDA. I found it strange that there is a voluntary reporting system that we were supposed to do, but we were not aware that it's even out there. And the dermatologist for sure isn't going to be sending in that type of report.

MR. WAXMAN: And this was how many months after your son's death?

MR. JACKSON: It was October or November of this year, when we sent the report in.

MR. WAXMAN: So it was after you heard about Congressman Stupak's son, and you started making this connection, and then you took it upon yourself to let the FDA know?

MR. JACKSON: Right.

MR. WAXMAN: Did you let the doctor know?

MR. JACKSON: No. It's extremely hard to go back in that office and all, because of everybody is so scared of getting sued, and nobody wants to say anything, so nobody will talk to you. And I don't want to put that attitude out there, but I was interested in knowing what was in Clay's medical file. And I called over there and asked to have a copy of all his medical records, and they said no problem, would you like to come by and pick those up, yeah, it would be fine. So I went by later that day and signed a release and picked up a copy of his files, and left, and it was just business as usual. There was no, How're you doing or anything like that, and it was really strange. And I go back out in the car and I sit in the parking lot, and what I could read of his handwriting, there is absolutely nothing in that file, you know, just the dates of the appointments.

MR. WAXMAN: As far as you knew, the doctor didn't even know about the association of Accutane with the suicide?

MR. JACKSON: No. And this is a highly respected dermatology clinic in our community, this isn't some rooky. This is a predominate, very well?respected dermatology clinic in our community, and the brochure that we come home with was dated in 1994. Clay, you know, when he was put on the drug was in '99, five years later.

MR. WAXMAN: Mr. and Mrs. Baumann, I am asking you the question, did you contact the doctor, the company or the FDA, not in any way to be critical, but just to know if you did, and if you didn't, I can understand your not doing it. What would be your answer?

MR. BAUMANN: I contacted the doctor two days after Dan's death to let him know that Dan had passed away, and that we wouldn't be making his next appointment that week. This was before I even knew that there may be a link between Accutane and depression and suicide. I don't know if the doctor reported it to the FDA. I can guess he didn't, because I would assume that someone would have contacted me. Like I said, I do know that five months after Dan's death, the doctor is now not in practice, and teaching at Loyola University.

MR. WAXMAN: Well, Congressman Stupak recommended further studies between the links between Accutane and psychiatric disorders, as well as for increasing the information for patients and families to receive that information about those risks. I assume all of you think, at the minimum, that we ought to know more about this problem, and people ought to be advised about the risk that they might have ever dreamt that they were subjecting their children to. Ms. Callais, did you ever contact anybody about your experience with Accutane and the relationship you started to think was there?

MS. CALLAIS: Actually I did, the next day, the day that I found out ?? after I found out about the warning, when it first came out from the FDA. I called Roche Pharmaceuticals because their number was on there, because I knew I was supposed to ?? it said report it. So I called, and I remember something that the person that I said that just struck me as horrible. She said, "You know, we've had a lot of calls about those things today." And I thought, my God, how many kids have died. And she said, "Hm, I don't know." I also talked to them again a couple of months later, because they were supposed to call back in 30 days to see how Amanda was, and they didn't bother. As you can understand, I was furious by this time. I have talked to my daughter's doctor, her dermatologist, and I talk frequently now. I still use that dermatologist. It took a lot to go back, but I trusted that she didn't know, and she didn't know. And since that time she and I have talked. She always wants to know what I'm doing with it, because we talk all the time. I go everywhere I can to tell about this drug, and she has said that since Amanda's case, she has pulled three patients off the drug, that she now asks them about how they are doing, if they are depressed. But she is the only dermatologist that I know of in our entire area that even bothers to ask, and she only asks because she knows about Amanda. I don't know that anybody else even checks. I mean, who tells your dermatologist that you're depressed? You go to your doctor, you don't go to your dermatologist.

MR. BAUMANN: I know that Stacy has talked to the pharmacy about it on a couple of occasions, and I think even recently that the pharmacist said that they had done some of their own investigating as well.

MR. WAXMAN: We do know that even before any of you had your experiences with Accutane, that the company knew that there was some association with the use of Accutane, and FDA had knowledge about it as well, and in Europe they were taking stronger action. My feeling is that they're the ones who should be telling you, not you telling them, so that we can avoid these problems.

MR. BAUMANN: The word that came to my mind when I did find out was I felt bushwhacked.

CHAIRMAN BURTON: Ms. Mirella. MS. MIRELLA: Thank you. I want to add my voice to those who've said we thank you very much for coming and telling the story. It's apparent to myself, and I think to all of us on this panel, we can empathize as much as we can with what you've been going through, as much as one can who hasn't experienced it. It seems to me, from what you said, Accutane has an almost immediate reaction, and I mean, we're talking about things that have happened within several months; is that correct? MS. CALLAIS: Probably several weeks.

MS. MIRELLA: Really?

MS. CALLAIS: Uh?huh.

MR. BAUMANN: From listening to Amanda in the back, giving a report to a news reporter, it's exactly happened with Daniel, too, and I can't remember the question that was asked, but it was so appropriate. It's not ?? the reaction is immediate, but it's continually worsening. I would say that's accurate. MS. A. CALLAIS: Since I have been on the drug, and I'm the only one on the panel who can state how it feels to be on Accutane, the physical side effects occur very quickly, but within days of taking Accutane, my mood began to change. Within a week I was crying for absolutely no reason. I think one of the easiest examples to tell people is that my dad bought me a jacket that I wanted. I had wanted it for a few months, and when he gave it to me I looked at it and I burst into tears because he hadn't asked me, and I didn't understand why I was so upset, but I was, and I couldn't stop crying. There was definitely ?? it takes effect very quickly, I mean, within days my mood had begun to change, along with the physical side effects of the drug.

MS. MIRELLA: Now, I'm trying to understand. The warning statement that is contained within the insert with Accutane now warns against depression and possible suicide; is that correct, it does now?

MS. CALLAIS: It does now, but I caution you about one thing of this depression. It is not a normal depression. It doesn't act like you would normally see. And also, if you don't know what teenage depression is, or I mean clinical depression, you have no clue. This doesn't happen in such a way that you wake up and say, oh, my child is depressed. It happens a little more each day, until finally you wake up one day, six to seven weeks later ?? it's generally about two months into the treatment, seven weeks ?? something's wrong. So it's very, very gradual. So while it may explain depression or say depression now, you know, you need an explanation of what depression is.

MS. MIRELLA: For someone who is on Accutane, they need to be watched and monitored every day to see if there are nuances that can be determined from one day to another. This warning was not on there back in what, '97? Did it happen like '98, is that what we're talking about?

MS. CALLAIS: February 26, 1998 the warning came out.

MS. MIRELLA: 1998. And the French did it before we did.

MS. CALLAIS: 1997. I guess French people were more receptive to depression than Americans. I hope not, but that's kind of what happened in the time ?? I realised that, and I wondered ?? I thought that if another country came out with such a warning that the FDA had requirements that Roche should have immediately told them.

MS. MIRELLA: FDA has that reputation of making sure that every precaution is taken well before other countries, generally. And I think all of you said that your doctors really were not aware of the intensity of the consequences of Accutane. Mr. Baumann?

MR. BAUMANN: I am not sure if they weren't aware. One of my customers is a physician, and he says that he does not routinely tell everybody all the bad things that can happen as the result of a drug being administered, because the instances in many cases are so small of bad things that it's just ?? whether it's not worth it or not, I don't know.

MS. MIRELLA: It seems to me that that should be in great big bold print, because I've read aspirin bottles which say, you know, all kinds of horrible things could happen as a result of taking, you know, more than two aspirin at any one time.

MR. BAUMANN: And I would like to respond to your previous question. We did meet our friend who was picking up an Accutane prescription for her son, and I asked her to look at the labeling, and I even asked her to save it for me, but apparently she didn't think that it was an important thing that I was asking her, so she didn't. But there was nothing on her labeling, and this was just last summer.

MS. MIRELLA: And sometimes labeling is such small print also, not only are we not accustomed to looking at warnings, but such small print. Again, it almost sounds as though doctors ?? either they are ?? they feel that they are worried about the risk of being sued, or whether that is a problem, a liability problem, or whether they just don't know. It seems like a recommendation that might come from this Committee, there should be something with regard to educating doctors. Do you agree? I'm trying to figure out what it is that we can do.

MS. CALLAIS: I would say some education and potential patient education. You know, we need to educate the children and the parents. One of the things that I noticed about physicians, dermatologists particularly, from what I have heard, said over and over from them, and you have to understand that I now go and talk, and I ask everybody about it, and they'll say, "Well, I've never seen it before." Or they'll say, "Well, the risk is so minimal that, you know, I've not seen this. It's not something to worry about." I don't think that the dermatologists actually believe that depression is a possibility. And if they don't see it, and if a child commits suicide, they'll never see him again. And if a child is depressed, the amazing thing about Accutane is you pull them off, and they get better. So once they stop the treatment, well then they're okay, so you never see that part of it. So I don't think they're really aware, or if they are, they just assume it won't happen to them.

MR. BAUMANN: I feel the parent education is most important, because it's the parents that monitor the children most of the time. The physician only sees them on occasion, once a month, and the parents ?? Had I know what Amanda here had said earlier, it would be very easy to see the signs as a parent. MS. CALLAIS: May I ask something that I have wanted to see done ever since then, because I realised it. If there was some way that every time that a child went to the dermatologist right now, they could fill out a little, just a little checklist, and the parent had to fill that checklist out of certain symptoms, that would clue you in as to what's going on as the physician. You could take it and do it. I even think there is one in existence today, and that could be done, a profile of some sort. Something that lets the parent and the physician know what's going on with that kid.

MS. MIRELLA: You mean a profile before the medication?

MS. CALLAIS: You know, you start before, what is your mood, how many hours of a night do you sleep, do you have insomnia, or something. Something so you have a base to start, and then once they start, if every visit that that child went to the dermatologist, and I'm saying very selective, not mild to moderate anymore.

MS. MIRELLA: Okay. So you continue to monitor ??

MS. CALLAIS: Continue the monitoring so that that physician has right in their hands ?? they can see something going on. But you need the parents to do that, because I'm afraid the kids would not necessarily tell the truth. They would be afraid they would be taken off.

MS. MIRELLA: Right, right, exactly.

MR. BAUMANN: One thing that seems to be a tie here is that I heard Mr. Jackson say, also in the back, was lean people seem to be ?? MS. BAUMANN: Low body fat.

MR. BAUMANN: Low body fat seemed to make a difference. Our son was very thin. He stopped eating, he slept all the time. He didn't want to go to school, he didn't care about his grades, he lost his desire to live, I believe. And he also was very thin at the end, and very depressed. He stopped taking care of our dogs, and he had done that all his life. He loved those dogs.

MS. MIRELLA: It almost seems like there should be a connection between mental health groups, as well as the physical health groups in this particular situation. Maybe we can work something out. I want to thank you very much. Did you want to make another statement?

MR. BAUMANN: I believe there are some obvious signs. As a parent now, hearing what I'm hearing today, I think there are some obvious signs that can very easily be interpreted, and maybe we can avoid other people having these problems.

MS. MIRELLA: And again the studies that have been mentioned, I would think we should move ahead fast with those. I think you very much. Thank you, Mr. Chairman.

CHAIRMAN BURTON: Thank you, Ms. Mirella. Mr. Horne.

