Aim:- To seek a formal inquiry on all studies, including pre trial studies, conducted by Professors Cunliffe and Leeds Hospital/Leeds University for and on behalf of Roche in connection with the drug accutane/roaccutane covering the period from 1978 to the present date
Submission Details
2. Allegations against Professor Cunliffe/Colleagues of Professor Cunliffe at the General Infirmary at Leeds/University of Leeds/United Leeds Teaching Hospitals Trust.In January 1998, a committee was set up to investigate psychiatric and other side effects of the acne drug Roaccutane. Dr. T.V. Middlekoop, research scientist, was appointed to carry out research on the project and to liase with a number of medical specialists, academics and others with a view to the collection of adverse drug reaction reports, review of published scientific articles and coordination of scientific studies and investigations commissioned by the committee. The Committee consist of a group of people from different countries (Ireland, U.S., Canada, U.K., France, Norway, Australia) who had suffered severe side effects, in particular psychiatric side effects from the ingestion of Roaccutane, together with the families of people who had suffered side effects from the drug.
It is alleged that the following parties participated in a major 'cover up' with regard to proper and adequate disclosure on serious side effects of the drug Roaccutane. That the parties effectively acted under the influence of Roche to promote increased use of Roaccutane and to neutralise serious side effects, thereby putting the safety of Roaccutane patients at risk, worldwide. The parties include :-
Professor Cunliffe - [3 Names Blanked out] - Dermatology Department, General Infirmary at Leeds - University of Leeds - United Leeds Teaching Hospitals Trust - Department of Dermatology, University of Leeds In excess of sixty articles were published in medical journals featuring the above parties and others attached to General Infirmary at Leeds/University of Leeds.
The articles failed to disclose the financial contributions made by the manufacturers of Roaccutane, Roche Pharmaceuticals Ltd/ Hoffman La Roche (hereinafter called Roche). The articles promoted increased use of Roaccutane for moderate and mild acne despite the fact that the licence for Roaccutane states that the drug should only be used for severe nodular cystic acne as a treatment of last resort when all other treatments had failed. Professor Cunliffe is on record as admitting receipt of fees and other benefits from Roche but failed to disclose the level of fees and benefits received from 1979 to date. Roche by letter dated 21 April 1989 states " I confirm that Roche has from time to time engaged the services of Professor Cunliffe." Roche have not quantified the level of financial and other benefits paid toProfessor Cunliffe. Out of the many articles written by Professor Cunliffe which promote Roaccutane, two acknowledge the financial backing received from Roche. The rest make no reference to any financial assistance received. It is suspected that all articles on Roaccutane written by Professor Cunliffe have been paid for by Roche.
3. Roaccutane/Isotretinoin - description of the product
Roaccutane, generic name Isotretinoin (13 - cis - Retinoic acid - an analog of Vitamin A) is an oral prescription medicine used in the treatment of acne. Ingesting Roaccutane at the doses prescribed for acne patients is effectively like taking an overdose of Vitamin A which causes the condition hypervitaminosis A. Many of the side effects of Roaccutane treatment are the same as symptoms experienced by patients with hypervitaminosis A.
4. Correspondence by Professor Cunliffe/Leeds Hospital aimed at understanding adverse reactions
At the initial stage of our enquiry it was discovered that certain dermatologists/doctors who received queries in connection with psychiatric side effects of Roaccutane quoted from Professor Cunliffe articles and, in some cases, featured correspondence from Professor Cunliffe in their efforts to minimise the concerns raised by patients/family of patients who had experience psychiatric side effects. The following copy correspondence between Mr.[Name blanked out] and Professor Cunliffe/Leeds University illustrates the nature of such correspondence and indicates that Professor Cunliffe took an active part in seeking to dismiss queries raised concerning side effects. Appendix 1, attached, sets out copy of relevant correspondence in connection with Professor Cunliffe viz
(I) Letter from Dr. [Name blanked out] dated 3rd October 1997.
The letter refers to EADV Conference held in Dublin in September 1997. The letter states that Professor Cunliffe contacted Dr. [Name blanked out] to say that, at the EADV Acne Meeting, none of the dermatologists referred to in his letter had a patient who committed suicide whilst on Roaccutane. However, his colleagues had patients where mood change was very obvious during the course of the acne treatment. Their view was that where Roaccutane was given and no apparent change in mood became obvious, it would be difficult to incriminate the drug as the prime cause. The letter states that Professor Cunliffe deals with a vast number of patients treated with Roaccutane in the U.K. and indeed tends to be contacted by his dermatological colleagues when difficulties arise in the context of acne treatment. He had never heard of a similar case (of suicide).
