Dr. Douglas Jacobs is the Associate Clinical Professor of Psychiatry at Harvard Medical School. Dr. Jacobs has been engaged as an expert witness by Hoffman-La Roche on a consultancy basis for a number of years on a wide range of issues relating to the drug.
| Date | Category | Description |
| 2002 | Expert Witness | Dr Jacobs testified as an expert witness at the Carla Gray - v - Hoffman La Roche trial in 2002 |
| 2001 | Publications | Dr. Jacobs publishes paper entitled 'Suicide, depression, and isotretinoin: is there a causal link?' The article discloses that the "article was sponsored by Roche Dermatologics Inc." and that "Dr. Jacobs has consulted with Hoffman-La Roche as an expert psychiatrict and suicidologist".
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| 2000 (December) | Congressional Hearings | At a US Congressional hearing held in Washington in the 6th of December 2000 to consider the product and its links to depression and suicide Dr. Jacobs admitted in relation to this relationship with Roche that "I have been doing this work since about 1980 and I have been involved in approximately 300 medical / legal matters, and in terms of my income, approximately 70% of my income comes from my consultation in medical / legal matters". |
| 2000 (September) | FDA Hearings | Jacobs appears at FDA hearings. Jacobs
presented his findings which concluded that there was no link between
Accutane and suicide. |
| 1999 | Adverts | Letter by Dr. Jacobs appears in Irish Medical Journal after increased label warnings introduced in Ireland. The advertisements contain |
| 1999 | Clincial Trials | Roche engage Dr. Jacobs to interview patients
in the New Formulation Accutane clinical trial. >> FDA criticize the design of the clinical trials. |
| 1997 | FDA Presentation | Roche engaged Dr. Jacobs to review literature
on Accutane and the link to depression and suicide. >> FDA rejects Dr. Jacobs submissions and introduce increased label warnings for Accutane in February 1998. |
FDA Presentation
January 1998 Presentation in order to Avoid Increased Label Warnings Featuring Suicide.
In early 1997 the FDA had sought representations from Roche
in connection with FDA proposal to increase label warning for the product
in the US. In 1997 Roche had engaged Dr. Bickers, Dr. Jacobs and Dr.
Judith Jones, to represent Roche in making presentations to the FDA
in efforts to convince the FDA not to proceed with such increased warnings.
The FDA document indicate that representations made by Bickers and Jacobs
to the FDA in 1997 (link) were rejected by the FDA for the following
reasons:
a. Dr. Jacobs statement regarding the lack of a biochemical basis for
an association which was echoed by Dr. Bickers "no evidence that
the pharmacologic effects of retinoids influence serotoninergic or dopaminergic
pathways in human brain" was addressed by Dr. O Connell of the FDA.
b. The FDA rejected these representations made by Bickers and Jacobs for a number of reasons, including " While none of these papers [four
references on retinoids and human brain] in isolation establishes the
role of retinoic acid in the regulation of adult brain function, they
appear to be strongly suggestive of a biologically plausible mechanism.
Given the well established correlation between findings of this nature
in murine and human brain (Dr. Stephen Goldman, personal communication)
the Science paper, in particular, clearly supports involvement of retinoic
acid in dopaminergic signalling".
The FDA (via Dr. Kathyrn O' Connell) cited the following additional
reasons for rejecting the presentations made by Bickers and Jacobs
-
a. "Many of the ADR reports as well as the published cases describe
irritability or uncontrolled anger, headache, fatigue, and severe depression,
some with suicidal ideation or action. A few case reports also note
hallucinations (visual where specified) or other symptoms of psychosis."
b. "The rapid resolution noted in many of the reported dechallenge
cases suggests that an educational message to practitioners and their
patients may prevent significant morbidity, and hopefully mortality".
c. "Given all the pieces of evidence available, it is difficult to
avoid the conclusion that Accutane (the product) can adversely affect
the adult human brain in clinically significant ways and that Accutane
use is associated with severe psychiatric disease in some patients"
d. "The reported effects on the CNS are not surprising given the
profound effects of the drug on the integument, and the common origin
of the brain and skin from the neural crest".