MR. HORNE: Thank you, Mr. Chairman. I have been very moved by your studies, and I have known a lot of children that have had Accutane when my own children were going to school, and fortunately we did not have the problems that occurred that led to death. But the dermatologists that I have known have put it under a very controlled manner of six weeks or that, and they haven't given it any more. Now, to what extent they have this knowledge, I think, Mr. Chairman, there's a nice list of major associations attached to an article in your opening testimony, and we ought to send them all the files we've got here, and copies, so that we can understand your daughters, your sons, what happened to them, and I think they ought to be getting increasingly conscious of the effect of this. Obviously the second panel will get into it, but we've got to do it on the human side, and certainly we could give you the package of testimony that we've had, and that might just sway a few doctors to asking the questions you want them to ask. Apparently, they, according to your testimony, do not ask. In my opening statement I said that I would like to know the difference between suicides that have had Accutane with suicides that don't, and the degree to which that is likely to happen. Maybe we'll here that from panel two, I don't know, but that is certainly a question we ought to ask, and try to deal with. I thank you and yield back my time.


Panel of Speakers

 

CHAIRMAN BURTON: Thank you, Mr. Horne. I want to thank the witnesses for their testimony. I know it's been very difficult for all of you. Let me just say that we, on this Committee, and in the Congress, will do everything we can to make sure that the information that you've given us today in your testimony is disseminated as widely as possible, so that parents and children across the country will have as much information as possible, so that these tragedies won't occur in the future. Once again, thank you very much. Thank you very much for being with us. Our next panel is Dr. Pariser, Jr. Jacobs, Dr. O'Donnell, Dr. Bull, and Dr. Huene. Have I pronounced that correctly, Dr. Huene? Dr Huene? Dr. Huene? Would you care to come to the table? unidentified speaker: Mr. Chairman, it was the Department's understanding that Dr. Huene was coming to accompany the witness, and would answer any questions that our witness, Dr. Bull, might not be able to answer for you. I thought that was understood by the staff.

CHAIRMAN BURTON: Does she not prefer to be at the table; is that correct? unidentified speaker: Yes, Mr. Chairman, that is our preference.

CHAIRMAN BURTON: Okay. Well, if you have questions for her, I presume she will come forward at that time?

UNIDENTIFIED SPEAKER: Yes, Mr. Chairman, that's the case.

CHAIRMAN BURTON: Would you stand, though, Ms. Huene, along with the rest of the table? (Panel sworn.)

CHAIRMAN BURTON: Please be seated. Okay, we'll start with Dr. Pariser. Did I pronounce that correctly, Dr. Pariser?

DR. PARISER: Yes, sir. David Pariser.

CHAIRMAN BURTON: And you're a dermatologist; is that correct?

DR. PARISER: Good afternoon, Mr. Chairman and members of the Committee. My name is David Pariser. I'm a dermatologist in private practice in Norfolk, Virginia. I am also the Chief of Dermatology and a professor of dermatology at the Eastern Virginia Medical School in Norfolk, and I'm on staff at four Norfolk area hospitals. For the last 24 years I've had the opportunity to treat thousands of patients with acne of varying degrees of severity, and furthermore I maintain an active practice in clinical research. For the last 8 years I've participated in over 150 research projects and clinical trials, including numerous acne clinical trials for a variety of pharmaceutical companies, including three trials funded by Roche Pharmaceuticals. I have received indirect funding in the past through the National Institute of Health, but not any from that agency in the past year. In addition to my daily medical duties, I am a member of the Board of Directors of the American Academy of Dermatology, and I am here today on behalf of the over 13,000 members of the Academy and millions of patients, and I wish to express my appreciation to appear before you and discuss the drug isotretinoin, commonly referred to today as Accutane. My number one concern when treating patients, and that of the Academy, is for patient safety. We are committed to insuring the safe use of this drug, and we are also committed to insuring that Accutane continues to be available to patients who need it. Like many of my colleagues, I was drawn to dermatology for intellectual as well as personal reasons. As a young man I personally suffered from severe cystic acne, and today my face bears the scars of my battle with this disease. I have a 20 years old son who suffers from severe cystic acne, and I have prescribed Accutane for him. He just finished his second five month course of Accutane at age 20, having taken the previous course when he was 15. Accutane is not simply a cosmetic problem. This is a disease, and in some cases a very serious skin disorder. The most common skin disorder of any age group, affecting 85 percent of all teenagers, approximately 20 million Americans. Acne is a disease of the pilosebaceous unit, the hair follicle, which consists of an oil gland connected to it. And although found all over the body, these pilosebaceous units are larger and more numerous on the face, on the scalp, on the upper back and the chest, the areas where acne was most prevalent. In normal skin, the oily substance called sebum, produced by the sebaceous gland, empties onto the skin surface through the opening of the follicle. While we do not know exactly what causes acne, we do know that changes in the lining of this hair follicle occur that prevent the sebum from passing through the follicle to the skin surface. In acne, the cells that line the follicle are shed too quickly and clump together, and these clump cells block the follicle so that the sebum cannot reach the surface of the skin. Then bacteria which would normally and harmlessly live on the skin surface begin to grow in the follicle, and all of these factors together produce the inflammation. Dermatologists will classify the type of acne by the presence of particular types of lesions, and in the written information that I provided for you there is a detailed description of the different forms of acne lesions. But in addition to these lesions on the skin, acne has a number of psycho?social effects. Studies have shown that people with acne suffer from social withdrawal, decreased self?esteem, poor body image, embarrassment, feelings of depression, anger, and also higher rates of unemployment. As a clinician I often see patients with moderate to severe acne, who have difficulty making eye contact when speaking, and many cannot even bear to look at themselves in the mirror. Many people believe that acne is a result of poor hygiene. Dirt or surface skin oils do not cause acne, and believe this myth can actually make acne worse, because vigorous scrubbing and washing can sometimes actually irritate and interfere with topical therapy. Acne is not caused by diet. Extensive scientific studies have not found any meaningful connection between eating things like fried foods and chocolate with acne, although in some individual patients there may appear to be a cause and effect relationship. Acne is not caused by stress, although stress can influence acne and many other medical diseases. Some people feel that acne is improved by sunlight, and some patients do get a drying effect from sun exposure. Sun exposure should not be recommended for a major treatment for acne, since it can lead to later skin cancer. Dermatologists have a number of effective acne treatments at their disposal, and after appropriate evaluation a dermatologist may recommend cleansing agents, over?the?counter medications, topical and systemic drugs to treat acne. Again, in the written information that I have supplied there is a more detailed discussion of some of the treatments. Nonprescription products such as cleansers, many over?the?counter medications area in fact quite effective for mild cases of acne. In advance cases, however, some of the stronger cleansers can irritate the skin even further, and further aggravate the acne. Prescription products such as benzoyl peroxide, topical treatments, work by destroying bacteria that are associated with acne, and it works well for mild acne if used continuously. Another product topically that is available over?the?counter without prescription, salicylic acid, does help to correct the abnormal shedding of skin cells and unclogging the pores. If acne fails to respond to some of these intermediate treatments, this is the place where the oral Vitamin A derivative known as isotretinoin, or Accutane. Now, Accutane has proven to be our most powerful weapon against recalcitrant cystic acne, and has dramatically changed the way dermatologists manage this terrible disease. Despite its tremendous benefits, though, this drug is not prescribed casually. It is a serious medication. Typically a patient with treatment?resistant acne are placed on a five?month course of Accutane, and after usually two to three months most patients begin to see a dramatic decline in the number of nodules and deep cystic lesions. A few patients, such as my son, may require a second course of treatment at a later time, but generally not more than two courses. Before prescribing the drug I counsel patients about the many risks that are associated with Accutane. I instruct them not to take any vitamin supplements containing Vitamin A while taking Accutane, since there may be some additive toxicity. I tell them to avoid sun exposure. I test their blood to assess liver function if needed, and always test for the level of triglycerides, or the fatty substance in the blood, which may be elevated up to 25 percent for people who take Accutane. Of course, women who are pregnant or may become pregnant during therapy must never take the drug. There is a pregnancy program that was developed by the manufacturer of the drug, which I have incorporated into the routine of my office. I speak frankly to all female patients about the devastating birth defects, and discuss the importance of using two forms of contraception. And all women of child?bearing potential, and that means any woman old enough to have a menstrual period, and not surgically sterilized, and who has been prescribed this drug must have a pregnancy test prior to the first dose, and should not begin their Accutane until the second or third day of menstruation. I am aware of the warnings on the label concerning changes in mood, depression, and I monitor my patients' behaviour. It is my belief that it is as important to be up?front and honest with the patients about the mood changes, potential depression, just as objectively as I talked to them about the dryness and chapped lips that they'll get, or about the potential elevation of the triglycerides. I am aware of the reports that have been mentioned already today about patients who take Accutane, who seem to go off it, and who go off it and the mood changes get better; they go back on it and the mood changes again recur. I have had one or two patients myself who have had that. I am also aware of suicide in patients who had severe acne but who had not been prescribed Accutane, mostly young men where the burden of the taunting of their peers was too heavy to bear. Far more commonly, however, far, far more commonly, I have seen the remarkable changes in patients' mood and demeanor due to the resolution or significant improvement of their disease. It's as if a great burden has been lifted from these people, and their faces and their bodies are cleared of acne. If I have any doubts about the patient, about whether a female will be compliant about using birth control, or if anyone has an underlying mental health concern or previous history of depression, I may not prescribe this medication. But I would say there are people who have clinical depression, and who are on anti?depressant medications, for whom I have prescribed Accutane when given appropriate psychological follow?up. Given the many benefits of this drug, I am concerned about efforts to create a mandatory registry. Mandatory registry may not be the best method to improve patient safety. Regulation cannot and must not be substituted for the frank, personal and complete discourse inherent in the physician/patient relationship. To this day, it's my understanding that the FDA has demanded only one mandatory physician/patient/pharmacy registration for a drug called thalidamide. This drug, there have only been 11,000 patients registered over the last two years. Accutane, on the other hand, is prescribed to nearly 500,000 new patients annually, a tremendously high number compared to thalidamide, mostly by practitioners in private practice. If there were a registry program, the economic burden and administrative burden of this would be tremendous for patients, for physicians, for pharmacists, and would tremendously increase the cost of therapy. Education of all parties, physicians, patients, nursing staff, medical support personnel, is paramount, and must be an ongoing enterprise. Efforts to educate patients should be and have been reevaluated and improved, and new knowledge must be incorporated into physician practices. Continuing medical education and nursing education programs are and continue to need to be amended to assure that new information is disseminated to all. This is how it should be. Education, and not regulation, is how we will further reduce the small number of inadvertent pregnancies and the psychological events that are occurring. Thank you again for allowing the American Academy of Dermatology to appear before you today, and I'll be glad to answer any questions at this time.

CHAIRMAN BURTON: Thank you. Mr. Jacobs.