(II) Letter issued by Mr. [Name blanked out] dated 15th October 1997.
The letter requests that Dr. [Name blanked out] contact Professor Cunliffe to expand on matters referred to in the previous correspondence. The letter also enclosed a copy of an article which appeared in The Irish Times on the 12th September 1997 where Professor Cunliffe is quoted as stating that "50 of his patients with acne had attempted suicide and 7 had succeeded, " (see appendix 2). The letter requested that Dr. [Name blanked out] ask Professor Cunliffe to provide a profile on those 50 patients (obviously concealing their identity) showing age, male/female, medication prescribed for the acne, dosage, year of occurrence etc. together with details on follow up on the 43 attempted suicides referred to in the article. The letter also asked for confirmation from Professor Cunliffe that the 50 cases which he referred to in the article had been reported to some agency or organisation and to provide details on same.
(III) Letter where Dr. [Name blanked out] out suggests that queries to be raised with Professor Cunliffe should be via Dr. [Name blanked out].
(IV) Letter from Dr. [Name blanked out] to Mr. [Name Blanked out] dated 21st January 1998 together with enclosure viz letter from Professor Cunliffe to Dr. [Name blanked out] dated 14th January 1998.
The Professor Cunliffe letter dated 14th January 1998 states that the number of patients who had direct or indirect contact with Professor Cunliffe and who have attempted suicide is in the order of 55 - 60 patients. The letter states " I should stress that none of these patients were on Roaccutane. Many were subsequently prescribed Roaccutane and were well pleased with the outcome of the therapy". The Professor Cunliffe letter states "depression and psychiatric disorders in relation to persons on Roaccutane - I have no precise facts on this, except to say that the percentage must be extremely small. As a guesstimate, probably in the order of 1 - 500, but depression is so common in society that any causal relationship is debatable". Point 3 of the letter states " I am computer illiterate and for years I simply record in a box folder/books the most pertinent facts to allow me to make a record of the most relevant of details. However, what I can dogmatically state is that no patient was on Roaccutane". Point 4 of the letter states " the approximate number of people who attended the Acne Meeting was of the order of 500. There was no questionnaire. I simply asked if anyone had had any such clinical experience. No one indicated that they had. The letter refers to the discussions which Professor Cunliffe had on the specific tragic case with his colleagues Prof. Shalitta, Prof. Strauss, Layton and Prof. Thiboutot from the United States. "All except Prof. Thiboutot have had enormous experience of treating patients on Roaccutane, that between the 4 of them they would have collectively treated or consulted more patients with Roaccutane than any other group of physicians in the World. My colleagues told me that they had not seen any such patients" Point 5 of the letter states " The six cases of suicide reported to Roche does not include any of my cases, because none of my patients were on Roaccutane."
(V) Letter from Mr. [Name blanked out] to Professor Cunliffe dated 10th February 1998.
This letter first refers to the personal attendance by Mr. [Name blanked out] at EADV Conference held in September 1997, attended by approximately 500 delegates. Professor Cunliffe and those who gave the lecture on the promotion of Roaccutane, at the EADV Conference, never asked the audience whether they had any experience of depressive or any other side effects of the drug despite a statement by Professor Cunliffe to the contrary. The letter once again expressly asked the question " what medication were these 55 to 60 dermatology patients prescribed?". The letter also refers to the figure of 6 cases of suicide quoted by Professor Cunliffe, and asks whether Professor Cunliffe is satisfied that the total number of suicides (world-wide) reported to Roche, in the period from introduction of Roaccutane is six.
(VI) Letter from Professor Cunliffe dated the 16th March 1998. The letter refers to the EADV Conference and states that the audience consisted of about 500 doctors and "no-one in the audience have had clinical problems of suicide in patients while on Roaccutane when this questioned was raised". Point 2 of the letter states " what I can state quite categorically is that no patient was on or had just had, or had previously received oral Isotretinoin. Point 3 states " yes, I have had much contact with Roche over the years. Again, as the data is confidential to Roche, and as I am a third party I cannot disclose information to a fourth party.
(VII) Letter from Mr. [Name blanked out] to Professor Cunliffe dated 23rd March 1998.
Point 1 of letter encloses memorandum of attendance by Mr. [Name blanked out] at the EADV Conference and refers to the fact that the audience was not asked byProfessor Cunliffe, or any of his colleagues who spoke on the promotion of Roaccutane, whether they ever had a patient who suffered from depressive symptoms or psychiatric disorders. Indeed, the audience were not asked any questions whatsoever. The letter also refers to the other issues previously referred to. Point 6 of the letter requests Professor Cunliffe to disclose - the level of financing made available by Roche to the Dermatology Department at Leeds University and the level of financing that Professor Cunliffepersonally obtained from Roche.