Clinical Trials of New Accutane Formulation Product
In 1997 Hoffman-La Roche conducted clinical trials of a new formulation Accutane product and compared it to the existing Accutane product. The labeling for marketed Accutane served as the safety guide for investigators -however because the trial was designed and implemented prior to the March 1998 labeling change regarding psychiatric adverse events, mood was specifically monitored. The purpose was protection of study subjects; the trial was not intended or designed to study the association of isotretinoin and psychiatric symptoms. However the study was sponsored by two consultants: Douglas Jacobs, MD, Associate Clinical Professor of Psychiatry, Harvard Medical School, and Robert Nelson , PhD, pharmacoepidemiology consultant.Dr. O' Connell made some interesting remarks at the FDA
Hearing in 2000 in relation to the mood assessment questionairres and
analysis by the investigator, Dr. Jacobs viz..
"In the new formulation arm, 4 patients the doctors taking care
of them made the decision to discontinue them from the trial for psychiatric
symptoms. None of them were considered serious by the investigators.
There was also an additional patient who was discontinued for a possible
pseudotumor cerebri, and that patient also answered yes to all four
of the screening questions for the psychiatric symptoms. In the Accutane
arm, there were no discontinuations for psychiatric symptoms. If we
go to the next slide, when I looked at this trial, I really don't think
that the number of discontinuations is probably a very good comparative
measure of safety because it appears that there were some problems with
the investigators perhaps understanding what the rules were. It was
very variable. Some patients that appeared to have mild psychiatric
adverse events were discontinued, whereas other patients who, by the
scales, appeared to have a greater adverse event were not. So, I think
there were some problems there. But be that as it may, there's no readily
apparent reason for the imbalance between arms because those probably
should have been balanced. The trial was very well masked by the sponsor.
So, that was discontinuations for psychiatric adverse events. Now, if
we look at the reported psychiatric adverse events. So, this isn't people
that discontinued. This is just how many patients had their doctor write
down on a case report form that an adverse event occurred. Again, we
have this disproportion. There were 11 such cases in the new formulation
arm and 1 in the current Accutane arm. Now, this disproportion is statistically
significant and it would be cause for concern if it was real. On the
next slide, it's important to note here that the reported number refers
only to patients who verbally complained of symptoms. So, in other words,
the patients answered this four-question screening tool about whether
they had had any significant depression or insomnia since the last visit
that "affected their work or ability to perform normal daily activities."
And patients with two or more positive responses went out and filled
out the Beck's Depression Inventory again. So, on the next slide, if
you add all those patients up -- so, the patients who verbally reported
their symptoms, the patients who Dr. Jacobs and Dr. Nelson did in analysis
of these cases in retrospect, if you add those cases that did not have
a verbal report but were analyzed by the sponsor's consultants, and
then you add in some extra patients that did not have a psychiatric
adverse event recorded but did answer yes to the self-injurious behavior
question or to two out of the four screening questions or had Beck's
Depression scores within a few points indicative of severe depression,
it comes out pretty even, not exactly equal but the difference isn't
anything that would catch your attention."
Adverts
Roche (Ireland), placed a full page advertisment in each of three Irish medical journals published in February/ March 1999 viz. Irish Medical Times, Irish Medical News and Irish Medical Weekly, to which R.A.G. issued a response.
The adverts featured letters by Dr. David R Bickers and Dr Douglas Jacobs, described as independent experts retained by Roche, which letters claimed that Accutane/Roaccutane does not cause the psychiatric side effects listed in the label warnings applied to this drug (featuring depression, psychosis, central nervous system disorders, pseudotumor cerebri, suicide, suicide attempt and suicide ideation etc). The advertisements were an attempt by Roche to reduce and diminish the increased label warnings applied for the drug a few months prior to the insertion of the advertisement.