MR. JACOBS: Thank you, Mr. Chairman, and good afternoon, other members of the Committee. I am Douglas Jacobs. I am a psychiatrist. I am on the faculty of Harvard Medical School. I am also Executive Director of the National Depression Screening Day, which is a nonprofit organization which does receive several federal grants. My interest in suicide began ?? and I am going to be summarizing my statement rather than reading it. My interest in suicide began in 1972 when my first patient who I was caring for hung himself in a hospital, only to be saved by another patients. As a young physician, psychiatrist in training, that was an overwhelming experience for me, and obviously for my patient. When I interviewed my patient, he said to me, "I've been a bad patient," and I thought to myself, No, I've been a bad doctor. That experience has stimulated and propelled my entire career. I have devoted myself to the understanding of suicide. I've learned a lot, and there's still a lot to learn. In that context I've treated suicidal patients, I've done research, and I've edited several textbooks. As part of this journey I've also become very interested in the problem of depression. Depression in the 1980's, with studies from the National Institute of Mental Health, it was determined that it was under?diagnosed and under?treated. And since depression is clearly linked to suicide, although not a cause of it per se, it was in that context that I decided to try out a model for screening of depression, and this might answer some of the questions of Ms. Mirella and Mr. Horne. Could we screen for depression like we could for other medical disorders? It's been in experiment, and it's an experiment that has succeeded in the sense that we can do it, the problem is that there's much more to be done. For example, of the 20 million Americans who experience depression each year, less than 20 percent are in active treatment. So we have many Americans, including young people. If we look at young people, and there are approximately 20 million 15 to 19 year olds, their prevalence of depression is about 6 percent, which is about a million young people that age experience depression each year. And of that group only 200,000 or so get treatment. Many of them end up in physicians' offices, and many of them end up not getting treatment. In order to answer your question, Mr. Horne, about 2,000 of that group goes on to commit suicide each year. I will explain that the suicides that I have looked at in the Accutane are no different than the suicides that are occurring throughout American. It is in that context that I have also formed the High School Depression Screening Program and a Suicide Prevention Program called SOS, Signs of Suicide, which we're trying to communicate to young people that it's better to have a mad friend than a dead friend, because it's young people who don't let their families know. The suicides occur out of the blue, and we see it ?? we see a suicide occurring. I was asked by Roche to evaluate the suicide and depression reports and the MedWatch Reports. I have been a consultant to them, and I am here today by your invitation. Let me say that in order to understand suicide, to put it in some perspective demographically, suicide is the eighth leading cause of death. There are about 30,000 suicides each year. In the young population, ages 15 to 24, it is the third leading cause of death. Suicide rose dramatically in that age group from 1950 to 1980, where it tripled. Since 1980 to now, it has remained about the third leading cause of death. It is clearly something that we have to address. Depression, as I indicated, occurs in about 6 percent of the population. What we know about suicide is that from a clinical perspective if occurs with severe depression. The majority are not in mental health treatment. The majority have seen a physician in the last six months. The majority are male. The majority commit suicide on the first attempt. If one looks just at the profiles of the Accutane suicides, just from a demographic standpoint, that is what we see: The majority are male; they are not in treatment; it is their first attempt. If we could show Table 1, and I think you all have this, but it is a graph to illustrate the complexity of suicide. It is a multi?factorial event. No one factor causes suicide, and there are 12 or 14 factors. I put this specific to adolescents who do have age specific stressors of self?esteem and image related to severe acne, academic problems, disciplinary crises and humiliation. When I was asked by Roche to look at these spontaneous reports, I said to myself, well, how could Accutane cause suicide? So from what I know about suicide, I said, well, does it somehow affect suicidal behavior, does it cause impulsiveness, does it affect the neurobiology, and does it cause psychiatric illness. That is my orientation, since I didn't see how it could relate to any of these other factors. In terms of neurobiology, and again what we know about depression, and I'll talk specifically about that, we believe that there is some alteration of the brain messenger chemicals that affect our mood centers. We do not believe that isotretinoin, Accutane, affects the neurotransmitter system, causing some alteration that would lead to a depressive illness. Impulsiveness, again, is related to neurobiology. There is no evidence that there is any neurobiologic substrate causing impulsiveness in terms of suicidal behavior, and this really relates to what we see in the spontaneous reports. And there is not a one?to?one relationship between suicidal ideation, suicide attempt and suicide. Of the 5 million Americans who have suicide ideation, less than 30,000 go on to complete suicide. Out of that group we believe about 600,000 attempt suicide. In the Medwatch Reports there are categories of suicidal ideation. The problem in evaluating those is that suicidal ideation from a clinical standpoint is defined as thoughts of suicide accompanied by an intent to die, whereas, thoughts of death, which has a prevalence of about 2.6 percent. Thoughts of death have a prevalence of about 28 percent. So what's in the Medwatch spontaneous reports, may or may not be suicidal ideation. The same for suicide attempts. And let me just say, and I know it's not a chart that I included, but if one were to simply look at the Accutane serious events that I believe are on Congressman Stupak's website, there are various numbers listed. If one took the prevalence that I'm reporting to you today, the numbers reported in these events are much, much smaller. For example, there are a total of 155 cases of suicidal ideation. In terms of prevalence, just in terms of the base population, one would anticipate 390,000 cases of suicidal ideation. In terms of hospitalization, there is 475. In terms again, prevalence, one would anticipate 13,500. Now this gets to psychiatric illness. Psychiatric illness is clearly the No. 1 risk factor for suicide, yet the majority of Americans, fortunately, will psychiatric illness, which is also part of the hope when I am consulted, that just because you have a psychiatric illness, you are not fated to die by suicide. That of the 20 million Americans who experience depression, less than 20,000 go on to suicide. But we've heard today descriptions of depression, and I thought I would try to define what we mean, and what is depression, and what is depressive symptoms. If you can show the next chart, the American Psychiatric Association has developed a diagnostic and statistical manual which has a criteria for depression, that really states that there has to be physical and social and occupational impairment for a two week period of time, which five of these nine symptoms. And what's important here is that there are multiple symptoms, not only emotional symptoms, which is depressed mood and loss of interest, but cognitive, the way one thinks about one's self, their bodily changes, and then the most serious thoughts of death or suicide. When looking at the issue of spontaneous reports in terms of depression, the question is, is this depression, or is this the blues, or is this just mood changes? In the majority of cases, in my opinion, what we're seeing are mood changes. They do not satisfy criteria for clinical depression. There were some comments made earlier about positive challenges and de?challenges. I looked at all those cases. Again, the majority of those cases, the mood symptoms go away without specific treatment, once the drug is stopped. That would not be the case if this were clinical depression. Clinical depression has a time course of six to nine months. Within the values of treatment, specific psychiatric treatment, is that it improves treatment within one to two months.

CHAIRMAN BURTON: Excuse me, Doctor. Could you summarize relatively soon, because we want to get to everybody.

DR. JACOBS: In terms of then the specific suicide cases, the spontaneous reports, I looked at them in terms of gender, the relationship to on/off Accutane, the issue of concealment of symptoms, and then the issue of does Accutane exacerbate underlying illness, and it was my conclusion that the gender distribution was the same; that there was a report of temporal association, that some committed suicide on Accutane, some off Accutane, there is no predominance. A compelling series of cases or group of cases, and there are about 10 to 12 of them, who had underlying psychiatric illness. They were given Accutane anywhere from six months to 18 months, and they didn't develop and symptoms, no exacerbation of their psychopathology. Anywhere from six to 10 years later they committed suicide. To me this is as close to a ?? obviously it's not a study per se, but if one were designing a study, say giving a drug to an at?risk group that causes suicide, this didn't happen. If I could just read the last part, you have asked my thoughts on the adequacy of a passive adverse event reporting system, in this context. Although I am not an expert in adverse event reporting mechanism generally, I believe that in this matter the adverse event reporting system has performed its function of providing a system of potential issue. In light of the overall incidents of these conditions, the appropriate focus is on the education of prescribers and patients, as well as further study, scientific study and analysis. In conclusion, although the current scientific evidence does not support a causal link between Accutane, depression and suicide, given the clinical population in dermatology, and all medicine committed in terms of my career. It is still important for health professionals to be aware of psychiatric risk factors. Monitoring patients for depression, depressive symptoms and suicidal ideation can help identify any patient who may be at risk, and improve patient care by facilitating appropriate diagnosis and treatment of patients experiencing clinical depression. It is my understanding that enhancements are being implemented in the communication of psychiatric information to Accutane prescribers and patients. I welcome these efforts, and I believe they will have a beneficial impact on the dermatological patient population as a whole. Thank you for this opportunity.

CHAIRMAN BURTON: Thank you, Dr. Jacobs. Dr. O'Donnell.

DR. O'DONNELL: Mr. Chairman, members of the Committee, thank you for the invitation to my comments with you regarding an overview of existing research and information linking Accutane, depression, psychosis and suicide, with other drugs like Accutane, and other drugs used to treat acne. I am an Assistant Professor of Pharmacology at the Rush Medical College in Chicago, and I am also a licensed pharmacist and a certified nutritionist. I do not hold any federal grants, although I have testified as an expert witness in matters against Roche. I would like to project my one slide, and leave it projected for the course of my comments. My review has included the basic pharmacology and toxicology of Vitamin A, and if we can focus just on the top three chemical formula there, from the audience you won't be able to see that, but please take my word that the three molecules of retinol, tretinoin, and isotretinoin, are practically identical. There is only an extremely minor change on the far right end aliphatic group between an OH and a COOH. That won't mean anything to you as a lay person, but as a chemist and a pharmacologist, looking at these three chemicals, not knowing anything different, you would predict the same actions, including the same toxicities. This is a part of the basic pharmacology and toxicology of Vitamin A and retinoids. This was considered as part of the Accutane clinical research database, and it is also referred to in published literature describing hypervitaminosis A, a condition which is caused by too much retinol, too much Vitamin A. Now, Vitamin A and ritinoids have been used to treat skin conditions for 50 years, and we now have almost 20 years experience with Accutane, and clearly Accutane is a very effective drug, and I am certainly not encouraging anyone to remove it from a therapeutic, armamentarium to treat severe acne. But I do question if 1.5 million prescriptions are written for 500,000 patients a year, how many of those patients qualify according to the prescribing indications, approved by the FDA for severe recalcitrant acne. And I would direct that question to the gentleman from the Academy of Dermatology, because he did not include that information in his remarks. The mechanism of action as to how Accutane improves or cures acne, from my reading, is unknown. We also don't know why Accutane and Vitamin A substances cause psychiatric conditions. Perhaps I'm using the word "cause" very casually, and I should correct myself. Clearly there are associated reports of psychiatric conditions that have been reported for the last 150 years with Vitamin A. Polar explorers used to eat anything they would find on the icecaps, and they ate polar bears, and they favoured the livers. Some of them became psychotic, and they reported conditions that since then, since 1856, of neurotoxicities, toxic psychosis, schizophrenia?like symptoms, and these have been published throughout the literature since that time. Similar toxicities to Vitamin A toxicity have been reported in the literature, as well as case reports for Accutane. In fact, the investigational brochure for Accutane in 1978 stated, and I quote, adverse reaction seen with the use of orally administered Accutane are essentially those of hypervitaminosis A. So in other words, you expected as a pharmacologist, as a chemist, when you are using a drug, you have to look at history and learn from history. We have a long history of psychiatric toxicity associated with Vitamin A. It's not surprising that we have similar reports of similar psychiatric toxicity associated with Accutane. I am not going to comment on Dr. Jacobs' or Roches' analysis. He made a very succinct and accurate presentation of their data, nor will I comment on the FDA's analysis because they are here to speak for themselves. I would like to mention an analysis that was undertaken in Ireland by a scientist who did a pharmaco epidemiological analysis of psychiatric side effects associated, reported with Accutane and five other drugs, five other oral treatments used to treat acne. The other drugs were primarily tetracycline antibiotics, which is a common first?line treatment for acne, and also some hormones which some dermatologists and other physicians use to treat acne. Dr. Middelkoop's findings were that there were more reports for psychiatric adverse events and suicide worldwide from isotretinoin than from the use of the five other acne therapies combined. Her statistics describe a several hundredfold increase in risk of psychiatric side effects with acne. Now, since we don't know the mechanism of action as to how acne works ?? excuse me, how Accutane works on acne, we also heard we don't know the mechanism of action of why Vitamin A, retinols and Accutane cause these toxicities. No one questions that they do, unfortunately, and we do not have warnings that say, because of these reports, this may be associated with suicides, suicidal ideations and so forth. The case reports are suggestive of an association. Clearly we don't have solid scientific information proving the cause, but this is a neurobiological issue. Sometimes we can't get into the brains to actually prove what works. We heard from Dr. Jacobs that we don't believe that the neurotransmitters are affected, but the neurotransmitters are certainly responsible for depression and other psychosis excuse me, and psychoses. But there is literature that does suggest that retinols are associated with schizophrenia, and retinols are associated with genes that transcribe the neurotransmitters in the brain. I am going to stop because my time is over, with a comment that I'm pleased to hear that an informed consent form will be provided. I will also state that since historically we know that Vitamin A is accepted to cause these toxicities, that instead of saying we need to prove that Accutane actually does this, I would turn the tables and say let's prove that it doesn't, and until we do, take precautions, and especially warn patients and their families, because otherwise they're the ones who are really the ones who have to monitor it and prevent it. Make a choice if they want to, take that risk, and if they do recognize it and be able to avoid a tragedy. And I thank you.