(VIII) Letter from Professor Cunliffe dated 15/04/1998 stating that he had sought advice from the Medical Defence Clinic who had advised him that it would be inappropriate for him to enter into further correspondence.
Similar type correspondence was issued by Professor Cunliffe to other prescribing doctors/patients. Points arising from correspondence:
- Professor Cunliffe disclosed that there were 6 cases of suicide reports held on Roche data base at January 1988. In fact, Roche had produced a limited list of 170 cases of suicide/suicide ideation at December 1997 see appendix 3.
- Professor Cunliffe appears to have told deliberate lies concerning what emerged at the EADU Conference held in September 1997
- Professor Cunliffe, who spent the years from 1980 to 1997 promoting Roaccutane for treatment of acne, claims that not one of the 50/55 acne patients he treated who attempted/committed suicide were treated with Roaccutane, but failed to identify what acne treatment had been prescribed to these 50/55 patients. It is curious that Professor Cunliffe who produced endless published studies promoting Roaccutane, would have treated none - not even one of the 50/55 acne patients with Roaccutane. Appendix 2, contains a copy of the newspaper report in The Irish Times dated 12th September 1997 where Professor Cunliffe is quoted as stating that " 50 of his patients with acne had attempted suicide and 7 had succeeded. It is a terrible problem for some people but it is important to remember that there are very good treatments available."
5. Published scientific journal articles on side effects of Roaccutane/Isotretinoin linked to psychiatric disorders
A significant number of published scientific articles are available setting out information on the side effects of Roaccutane.
Appendix 4 contains a summary of twelve published articles produced by a range of medical doctors/scientists setting out results of clinical trials and other studies showing the link between the ingestion of Roaccutane and the development of a number of serious psychiatric disorders including depression, psychosis, and on rare occasions, suicide, suicide attempt and suicide ideation. By contrast, articles produced by Professor Cunliffe and his colleagues at Leeds, (referred to in point 6 of this submission), make little or no reference to side effects of Roaccutane.
In fact, the Professor Cunliffe/Leeds articles not alone ignore the serious side effects but appear to be solely devised to promote increased use of Roaccutane. Appendix 4 also sets out a copy of the twelve published studies on the link between the ingestion of Roaccutane and emerging Depression. These are published articles that have no connection with Professor Cunliffe/Leeds University.
6. Published articles by Cunliffe and his colleagues at The General Infirmary at Leeds/University of Leeds
Professor Cunliffe is shown to be the author/co-author of 419 published articles listed in Pub Med. More then 50 published articles by Cunliffe and his colleagues at Leeds relate to Roaccutane. Some of these published articles promote increased use of Roaccutane and encourage the use of Roaccutane outside the prescribed licence (i.e. recommend the use of Roaccutane for moderate and mild acne). The Cunliffe /Leeds articles make no reference whatsoever to the fact that Roaccutane has been linked to psychiatric disorders including depression, psychosis, and, on rare occasions, suicide, suicide attempts and suicide ideation (featured in the label package insert warnings since 1997/1998).
This must be viewed with extreme suspicion given that Articles.htm and Roche have both formally acknowledged that Articles.htm has been in the pay of Roche and in receipt of significant income, financial and non-financial benefits from Roche since the early 1980s. There is also a very high probability that the Dermatology Department at the University of Leeds and the associated Trust, incorporating the Leeds Teaching Hospitals, have also been in receipt of significant financial support from the manufacturers of Roaccutane. It is significant that all of the published articles ominously display the fact that the authors (such as Cunliffe, Layton, Goulden, Cotterill) are attached to the General Infirmary at Leeds/University of Leeds, which add greater credibility to the said published articles.
Around 1980, Roche applied for a license to sell Roaccutane in the U.K. As part of the licensing process it was necessary for Roche to carry out pre-trial studies. Articles.htm and Leeds Hospital conducted the pre-trial studies for Roaccutane in the U.K. on behalf of Roche. The drug obtained a license from the MCA (U.K. Health Authority) in 1983.
It was observed that a correlation between separate investigations initiated by the Norwegian and French Government Health Authorities on psychiatric disorders associated with Roaccutane coincided with publication of articles by Cunliffe which articles sought to dismiss increased concerns expressed with regard to psychiatric side effects. It is considered necessary to make reference to some of these articles, referred to hereunder.
Appendix 5, attached is a copy of article published in the British Journal of Dermatology 107,583-590 (1982) which refers to a double blind study of the effects of retinoic acid on acne. Three of the four authors are described as being associated with Leeds Universities, Department of Immunology and Departments of Dermatology, The General Infirmary Leeds and St. James' (University) Hospital Leeds. The article was accepted for publication on the 10th March 1982. The only side effects disclosed are cheilitis and dryness of the skin.