Our group established that in 1997 Roche had engaged Bickers and Jacobs to make presentations to the FDA in an effort by Roche to avoid the inclusion of psychiatric disorders, including suicide, in the increased label warnings proposed by the FDA at that time. Therefore, when Bickers and Jacobs allowed their name to be featured in Roche advertisements, they failed to disclose their financial involvement with Roche and failed to disclose that their efforts, on behalf of Roche, had failed (FDA proceeded to impose increased label warnings for the U.S in February 1998.
Roche recently applied to the FDA for license for Accutane which would extend Roche Accutane patent for a further 21 years. At the FDA public meeting held in Washington on 19th September 2000, details of pre trial study results for the proposed Accutane product was presented by Roche. The following points were noted from the Roche presentation:
- Dr. Douglas Jacobs had carried out pre-trial studies in 1999 for the proposed revised Accutane product. Accordingly, Dr. Jacobs, despite his financial and other dealings with Roche,despite his unsuccessful efforts to persuade the FDA not to introduce increased label warnings, despite Jacobs allowing his name to be used in Roche advertisements promoting increased sales of Accutane and attempts to dilute label warnings, Dr. Jacobs is considered to be objective enough to monitor patients in 1999 during trial studies as part of license application for Accutane and to honestly record and report all side effects.
There are numerous examples of medical people in the pay of Roche who carried out pre trial studies on Roaccutane/Accutane in 1980/82 on behalf of Roche, who contineously published articles promoting increased use of Roaccutane/Accutane without any reference to known serious side effects. Such pre trial studies and base data featured in articles produced by medical people in the pay of Roche must be immediately investigated by independent investigators.
Articles
Jacobs and his co-authors (Deutsch NL, Brewer M) published article entitled 'Suicide, Depression and Isotretinoin: Is there a casual link?', in the American Academy of Dermatology in 2001. The article discloses that the "article was sponsored by Roche Dermatologics Inc." and that "Dr. Jacobs has consulted with Hoffman-La Roche as an expert psychiatrict and suicidologist". The article was presentated at the Conference entited "Isotretinoin: A State-of-the-Art Conference" sponsored by Roche.
Criticisism of Paper by Medical Review Officer of the FDA
Dr. Kathyrn O'Connell (Division of Dermatologic & Dental Drug Products & Office of Drug Safety) and her colleagues issued letter to the American Academy of Dermatology which was published in February 2002. The letter entitled "Isotretinoin (Accutane) and serious psychiatric adverse events" criticised 3 papers which appeared in the supplement of the November 2001 issue of the American Academy of Dermatology. The full letter can be downloaded here. O' Connell states a) Dr. Jacobs and his colleagues do not address rechallenge cases even though "positive rechallenges are very important evidence in overall casusality assessment of isotretinoin and psychiatric events". Dr. O' Connell further states that at the FDA hearing in 2000, the Committee "discussed 40 reports of patients who experieced psychiatric symptoms while taking Accutane, recovered after the Accutane stopped, and had recurrence of symptoms during a second course of Accutane (positive rechallenge)". Dr. O' Connell and her colleagues criticised Dr. Jacobs statement viz "It is important to note that there were no reports of depression in the controlled clinical trials of isotretinoin". Dr.O'Connell states that "no reference is provided for this important statement". She states that if Jacobs was referring to the 1982 initial studies that supported the 1982 approval of Accutane, "it is important to note that adverse events in these long-ago trials were reported only if the individual investigator thought they were casually related (a clinical trial pracitce no longer considered acceptable)." She finally criticises the discussion of biologic plausibility that does not include the reported psychiatric side effects of hypervitaminosis A. O' Connell states that "A complete discussion of biologic plausibility is beyond the scope of this letter, but we think it important to note that none of what is known about retinoids and the adult mammalian brain is inconsistent with a biologically plausible association between isotretinoin and psychiatric events".Presentation at the Congressional Hearing in December 2000. At a US Congressional hearing held in Washington in the 6th of December 2000 to consider the product and its links to depression and suicide Dr. Jacobs admitted in relation to this relationship with Roche that "I have been doing this work since about 1980 and I have been involved in approximately 300 medical / legal matters, and in terms of my income, approximately 70% of my income comes from my consultation in medical / legal matters".
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