CHAIRMAN BURTON: Thank you, Dr. O'Donnell. Dr. Bull.

DR. BULL: I would first like to thank the families for being here. I think the human face that they place on this is far more compelling than any Medwatch form that I've ever viewed in this area. (Document quoted to page 2, paragraph 2.) Because Accutane is the only product that can potentially cure cystic acne, FDA permitted the continued marketing of the product in spite of the known risk of birth defects and other serious reactions. FDA has proceeded to periodically reassess the risk/benefit equation. From 1983 through 1990, FDA and the manufacture stepped up efforts to communicate the significant risks to women of child?bearing age. The original clinical trials for market approval for Accutane did not contain significant reports of depression or mood disorders. However, in the mid?1980's, due to post?marketing reports of depression, a labeling revision was done to include changes in mood and depression as part of the adverse reaction section. FDA began a re?evaluation of the psychiatric illness reports in 1996, when a physician in the reviewing division noted two cases of suicide, and a routine listing of recent adverse events associated with Accutane. Reports such as this do not necessarily mean that the event has any relation ship to the drug. Accutane, however, had previously been associated with depression as already noted in the Accutane labeling. Because suicide is the most serious consequence of depression, the FDA reviewing division enlisted the help of specialists in the FDA epidemiology division to try to determine whether the cases could possibly be related to Accutane use. The divisions undertook the systematic analysis of the published literature, previously reported cases entered into databases, and incoming safety reports. These reports were not numerous relative to the rate of depression and suicide expected to be seen in the population likely to receive Accutane, teens and young adults. Some of the reports, however, included important details that did suggest the possible involvement of Accutane. Therefore in May 1997 FDA began working with the manufacturer to fully evaluate the data and determine appropriate next steps. In February of 1998 a labeling change moved psychiatric adverse events and the professional labeling to the warning section. While Accutane labeling had previously included depression in the adverse reaction section, it was hoped that the addition of wording that calls attention to possibly suicidal behaviour would help further insure that prescribers would take appropriate actions in patients who developed mood changes. Even though a causal relationship between Accutane and suicidal behaviour had not be scientifically established, this action was thought prudent, given the available information. In addition, a letter was sent to doctors who might prescribe Accutane, as well as those likely to see patients who developed psychiatric disturbances. FDA also posted a special notice about Accutane on its public website, and released a talk paper to the press to further insure wide attention and dissemination of this warning. There was also an update placed on the FDA Consumer website. FDA also instructed the manufacturer to discontinue promotional claims regarding the psychosocial benefits of Accutane treatment for acne. Patient information is intended to remind the patient about important things they discussed about their treatment with their prescriber. It is often not identical to the wording of professional labeling. Prior to the 1998 change in the professional labeling, there were five signs of potentially serious problems listed as bullets for patients, with all capital letter instructions to stop Accutane and call their doctor immediately. All of these bullets except mood changes reflected serious adverse events in the warning section of the professional labeling. Thus when psychiatric problems were moved in 1998 to the warning section of the professional labeling, it was already in the proper list in the patient information, as with other symptoms of possible serious or fatal problems, the patient information on mood changes did not include specific information about the possible outcome; that is, suicide, instead being followed by the advice to stop the drug and call the doctor immediately due to the possibility of serious consequence. After the 1998 labeling change about psychiatric disorders, FDA embarked on a very comprehensive reassessment of the overall labeling and risk management for Accutane. The revised patient information resulting from this work was implemented on an interim basis, with a commitment by the manufacturer to conduct patient comprehension testing, and to pursue further revision. The interim revision implemented in the summer of 2000 captures the possible outcome for mood disorder; that is, suicide. The need for research to determine if the linkage was causal began soon after the labeling change. The manufacturer undertook multiple epidemiological studies. Results reported thus far have been inconclusive. Epidemiological studies by the FDA of the challenge, re?challenge cases, also analyzed by Roche study are suggestive of the critical need for further research. It is very likely that a controlled mass clinical study would not be feasible for ethical and technical reasons. Therefore, an important goal of seeking outside expert advice was to explore other approaches. In September of 2000 the Dermatologic and Ophthalmic Drugs Advisory Committee again discussed Accutane. The two major topics were prevention of fetal exposure and risk management strategies for the uncertain risk of psychiatric effects associated with the use of Accutane. On the issue of psychiatric events the Committee unanimously agreed that there was sufficient concern about Accutane to justify exploring additional risk management strategies, even though the risk was uncertain. The Committee recommended that the manufacture add the information about the adverse events to the informed consent document signed by patients and their parents or guardians prior to receipt of Accutane; that they develop and distribute a prescriber educational program about the psychiatric events; that a medication guide be developed and implemented for Accutane. The Committee was also asked whether further studies to help clarify the relationship between Accutane use and psychiatric events were needed, and if so, what kind of studies. The Committee discussed the many ethical and technical problems with controlled clinical trials in this instance, and offered ideas for other types of studies with an emphasis on basic science research, particularly focused on the adolescent central nervous system, as well as epidemiologic studies in addition to those already underway. The agency is working with the manufacturer as well as the National Institute of Health to implement the Committee's recommendations. In conclusion, Accutane continues to be one of the more challenging products that FDA regulates. We think the record demonstrates the Agency's continued concern regarding this product and our efforts to manage the associated risks. We are hopeful that research will establish whether or not the psychiatric events associated with the use of Accutane are truly caused by the drug. We will continue to work with the manufacturer to keep health professionals and consumers aware of the risk associated with Accutane and the circumstances under which it should be used and prescribed. Thank you for the opportunity to discuss this important matter.


Questions for Panel

CHAIRMAN BURTON: I presume that Dr. Huene (phonetic) does not want to make an opening statement; is that correct? Okay. We'll probably have a couple of rounds of questions, at least as far as I'm concerned, so bear with us, we're going on five minute rounds, and then we'll come around for a second round for those who want to ask more questions. Dr. Jacobs, are you aware that a month after the "Dear Doctor" letter was sent out warning doctors about the concern about Accutane being linked to depression, that the FDA sent a warning letter to Roche Laboratories about advertising that made false or misleading statements, and promote Accutane for an unapproved use. According to the warning letter, and I quote: Roches' promotional materials state or suggest that Accutane is safe and effective in the treatment if what Roche describes as the psychosocial trauma and emotional suffering associated with acne, including negative psychosocial affects such as depression and poor self image. This claim is particularly troublesome in light of information recently presented in a Dear Doctor letter, that Accutane may cause depression, psychosis, and rarely suicidal ideation, suicide attempts and suicide. As someone who is an expert in suicide, how would you respond to a company promoting a drug that reported suicides for treatment for psychosocial trauma? DR. HUENE: Well, first of all, I am not aware of any communications between Roche and FDA. I mean, you are bringing that to my attention, I have not seen that. The issue for me as an expert is that suicide, depression, can occur in the Accutane treated population. On the other hand we know that persons who have severe acne, as was indicated by Dr. Pariser, can have psychiatric symptoms, including depressive symptoms, anxiety symptoms. The Accutane can be helpful. Clearly the need to communicate accurate information I certainly support. I was aware of that label change. From a scientific standpoint I do not see that Accutane causes depression, or causes suicide; the issue is, should a physician be aware of mood changes in their patients? Should a physician be aware of a suicidal ideation? Part of the project I am involved in, the National Depression Screening Day, and to answer Ms. Mirella, we have a primary care outreach, and part of what we do is we educate physicians about what the signs and symptoms of depression are, how to ask about suicide. So I think it's important ?? should it be specific for Accutane? I think it should be for all physicians, including dermatologists.

CHAIRMAN BURTON: You were not aware ?? that was the question; you were not aware that the FDA wrote a letter to or contacted Roche, saying that they were giving questionable information?

DR. JACOBS: No. Maybe it's important to clear up. My relationship to Roche, I've served as a consultant, specifically from a scientific standpoint, in looking at the data in these spontaneous reports, and that's the nature of my consultation.

CHAIRMAN BURTON: What drugs are you aware of that can cause depression and suicide?

DR. JACOBS: Well, that's also a very interesting question. In my opinion there is no one drug out there that causes depression or suicide. In the PDR, and I have researched this, there are about a hundred drugs listed that "cause depression." However, that is not a scien ?? just because it's in the PDR, that is not a scientific study. What this is is, these are drugs that cause depressive symptoms.

CHAIRMAN BURTON: Okay.

MR. JACOBS: I think it's important, and the issue of beta blockers, and which many people are familiar with, caused lethargy, lack of energy, and physicians are aware that it can cause "depression." But it's not depression, per se, it's depressive symptoms. And none of those drugs are associated with suicide, and if you are asking about drug induced depression, it's symptoms of depression that don't satisfy the criteria that I indicated earlier, but there's no study that shows that type of "depression" is associated with suicide.

CHAIRMAN BURTON: Well, you're a consultant to Roche. Are you still a consultant with Roche?

DR. JACOBS: Yes, I am.

CHAIRMAN BURTON: Have you done similar reviews and suicide and possible drug causal link for any of these drugs you are talking about?

DR. JACOBS: In terms of looking at, I've looked at some of the issues, peroxetine or Prozac ?? in the context of my consultation with Roche, I reviewed the entire literature on drug induced depression, and I mentioned about beta blockers, so I went to ?? I didn't do the research ??

CHAIRMAN BURTON: But you found no causal link?

DR. JACOBS: I found no causal link, but as to ??

CHAIRMAN BURTON: That answers my question. Mr. Waxman.

MR. WAXMAN: Thank you very much, Mr. Chairman. Let me start off with you, Dr. Pariser. I have heard estimates that as many as 80 percent of patients for whom Accutane is prescribed have only moderate or mild acne, not the severe cystic acne for which Accutane is approved. This is undoubtedly why Accutane had over $485 million in sales in the United States last year. This over prescribing exposes significantly more people to the very serious, and as we discussed, unknown risks of Accutane. How much does the Academy believe that Accutane is over prescribed, and what is your position on what should be done to limit it?

DR. PRAISER: Thanks for the question. I don't know that we've had any systematic information on exactly how much acne may be prescribed, technically speaking, off label.

MR. WAXMAN: Accutane.

MR. PRAISER: Accutane, I'm sorry, how much Accutane is prescribed for acne, which is not nodular, cystic and recalcitrant, and unresponsive to other therapies. I think that it's a clinical dilemma that many of us who treat acne all the time face. I will commonly see a patient who has acne which may be recalcitrant, which may be nonresponsive to other therapies, but which may not be cystic acne. Yes, I have prescribed Accutane in this situation. There is no statistics that I'm aware of.

MR. WAXMAN: Do you believe that there's an over prescribing of Accutane?

DR. PRAISER: Well, I would have to know what the numbers are first. Accutane is prescribed for many off label indications, and ??

MR. WAXMAN: Off label means not for ??

DR. PRAISER: It means not for nodular/cystic, right, for acne which is recalcitrant, which is nonresponsive.

MR. WAXMAN: So there could be dermatologists who are prescribing it for acne cases for which the FDA never envisioned this particular drug to be prescribed?

DR. PRAISER: I think that's a correct statement, but it's in the context of many drugs we prescribe in ways that are not directly labeled.

MR. WAXMAN: What's the Academy doing to assure its members are better informed about these risks?

DR. PRAISER: Well, every year at our annual meeting, which was attended by, last year, over 90 percent of our membership, and we have seminars on acne, many other factors, we have various continuing medical education efforts that are going on, and that ?? those are the major efforts, education that the Academy sponsors. There are others venues from which our members get information.

MR. WAXMAN: Our earlier witness, Amanda and her mother, testified that their dermatologist and other treating physicians did not know about possibly relationship between Accutane and depression. How do you explain the ignorance of her dermatologist and other psychiatrists and treating physicians about the relationship? Are they not informed by the Academy; are they not informed by the FDA; are they not informed by Roche?

DR. PRAISER: Well, I think all of the above would be applicable. I personally am saddened by the fact that many of my colleagues seem to be less informed in this than they should be, and I have no defense for that; I think it's something which we all have to work harder to do. Education has to happen.

MR. WAXMAN: Dr. Jacobs, I want to begin by asking you a few questions about your background. Have you served as an expert witness, or been deposed on behalf of defendants in cases involving patient suicides?

DR. JACOBS: Yes, I have.

MR. WAXMAN:: And have the defendants been practicing doctors or drug companies like Roche?

DR. JACOBS: The defendants have primarily been physicians or health care providers, and very few cases in which I've actually testified on behalf of pharmaceutical companies in a medical/legal matter.

MR. WAXMAN: How many cases have you been involved with, and what percentage of your income comes from these cases?

DR. JACOBS: I've been doing this work since about 1980, and I've been involved in approximately 300 medical/legal matters, and in terms of my income, approximately 70 percent of my income comes from my consultation in medical/legal matters.

MR. WAXMAN: You represented Roche before the FDA when the Agency decided in 1998 to strengthen the warning on psychiatric disorders; isn't that correct?

DR. JACOBS: I was asked to serve as their consultant. I don't know if I would officially say I represented Roche. I was a consultant for them, certainly. MR. WAXMAN: For Roche, and then you testified at ??

DR. JACOBS: At the FDA hearing; that's correct.

MR. WAXMAN: And do you think the FDA was wrong to strengthen their warning, and do you think the French and British governments were also wrong to have similar warnings on Accutane?

DR. JACOBS: I certainly don't think they were wrong. From the data I saw, if I were asked, is that accurate, is that an accurate statement, that Accutane, and I think the label reads, Accutane, and I don't know if it's "may cause" or "Accutane causes depression, psychosis, and in rare cases suicide attempts and suicide." As a scientist, I did not see that. From a public health standpoint, to alert patients ?? to alert families and physicians that the Accutane treated population are at risk, just as other populations are at risk for depression and suicide, as a physician dedicated to informing the public about suicide, you know, I don't think that's wrong at all.

MR. WAXMAN: Just on this one point, I know my time has expired, but FDA requires Roche to add the following new bold faced warning to Accutane's package insert. FDA is still unaware of the new French warning. "Warning: Psychiatric disorders. Accutane may cause depression, psychosis and rarely suicidal ideations, suicide attempts and suicide. Discontinuation of Accutane therapy may be insufficient. Further evaluation may be necessary, and no mechanism of action has been established for these events." And then there's adverse reactions. "In the post marketing period the number of patients treated with Accutane have reported depression, psychosis and rarely suicidal ideation, suicide attempts and suicide. Of the patients reporting depression, some reported that the depression subsided with discontinuation with therapy, and recurred with reinstitution of therapy." My question to you is, would that warning label, were you testifying in support of that warning label, or were you testifying in opposition, and if you were asked your opinion, would you have urged FDA to have that warning label?

DR. JACOBS: I wasn't testifying for or against a label; that's not my area. I was asked to testify on my scientific analysis of the spontaneous reports. It's up to the FDA to make their conclusions, based upon my testimony. As I indicated before, because there's not a scientific rationale for that label, I am certainly not in opposition to that label. It is certainly conservative. There are certainly some patients, as we heard today, who have had unfortunate experiences while on Accutane, and to the degree that physician awareness and family awareness that depression can occur in young people, that suicide can occur, and that this is a way to alert people, I am all for it. MR. WAXMAN: Thank you. Was Roche advocating this, or was Roche just urging, to your knowledge, that they not go with this label?

DR. JACOBS: I was unaware of ?? that's not the level that I get involved in. I know that there were discussions after my presentation between Roche and the FDA, and then I heard that ?? I only heard the outcome, I wasn't involved in the process.

MR. WAXMAN: Thank you. I'll wait for another round.

CHAIRMAN BURTON: Ms. Mirella.

MS. MIRELLA: Thank you, Mr. Chairman. I'll try to ask each of you quickly a question so that I can get to all of you. First of all, Dr. Pariser, you mentioned that it's not prescribed casually, and I'm wondering, and it seems that there's no system in place to educate parents and families. With your extensive experience in dermatology, do you feel that physicians prescribing Accutane are doing enough to educate parents and families of the possible dangers of the drug? DR. PARISER: Well, there are many venues and many modalities of education. There are pamphlets, there are consent forms, education.

MS. MIRELLA: And that you feel is particularly good?

DR. PARISER: But the main responsibility and the main place to educate is when the physician and the patient are together in the treatment room, with all other outside influences outside the closed door. I think it's the physician's responsibility to do that. If the physician chooses to use some of these educational aids to help that, that's fine, but it is the responsibility of the physician to do that. I spend more time in my practice talking to somebody about Accutane than I do ?? it takes me longer to do that than to take off a skin cancer, or to do many other procedural services.

MS. MIRELLA: So what you're saying is that it should be done, and it is the responsibility of the physician, but you don't have any guarantee it is being done?

MR. PARISER: That's correct.

MS. MIRELLA: You also talk about, you would see the symptoms develop ?? actually, let me put it this way: Accutane is prescribed for like a five?month period, and maybe its prescribed again, and yet hearing from our previous panel, they seem to see adverse symptoms almost immediately, and certainly within a couple of months, and they even said during the first week.

MR. PARISER: Well, the clinical studies that I've ??

MS. MIRELLA: Is there a disconnect, then?

MR. PARISER: Well, with the clinical studies that were done with Accutane, that derive the data on its efficacy, were done with defined courses of 16 ?? usually 16 to 20 weeks of treatment, a defined period of time. Usually once, and sometimes that 16 to 20 week period can be repeated again later if adequate treatment did not occur prior to that. But usually not more than that. I don't think Accutane should be or is casually prescribed in the situation. It was take a little bit now and a little bit later. I think that's misuse of a drug.

MS. MIRELLA: Except I guess that what I'm pointing out is that we've heard in previous testimony that that is a very long period of time for a course of action, because we can detect adverse consequences sooner than that. Let me go on to Dr. Bull, picking up on what Dr. Pariser has said in his testimony, he discusses the difficulties of the creation of a registry, a mandatory registry for Accutane, and uses thalidamide as an example, and says that there'll be a lot more that would be required. I guess is FDA considering a registry of that nature, and do you see some similar problems as beset the thalidamide registry?

DR. BULL: I would add that the thalidamide experience with the registry certainly informed how the registry is approached. There is also another drug, RU46 which does have a patient registry in place. With regard to Accutane, and I think actions that ensure the safe use of the drug, particularly for a potent drug with a risk profile that Accutane has, I think really compels that we investigate other options in terms of the sufficiency of our current risk management structure, and we're working with the manufacturer in terms of instituting the registry.

MS. MIRELLA: So is there a time line or something that you could ??

DR. BULL: What we hear from the sponsor at this point in time is as early as next summer, the summer of 2001. And I would like to add as well, with regard to the Medguide, and the enhanced informed consent, we expect to have those out by the first of the year, sometime in January of 2001. Roche has gotten in a draft to the Agency, and we've responded, and we're optimistic that it's in its final stages to be distributed, and available to patients.

MS. MIRELLA: I feel the Chairman would probably want to have the Committee notified of what is happening in that regard. And then finally, for Dr. Jacobs and Dr. O'Donnell, just briefly, if you think the dangers of Accutane were made clear to patients and their families, do you think there is a connection that that would lessen the chances of depression and suicide? I mean, has there been any evidence to show that patients who knew about the dangers of the drug were less likely to experience depression or attempt suicide?

DR. JACOBS: I am not aware of any ??

MS. MIRELLA: I know this is a difficult thing, as I say, cause and effect at this point.

DR. JACOBS: I am not aware of any study that has looked at that. Certainly, making families aware of signs of depression, signs of suicide, as I indicated before, would not only be helpful in the Accutane treated population, but in all families with suicide, the suicide rate, unfortunately, has remained about the same. Most people are not aware that depression can occur in young people, about 6 percent; that suicides do occur, and what the warning signs are. So education clearly would be helpful.

MS. MIRELLA: Fine. That's my time. Thank you, Mr. Chairman. Sorry, I didn't give you a chance to answer, Dr. O'Donnell. Thank you.

DR. O'DONNELL: I think your first question was, if you tell them about it, would it decrease the occurrence. It's not going to decrease it, but as you heard from Amanda, that had they known, they would have recognised the association and stopped it. That's a basic premise in any drug treatment. That's why it's important to put warnings and package inserts, so that if it occurs the doctor can look and say, oh, yes, this is associated. If not they are not going to make the connection. And I do believe that for the patient who goes and demands to their mother or father to go to the dermatologist and demand Accutane because they have one pimple, that if they learn about the risk they are going to realise that maybe we shouldn't take this risk. For those who need it because it's a severe acne, or maybe it's not so severe, but it's disturbing to them, they recognise the risk, and they can avoid tragedy by educating the child. And I have heard, and I agree, this is not clinical depression according to DSM IV. Maybe it's Accutane Depression. We have Accutane, we have Accutane induced birth defects, which has its own diagnosis. Children say ?? they don't say "I'm depressed," they say, "I feel weird," or they just spend more time in their room. And having raised teenagers, you don't always know what they're thinking, but if you know they're put at risk, or they may be at risk, and since we hear from psychiatrists that they are at risk already because they are in that age group, do we want to give them another possible risk factor without doing whatever we can to recognise it and avoid the tragedy?

MS. MIRELLA: It seems like we're looking for a balancing act, too, the fact that maybe physicians should not prescribe it just because someone comes in and says I want it, even though you're saying it's not prescribed casually. Maybe we do also need a registry, and maybe we want to make sure that the physicians educate the parents and families, and put that all together. Thank you, Mr. Chairman.

CHAIRMAN BURTON: Mr. Horne?

MR. HORNE: Thank you, Mr. Chairman. I'm curious. What are the major magazines, professional magazines that dermatologists usually receive, and that you receive? Would you say it's five or ten or twenty, or what is it?

DR. PARISER: A smaller number specifically related to dermatology. The Academy publishes a journal, The Journal of the American Academy of Dermatology, which is the premier educational journal for dermatologists. This journal routinely carries articles about acne, about Accutane, the guidelines for care, for example, is published in that journal. The other major clinical journals, The Archives of Dermatology, which is an AMA publication, one of the AMA specialty journals that are read by most dermatologists, and there are probably two or three others that would be ?? that most dermatologists would be familiar with in some way, shape or form. It's not ten, but it's probably five.

MR. HORNE: Okay. Dr. Jacobs, do you agree with that, or are there other magazines that would be professionally used by the typical dermatologist?

DR. JACOBS: Well, I would really have to defer to Dr. Pariser in terms of that. In terms of psychiatry, generally psychiatrists read professional journals of their particular specialty. But now, with the information explosion on the internet, certainly reviews are accessible to physicians, which actually make the reading of whole journals probably less, but particular information is more available to physicians today.

MR. HORNE: Dr. O'Donnell, would you agree with your two colleagues on that?

DR. O'DONNELL: Yes, I would.

MR. HORNE: Dr. Bull, do you generally read the kind of journals that the professors have noted?

DR. BULL: Dr. O'Connell, who is with me today, would you agree with that, that the publications that dermatologists generally read The Archive of Dermatology

MR. HORNE: Well, I'm interested in what are the major professional journals for a dermatologist?

DR. BULL: Those are the major ones.

MR. HORNE: Especially board certified dermatologists. The reason I ask that is, aren't there a number of pharmaceutical ads that you find in most of these magazines? I mean, the pharmaceutical companies do advertise in magazines, don't they?

DR. PARISER: Yes. And these are professional magazines, and they advertise in those?

DR. PARISER: Absolutely.

MR. HORNE: I'm just a country boy that wants to sort of figure out how it works. Have you ever seen a pharmaceutical add that says we have a problem regarding clinical depression, suicide, whatever, and maybe you should be careful about this ad? Have you ever seen one of those ads?

DR. O'DONNELL: I am not an expert on advertising. I generally don't read the ads, but what I do know is that generally when a pharmaceutical product is advertise, that the whole package insert is there with both the risks and benefits of the medication. I am not saying that I read that, but it's there.

MR. HORNE: Well, that's part of the problem. People are busy and they have offices filled with people they are trying to treat, and generally they treat very well. But I am just curious when the pharmaceutical company or the Academy puts and ad in, or at least a warning in one of the professional journal pages, so that they could say, now you should really be very careful in prescribing this.

MR. O'DONNELL: It's my understanding that all advertising, whether it's in a journal or whatever venue that any pharmaceutical company undergoes is reviewed by the FDA, I thought. I know in the case of the Academy ?? the Journal of the American Academy of Dermatology, our premier journal, that there is medical oversight for all the advertising and nonscientific pages that are in there, such that there is nothing, you know, off the wall gets through.

MR. HORNE: Well, I guess my impression, and I've looked over the years at maybe 130 medical journals that was in the university library, and they sort of were usually pretty glowing and flowers were in the ad and all the rest of it, and I just wondered where does reality come from if it doesn't come from the profession?

DR. PARISER: Well, the issue of where reality comes from, it is a serious matter, and when I say I don't read those ads is because I am aware of the medications. There is no difference in what's in there and what's in the PDR or what's available. The prescribing of medication is a very serious matter, whether it's Accutane or any other medication, that has to be addressed between a physician and the patient. Sometimes if it's a minor, with the family, and that's ?? the reality has to come from the physician. I think, you know, medical journals have a responsibility to provide information, and the issue of economic support, that is a reality. But the reality of medicine is that it's a practice, it is something that has to be taken seriously between the physician and the patient.

MR. HORNE: How many MD's are board certified for dermatology?

DR. PARISER: I would have to defer to ?? there are approximately 8 to 9000 in the United States, and that's a close guess.

MR. HORNE: That's the Board certified?

DR. PARISER: Board certified. 97 percent or so of those are members of the American Academy of Dermatology.

MR. HORNE: So how many of those are not certified?

DR. PARISER: A few.

MR. HORNE: A few. Because the problem comes, they don't go to put in their standing hours or something in order for licensure, why they're not going to hear it very much, and often they pick nice places to go, and I understand that most professions do that, and it's a good way to get people in the door. But I just wonder to what extent, or is there a vigorous effort made by the professional leadership when there's a drug of one sort or the other, or a practice of one sort or the other. It seems to me that that would be one of the main channels, eyeball to eyeball, or send them an e?mail, or whatever it is.

DR. PARISER: Well, at the last annual meeting of the American Academy of Dermatology we had 17,500 registrants. There were seminars and symposiums on acne, as well as on dozens of other topics.

MR. HORNE: Do you think it made an effect?

DR. PARISER: I think every little incremental change helps some. I don't know that there's a way that we measure the details of that particular kind of educational effort, but certainly a lot of effort goes into it.

MR. HORNE: I'm going to have to leave, so I just ask one more question?

CHAIRMAN BURTON: Sure.

MR. HORNE: Have there ever been major studies of just plain old Vitamin A versus Accutane? What is the effect, if any? Does Vitamin A have suicidal tendencies, or what?

DR. PARISER: I am not aware of any such study. The only ?? what I am aware of about Vitamin A, and that is mostly from reviewing the literature, is that it can cause symptoms that we can see in depression, such as irritability, anorexia, energy. It does not, from my understanding, cause clinical depression, and in that sense I have not seen it in any association with suicide.

MR. HORNE: Don't you think it would be worthwhile ??

CHAIRMAN BURTON: Why don't you let Mr. O'Donnell answer that? I think he has some information on that too.

MR. O'DONNELL: While there have been no studies, because old drugs are not studied to determine what people already believe about them, and the reports that are in the literature that Dr. Jacobs referred to, and I referred to earlier, describe patients who are psychotic, who have schizophrenic like symptoms, and suicides have been associated with Vitamin A toxicity. The condition of Vitamin A toxicity causes a change in the brain chemistry. The condition that brings Vitamin A toxic patients to the hospital is a swelling of the brain. When we talk about mental health, we have to convert that to chemical actions in the brain, and there was a damaging chemical action in the brain that's been known, and I don't know that anybody's done large?scale studies in rats, but we certainly wouldn't do that purposefully in patients. I hope that answers your question.

MR. HORNE: That's very helpful, and I assume that some of the pharmacists who have to write a dissertation or a thesis of some sort, and I would think that that is something that they ought to really go after.

MR. O'DONNELL: Well, of the vitamins, the first thing in Pharmacy 101, or Pharmacology 101, is that the fat soluble vitamins are toxic, can be toxic, and Vitamin A and Vitamin D are major fat soluble vitamins, and we constantly ?? especially with people vitaminising themselves and herbalising themselves, we are seeing more and more toxicity from these products that they can go and buy. And of the vitamins, that's where we see the major toxicity.

CHAIRMAN BURTON: Thank you, Steve. Let me ask Dr. Pariser, does Roche Laboratories pay for any of your Academy's annual conference? Do they pay any fees for that?

DR. PARISER: Roche, as well as many other pharmaceutical companies give unrestricted grants to the Academy of Dermatology for various educational and other efforts. But they do not sponsor specific academy ??

CHAIRMAN BURTON: No, but I mean none of their money is being used to help pay for some of these events?

DR. PARISER: That's correct.

CHAIRMAN BURTON: You know, I've been to conferences all my life, and when you have a large number of people, like 17, 18, 19,000 people, and you have different meetings to inform those people, usually a very small number go to any one meeting because there are so many other things going on at the same time, including extracalicular activities such as golf and tennis and other things like that. You know what I'm talking about. I'm sure you do.

DR. PARISER: I do, yes.

CHAIRMAN BURTON: There's no way, at a conference like that, that you could disseminate the information on a wide?scale basis, that everybody would be able to understand and digest. One of the things that troubles me about this hearing today is we had people whose children committed suicide, or were adversely affected by Accutane, and they had no knowledge whatsoever from their dermatologist or their pharmacist about this, and in fact the dermatologist didn't know anything about it, even though it had already been publicised. The pharmacist knew nothing about it, even though it had been publicised, so your conference has not really gotten the job done insofar as informing dermatologists across the country about the possible dangers psychologically, or of suicide, of Accutane. What I don't understand is, if you're a member of an organisation like that, why can't you just send out a fax to everybody with big bold black letters, saying Accutane can cause severe depression, and possibly suicide, as has been said in current warning letters in France and in other parts of the world. Why don't you do that?

DR. PARISER: Well, perhaps if our membership hasn't availed itself of the other means of education, perhaps they wouldn't read that either. I mean, you could argue that, but I agree with you that it's not ?? the annual meeting, where there are many things going on, may not be the best way to reach the masses.

CHAIRMAN BURTON: Let me ask you this. Do you think it would offend Roche Laboratories if you sent a fax out to every single one of your dermatologists around the country, informing them of the possible dangers? Do you think it might offend them?

DR. PARISER: I don't think it would.

CHAIRMAN BURTON: You don't? You don't think it would endanger the money that you get for these conferences?

DR. PARISER: I don't think it would endanger the money, and even if it did, that would not be the mission of our Academy to yield to those kinds of economic pressures.

CHAIRMAN BURTON: Then why don't you just go ahead and send a fax out to all the dermatologists in the country, saying this is a risk, and many dermatologists evidently don't know about it. There was testimony before the Congress of the United States by people who have lost children, who knew nothing about it, even though it had been publicised on the internet, and so we want to make sure you know about it. Why don't you do that?

DR. PARISER: I'll check into it.

CHAIRMAN BURTON: Would you do that?

DR. PARISER: All right.

CHAIRMAN BURTON: And if you don't, do me a favour. Give me a list of all your members, and I'll send the dammed thing out. Because I don't want to have other people coming before our Committee with their kids being dead because possibly Accutane caused it. Now, let me ask you a question, Dr. O'Donnell. You said that the people who ate polar bear livers in the middle 1880's that were on polar expeditions ??

DR. O'DONNELL: That's right.

CHAIRMAN BURTON: ?? had psychotic events because of the large amounts of Vitamin A they were consuming in the livers of polar bears; is that correct?

DR. O'DONNELL: Yes, sir.

CHAIRMAN BURTON: And was this just an isolated incident, or was this something that happened more than once?

DR. O'DONNELL: There were more than ?? there were several reports. Not many were published, but it was common knowledge that people had to avoid excessive use. But similar reports through ?? since then have published neurotoxicity, toxic psychosis, but the first report that I referred to was a polar expedition in 1856.

CHAIRMAN BURTON: So Vitamin A in large quantities definitely causes the kinds of problems you're talking about, and that is what Accutane, in main part, is made up of?

DR. O'DONNELL: Yes, sir.

CHAIRMAN BURTON: You know, Dr. Bull, one of the things that I don't understand, and I won't be able to ask Dr. Wayne Huene about this, I guess, but I'd like to know just a little bit about how Accutane was approved, and what kind of testing took place at the FDA before it was approved. I understand that this was approved before advisory committees were being utilised, and so Dr. Huene an others evidently did some of the research on that before it was put into the public domain. Can you tell me what kind of testing was done, and if not, can Dr. Huene give us that information?

DR. BULL: Well, I can get it started, and certainly if Dr. Huene would like to add to my statement, that would certainly be suitable. FDA does not conduct research. We review research conducted by the manufacturer. So all the research that we review was done by Roche Pharmaceuticals.

CHAIRMAN BURTON: Yes, but let me interrupt you. When you review ?? when your advisory committees today, or whatever it was back in those days, reviews it, and they review the scientific data in detail before they give an advisory opinion to the head of the FDA so they can be approved.

DR. BULL: The process begins with a review of the protocol for the study, and once the studies are completed, review of the actual data, how well the study adhered to the standards that were set out for powering the study, there were patients enrolled in the study. The parameters that were to be assessed to determine efficacy, what parameters to assess the safety of the drug, and how well it meets the mark for what it asks to have as its proposed syndication.

CHAIRMAN BURTON: Okay, I have to yield to my colleague, but let me just cut through this and say, what I want to find out is how extensive was the research, and was it thoroughly examined before they put this on the market. Did they have any kind of information about adverse impacts, about depression, about possible suicide, was any of that looked in to before they put this on the market?

DR. BULL: The typical way that safety is assessed is based on what is reported. There are adverse events that are anticipated that studies I think probably bring a higher level of precision in terms of soliciting comments and direct information from investigators, and then there are others that are ?? could be considered as a discretion, and going back to almost over 20 years ago when these studies were conducted may not have had quite as high a level of stringency applied to them in terms of reporting all things, because there's so much about a new drug that you don't know. And so in a sense, every event that a patient may experience is sort of in play.

CHAIRMAN BURTON: I have more questions on this, but I will yield to Mr. Waxman right now.

DR. BULL: Certainly.

MR. WAXMAN: Thank you very much, Mr. Chairman. This drug was approved in 1982. This is now the year 2000. We have heard more and more about the possible link between Accutane and depression and suicide, and suicidal ideation and all of that. In September of this year there was an advisory committee meeting, and FDA found out that as of May of 2000 37 suicides were associated with Accutane. Is that still the number of suicides associated with Accutane?

DR. BULL: 37?

MR. WAXMAN: Yes.

DR. BULL: In that ballpark. The numbers are ?? in terms of ones that have been assessed for not having duplicate reports in the database is in that ballpark. I have to admit the latest number I have seen is 41, so there may have been some additions to the database since September.

MR. WAXMAN: So there have been more reports of suicides since September.

DR. BULL: And certainly the publicity attendant to Representative Stupak's website, and the reports on that have certainly stimulated more reports. MR. WAXMAN: Now, FDA has always stated that Medwatch catches only 1 to 10 percent of actual adverse events. Can we assume that the number of reported suicides only represents a small fraction of the actual cases? DR. BULL: That is certainly reasonable.

MR. WAXMAN: In 1997, a year before FDA required Hoffman?La Roche to place a warning about suicide on its label, French authorities required Roche to add a warning to Accutane about its risk of suicide, and Roche did not inform the FDA of this warning change, and it was not until FDA required Roche to warn of suicide that FDA learned of the French regulatory action; is this correct?

DR. BULL: Yes, sir.

MR. WAXMAN: Was Roche under any legal obligation to tell you of the French regulatory action, and wouldn't this information have been helpful to you in requiring new warnings for Accutane?

DR. BULL: I'll answer your second question first, which certainly it would have been helpful to have known. Your first question in terms of whether or not there was a legal responsibility, we have researched that. It was certainly addressed once we learned of the French labeling change, and our regulations are unclear as to whether or not labeling changes must be submitted. The action the agency is taking to address is that we have a proposed rule that will address these kinds of gaps, because certainly that kind of information is quite important.

MR. WAXMAN: So for the future you will require this information from the pharmaceutical manufacturers?

DR. BULL: Yes, sir.

MR. WAXMAN: You had clear statutory authority from Medguide in 1997 and 1998, when you were considering changes to Accutane labeling. Why didn't FDA require issuing a Medguide with Accutane at that point, warning of birth defects, suicide and psychiatric disorders?

DR. BULL: I think part of the decision making at that point had to do with looking at Medguide as a forward looking tool, and I think initially was anticipated to be put in place for new drugs. Certainly I think by all criteria, Accutane, in terms of serious and significant adverse events, fits the criteria, and it will certainly be ?? it will be a drug that will have a Medguide attached to it. I think in terms of why it wasn't considered in 97/98, in terms of what our strategies were for implementing the rule, it was considered. I think certainly the continuing reports have compelled us to say it makes sense to have a Medguide attached to this drug.

MR. WAXMAN: Just for people who may be watching on television, on C?SPAN, what is a Medguide?

DR. BULL: A medication guide is ?? I like to think of it as a plain language tool to convey serious and significant adverse events to patients. What is special and unique about a Medguide is that it is required to be given to the patient at the time of dispensing at the pharmacy.

MR. WAXMAN: Now, a Medguide is different than the information to the dermatologist, or the professionals, isn't it? DR. BULL: Uh?huh, yes, sir.

MR. WAXMAN: And when did information go to dermatologists first, under the direction of the FDA, about the possible association with Accutane and depression and suicides?

DR. BULL: To dermatologists?

MR. WAXMAN: Yes.

DR. BULL: In February of 1998 was the time of ?? that letters were sent out to the Academy of Dermatology members, the family practitioners and psychiatrists.

MR. WAXMAN: Has the clinical data about Accutane and psychiatric disorders changed since 1998, and do Roche and FDA know significantly more about the risks of suicide?

DR. BULL: I think more work has been done. I think we still, in terms of data that is conclusive, we don't know ?? we don't have conclusive findings. There has certainly been some fairly large epidemiologic studies that have been undertaken, one of which was published in the Archives of Dermatology in October of this year, and I think certainly there is a need for more work, but the data remains inconclusive. Do we really know more? I think, unfortunately, no.

MR. WAXMAN: I guess the question I have to ask you is that if we don't know any much more about this whole problem of association between Accutane and depression and suicide than we did in 1998, why shouldn't the new box label warning, new informed consent form, and new Medguide have been made two years ago?

DR. BULL: Because we don't ?? I ?? in terms of tools, and I think the ?? one thing that FDA is learning is that our traditional tools for conveying safety information do not work as effectively as we would like to see them work. I think as we are learning more, I think in the overall changing paradigm of health care, given that we are realising as well that the physician, as the intermediary to the patient for information, that that linkage was not working as effectively as it used to. We really are having to look much more critically at what other mechanisms we can engage to make sure that consumers are fully informed about the adverse events of drugs. So this is part of an evolving picture for us, and something that we are actively engaged in refining, and enhancing our abilities to meet this need.

MR. WAXMAN: Thank you very much. Thank you, Mr. Chairman.

CHAIRMAN BURTON: We'll let you ask more questions if you chose.

MR. WAXMAN: Okay.

CHAIRMAN BURTON: One of the things that bothers me, the question that was just asked by Mr. Waxman, you kind of just ?? we aren't really geared up to get that kind of information out to the American people. That's kind of a cop?out, I think, isn't it? I mean, the Food & Drug Administration is supposed to be the person or the group that guarantees the safety and the efficacy of pharmaceuticals and drugs for the people of this country, and if something is going awry, you're saying, oh, it takes so much time to get the information out, and I mean, 19,000 dermatologists, you could send letters out tomorrow to all of them, in big bold print, to all the pharmacists in the country, and you don't send ?? put it on the e?mail. You know, there's all kinds of ways to communicate in this age, and I think it's a real cop?out for the FDA to say, oh, we can't do that. The other thing I want to ask you is this: In 1850 something, polar bear livers were causing psychiatric problems on people that were eating them, because of large amounts of Vitamin A. This pharmaceutical expert, or pharmacologist ??

MR. O'DONNELL: Both.

CHAIRMAN BURTON: Both. ?? indicated that the brain swells up when you have too much Vitamin A in it, which causes severe problems. When the testing was done, back in the 1980's, before you put Accutane on the market, did anybody check mice brains? Did they give them large amounts, or any kind of animals large amounts of Vitamin A, to check to see if it caused any side effects? Did anybody check that out?

DR. BULL: Mr. Chairman, what I would like to do is for us to look back at the pharm/tox data and get back to you on that. CHAIRMAN BURTON: You came today and weren't prepared to answer this question?

DR. BULL: In terms of the specificity of your question regarding mice brains, I'm not ??

CHAIRMAN BURTON: Well, any kind of research. Rabbits, I don't care. Was large amounts of Vitamin A ever injected into any laboratory animals in a test to see if it caused any kind of mental problems in the animal, rat, or whatever?

DR. BULL: I think the responsible thing on my part to do would be to go back and have our pharmacologic and toxicologic experts look back at the original database.

CHAIRMAN BURTON: Dr. Huene, do you know if any kind of tests were done like that?

DR. HUENE: Well, I'm sure the toxicity of Vitamin A has been quite well known for a long time. This is a derivative of Vitamin A. I am not certain that the effects were publicly ??

CHAIRMAN BURTON: Why don't you come to the microphone so we can hear you? I won't try to badger you too much, I won't cause you too much problems. I think it's really important ??

DR. HUENE: I'm not a toxicologist, but I'm sure that there have been extensive studies done on the effect of hypervitaminosis A on animal brains.

CHAIRMAN BURTON: When you approved this, or when you made your recommendation, did any of the studies talk about this at all, about the possible toxicity or mental side effects, or anything else that might occur because of this? Because we're talking about Vitamin A, or a derivative of Vitamin A.

DR. HUENE: Right. Well, I don't remember in detail; it was a long time ago, but I know that extensive toxicity studies were done prior to even initiating clinical studies in any drug that is planned to be marketed.

CHAIRMAN BURTON: Can you, Dr. Bull, for our record, and I would like for you to send it to my right hand here, sitting on my left, could you send me any information you have on the studies that were conducted on the Accutane product before it was approved? And also I would like to have any information that you have on Vitamin A. Because it just seems like to me, and I don't know what my colleague here feels, but it seems like to me that if Vitamin A does have these kinds of side effects when given in large amounts, and you're talking about giving children who have acne a Vitamin A derivative over a long period of time, that she would think it might have some kind of side effects which should have been mentioned prior to 1997 in France, and 1998 here, about possible mental or worse problems from large amounts of that being ingested.

DR. HUENE: I would add that the label does address a condition known as psuedotumor cerebri, which is I think the brain swelling that you referenced, that was know to be related to Hypervitaminosis A.

CHAIRMAN BURTON: That may be, but when we hear of people whose children who have committed suicide, or who have had adverse events occur because of Accutane, and they didn't even know anything about this, were never warned by their dermatologist, were never warned by their pharmacist. They had no knowledge. They went home, started giving their child the pills, and those side effects occurred. My gosh, what a mistake. What a tragedy. In any event, we would like to have that information submitted for the record, and I would like to have a list, if you don't have it, of all the dermatologists in the country, and if your association won't contact them, then I'll figure out a way to do it myself, and the Committee will. And I think that we ought to put on our e?mail to all pharmacists in the country the warning that Roche is now putting on their label so that they will all be aware of it as well. Mr. Waxman.

MR. WAXMAN: Yes, thank you. I would like to review some chronology about this Accutane product. In June 1985, Roche amended the Accutane package insert under adverse reactions to state: "The following CNS reactions have been reported, and may bear no relationship to therapy: seizures, emotional instability, including depression, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy and paresthesias." That was in 1985 when they first mentioned that there may be an adverse reaction, including depression. Now, this was after the drug had already been approved, having been approved in 1982. But in May 1988, FDA required stronger warnings and physician mailings on Accutane's risk of birth defects, and FDA also required additional studies, including follow?up patient surveys. An advisory committee to the FDA said that they recommended that FDA restrict prescribing Accutane to board certified dermatologists, but FDA wouldn't go along with that recommendation. Predictably, the AMA and the industry didn't want the prescriptions limited to this board certified specialty, they wanted any doctor to be able to prescribe the drug. Then, it's interesting that in 1997, FDA issued a warning letter to Roche for failing to submit serious adverse event reports in a timely manner, and then Roche said that their computer systems were responsible for delays of up to eight years in complying with the law. So you shouldn't be criticised if you're trying to get the information and Roche is not giving it to you. Then, finally on February 25, 1998, FDA required these warning labels in new, bold face warnings, about Accutane association with suicide and all of that, and that was at a time when FDA was still not informed that the same warning labels had already been full on the year before in France, and Roche never informed the FDA. So it seems like ?? and I gathered, Dr. Jacobs, that you testified at the hearing, when they finally ?? which resulted in these warning labels, when you testified, giving some suggesting that maybe it was more complicated than the causation or clear relationship; is that a fair statement?

DR. JACOBS: Yes. And I think ?? because I think it's important to emphasise, because I think even, Mr. Chairman, if I may state something ??

MR. WAXMAN: Well, let me just ?? because I have some things I want to pursue in the few minutes that I have. But your position is it was a lot more complicated at that time. FDA heard your testimony, Roche, I presume, did not willingly agree. Do you know if they did, Dr. Bull, to these warning labels in 1998?

DR. BULL: When you say "willing," to regulate a change?

MR. WAXMAN: At the time FDA was telling Roche they ought to put a warning label, you have to put a warning label about the association of Accutane and psychiatric problems, Roche issued a press release saying there is no proof of causation, and that: "Teenagers are at particular risk for depression." which suggests that they were saying to the public that teenagers are often depressed, and that because of that, may commit suicide, in effect suggesting that it's not related to Accutane. Now, FDA did its job, and said the warning labels have to be on this product. When that warning label was put on the product, what was it put on, the patient package insert, the box, where would it go?

DR. BULL: The warning label in '98 went into the professional labeling. The existing patient label at that point already included in capital letters, changes in mood.

MR. WAXMAN: Right. So the clearer warning label identifying the possible association of Accutane with suicide and depression went to professionals?

DR. BULL: Uh?huh, yes, sir.

MR. WAXMAN: Isn't is fair to say, Dr. Pariser, that most of the Accutane prescribed in this country is prescribed by board certified dermatologists? DR. PARISER: It's my understanding that it's about 85 percent.

MR. WAXMAN: Now, don't dermatologists, as professionals, get the information from the FDA about warnings?

DR. PARISER: Sure, they would have all received that letter in that year.

MR. WAXMAN: So they received the letter in '98, and they didn't have to wait for an ad in a dermatological publication, they got a warning right from FDA to the professionals?

DR. PARISER: Yes, sir.

MR. WAXMAN: Well, then the issue that has been raised by my colleagues is, does the association of dermatologists try to continue to impress upon dermatologists that this is a real concern? I assume that dermatologists are informed in a number of ways. They get their warnings from the FDA when they prescribe this drug, and when they are contemplating using the drug for their patients; they get publication information from the Association ?? whatever your association is called ?? DR. PARISER: The American Academy of Dermatology.

MR. WAXMAN: The American Academy of Dermatology. I assume that the American Academy of Dermatology would put in its publications information about this problem?

DR. PARISER: Yes, sir.

MR. WAXMAN: And then there are the ads, but then of course the ads are the weakest link, because the ads are put in by the manufacturer. But even an ad put in by the manufacturer, they have to put in all the warnings that goes into the ?? as required by the FDA, in the fine print of the ad. So the issue is, what other ?? are there better ways for your association to inform dermatologists? They get the information, they are professionals, they get it from the FDA, they get it from you. At your annual meetings, do you think there ought to be a greater emphasis on trying to educate dermatologists about this problem, and aside from the annual meetings, are there other ways that you might try to drive this issue home to dermatologists? At least for the simple reason that one, they ought to be careful not to prescribe the drug unless it was a severe case, and secondly, if they have a patient, they ought to be asking the patient, are you suffering from ?? do you see any change in your mood, do you feel weird, do you feel sad, sort of to follow up, to see whether that patient might be experiencing some reaction to the drug?

DR. PARISER: Well, I agree with what you're saying. Obviously the message has to get out, and in the cases we heard testimony from today, in some cases it hasn't. I don't know what the numerator and the denominator is in this equation of how many dermatologists who really get the message, and really do it correctly, all the venues that you described that are ways that professionals such as dermatologists educate themselves. Another venue, which is perhaps not the greatest, but it happens, is education through the pharmaceutical representatives that call on physician offices. That's a sales situation, not an educational situation, but there is an opportunity there to provide some education as well.

MR. WAXMAN: Well, it could be, but it could be a rush to hand out the press release saying that there was no proof of causation, and that teenagers are at particular risk, there is no root of causation, and teenagers are generally at risk of depression.

DR. PARISER: That's true, but anything that's handed out in a physicians office has to be approved by the FDA, so if they were going to hand that out, the FDA would have had to have approved it.

MR. WAXMAN: And then the Chairman raised, it seems to me, the most important point, let the patients and their families know. We generally assume doctors know, because they are the professionals, they have gone to medical school, they are dermatologists, they have gone through specialty training, and they have had to get board certification, which means they had to show some skill and proficiency in their specialisation, and we assume they keep up with the information from the FDA and the pharmaceutical companies, and from your association. But just in case, does anybody disagree that the patient should get this information as well? DR. PARISER: No, they should, and it should be the patient's choice as to whether they are going to go on Accutane or not, and it should be an informed choice. I personally never tell a patient you have to take Accutane, never.

MR. WAXMAN: Do you ever tell a patient not to take Accutane?

DR. PARISER: No.

MR. WAXMAN: Do you ever tell a patient that if you take Accutane, there's an associated risk of depression and suicide, and that you ought to recognise that and balance it out with the fact that the patient may be very down on himself or herself because of the acne, but could ?? things could be worse?

DR. PARISER: Well, in my own personal practice I always do that, and I discuss the issue of mood changes, depression and potential suicide as objectively upfront as I do getting chapped lips or elevation of triglycerides, and the issue of pregnancy. I personally do. I can't speak for every other dermatologist in the country. Obviously there are some who don't do that, but I think it's important that it be done.

MR. WAXMAN: I have to tell you that as a father of a ?? no longer a teenage boy ?? but if the doctor said to me, by the way you have an elevated risk of chapped lips, I may not pay so much attention, but if someone told me there was an elevated risk of suicide, I certainly would want to pay more attention to it. So the question is, do the dermatologists know about it, and are they telling the patient, and whether they're telling the patients or not, shouldn't the patients know directly from either the company or the FDA? And I guess the FDA is working on this Med alert in order to inform the patients. Thank you, Mr. Chairman, for allowing me to pursue this.

CHAIRMAN BURTON: No problem. Thank you, Mr. Waxman. Let me just say, I don't want to prolong the hearing, but I would like to have as much information on the research on the Vitamin A as possible, and also, I just cannot fathom how, with all the methods of communications that are available from the FDA to the doctors and everything else, how dermatologists would not be aware of the side effects of Accutane, and how that would not be conveyed to the patient and the parents of the patient, and how all these tragedies could be avoided just through simple communication. Let me just say, while we're talking about Accutane's connection to depression and suicide, I was disturbed to learn that both the FDA and the manufacturer feel that pregnancy prevention program is not working at optimum. Is it true that over 1900 women have become pregnant on the drug, and that over 1400 have been terminated through abortion? I don't understand how that is after 18 years of this program, that it hasn't been fixed so that you don't have that kind of problem. Is that still the case, that a large number of women are getting pregnant while on Accutane, even though? DR. BULL: That data was reviewed at the recent advisory committee, and the data that you have referenced is generally accurate, which has led to the Agency's actions to institute the registry that would insure that women have a negative pregnancy test, too, before starting the drug, and that they only get a month's supply of the drug, and to get another month's supply would have to be fronted by a negative pregnancy test.

CHAIRMAN BURTON: So that is being done?

DR. BULL: That is going to be part of what the registry will entail. Because what we have learned is that the system that was put in place in the 80's simply is not working.

CHAIRMAN BURTON: Okay. The Surgeon General initiated a suicide prevention program last year. His call to action makes no reference under risk factors to drugs that can lead to depression and possibly suicide. What role has the FDA played in development of this program, and have you considered having the Surgeon General do public service announcements about this as well? DR. BULL: I'm sorry, in terms of the program, the Surgeon General's program on depression?

CHAIRMAN BURTON: Yes. Have you considered talking to the Surgeon General about doing public service announcements about possible depression and possible suicide because of things like this?

DR. BULL: I think it's a very intriguing idea. I think we could certainly get in touch with his office. We haven't considered it, but it is certainly a very intriguing idea.

CHAIRMAN BURTON: Okay. Well, we would like to have the information that we talked about regarding the studies and what kind of research was done. Do any of you have any final comments you'd like to make to the Committee before we adjourn?

DR. JACOBS: I suppose I have one, Mr. Chairman, and it's a very delicate comment, and it has to do with the issue of the suicides that we heard about today, that they have been caused by Accutane. These suicides are tragic, and they occurred in relationship to Accutane. I think there are steps that are being taken to address this issue. I think suicide, after studying it for, you know, nearly 30 years, it's one of the more complicated behaviours, and we don't ?? we only understand that it occurs. We don't have any studies that shows that our treatments prevent it, that with all the outbursts of psychopharmacology, the suicide rate has not dropped. We do not stop our efforts. Can one thing prevent suicide? Would informing a family about the risks of Accutane prevent suicide? I cannot say. However, is it useful? Obviously the answer is yes. But I think it's important to keep into perspective that not one thing, from my professional opinion, causes suicide.

CHAIRMAN BURTON: Well, I understand your position, Doctor, you made that very clear. With all due respect, we had parents here today who saw dramatic changes in their children when they started using it. They had no reason to believe it had anything to do with Accutane, and yet that is when it started. Two of the three that testified today, two of the three families, the suicide was successful. One, fortunately, was not. All I can say is that, those parents, had they known about the possible side effects, which has not been given to the public until recently, for that information to have been give them in a timely fashion, their children would probably be alive today. At least I believe they think that. Anything else, Henry?

MR. WAXMAN: The only request, Mr. Chairman, if these witnesses would be willing, some of us may want to ask them additional questions in writing, and ask them to submit responses for the record in writing.

CHAIRMAN BURTON: Yes, we would request that as a Committee, and thank you, Henry, for mentioning that. We will look forward to your response from the FDA regarding those studies. Thank you very, very much. We may have additional hearings on this, but we really appreciate your cooperation today. We stand adjourned.

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