The article under the acknowledgements section states " we wish to thank Roche Products Ltd (in particular Dr. A.J. Miller) for providing the drug (Roaccutane) and financial support, also Ms. V.B. Cimiech and Mr. R.A. Foster (employees of Roche) for their technical expertise.
Appendix 6, is a copy of an article published in the British Journal of Dermatology 108,333-343, 1983 viz " Dose-response study of 13-cis-retinoic acid in acne vulgaris" Two of the authors viz D.H. Jones and Articles.htm are described as being attached to the Department of Dermatology, the General Infirmary, Leeds and St. James (University) Hospital, Leeds. One of the four authors, A.J. Miller is described as Head of Clinical Research, Roche Products Ltd., Welwyn Garden City, Herts. The article was accepted for publication on the 30th July 1982, prior to the introduction of Roaccutane in the United Kingdom.
The acknowledgements state " we wish to express our thanks to Roche Products Ltd. for supplying the drug and Dr. D. Daltrey, Mr. R.A. Foster and Ms. V.B. Cimiech (employees of Roche) for invaluable technical help and advice. The article indicates that one of the co-authors was A.J. Miller, head of Clinical Research, Roche Products Ltd. On page 341 the authors state " the clinical side-effects are similar to those seen in Vitamin A toxicity'' (Kligman, A.M. Layton, J.J. and Mills, O, 1981).
The article states that although side effects were frequent, the drug schedule had to be altered in only 3 patients and that these 3 patients were excluded from the study.
It seems that 3 patients were excluded from the study because of side effects, yet no explanation or details of side effects are provided in respect of these 3 patients. Table 2 in the article sets out % incidence of side effects which shows 16% of patients suffered malaise, yet no further details or explanations are given.
It is incomprehensible that 3 patients were excluded from the study and from the results referred to in Table A and that no disclosure is made on the side effects suffered by these 3 patients. When Roche are forced to withdraw drugs because of serious side effects, they normally issue P.R. statement that it was the dosage, not the drug, that caused the A.D.R.'s. It is significant the Professor Cunliffe, in the Roche financed study, used the dosage to eliminate A.D.R.'s suffered by the three patients excluded from the study results.
Cunliffe/Leeds Hospital/Promotion of Roaccutane:
Appendix 7 is a selection of published articles where the author/co-author is Professor Cunliffe or other members of the Dermatology Department, the General Infirmary of Leeds/University of Leeds. These articles promote increased use of Roaccutane with no reference whatsoever to depressive/psychiatric side effects of the drug. · 1982 article appears to dismiss severe ocular side effects. Photophobia for example, is a known side effect of Roaccutane treatment. · 1993 article sets out 'Factors which may predict the need for more than one course of treatment.' · 1995 article sets out why Roaccutane should not be confined to treatment of cystic acne and should be extended to treatment of "moderate acne" and that it can be considered cost effective. · 1993 article describes 10 years experience of oral Isotretinoin - no long term side effects - it is "a safe and effective therapy - repeat courses encouraged." · 1993 article entitled "Isotretinoin - 10 years later: A safe and successful treatment." Appendix 8 is a copy of articles and journals collected at the Roche stand at the EADV Conference held in Dublin in September 1997. The articles feature Cunliffe and other colleagues at Leeds as the authors/co-authors and many of these articles suggest that Roaccutane/Isotretinoin should be used more extensively in the treatment of mild and moderate acne including the promotion of increased uses for younger and older patients. The appendix includes: -
- 1991 Cunliffe was co-author of article entitled "Cost effectiveness of Isotretinoin/Roaccutane" (J. Dermatol 1991:1:285-288).
- 1996 Layton - Long-term safety and efficacy of Isotretinoin in less severe acne.
Appendix 9 includes copy of the following article; -
'Suicide in Dermatological Patients' published in the British Journal of Dermatology 1997 - 137:246-250, written by J.A. Cottrill and W.J. Cunliffe (General Infirmary at Leeds), accepted for publication on the 19th March 1997.
It appears that this article was intended to be used to put forward the idea that young people with acne (normally in the age group from 13 - 22) were somehow more prone to suicidal thoughts or actions. This article is extensively quoted by Professor Cunliffe, representatives of Leeds, Roche and other persons, particularly medical people in the pay of Roche. Yet the article has no bearing whatsoever to ordinary young people who suffer from acne.
Another significant matter with regard to this article was the date that the article was accepted for publication on the 19th March 1997, which co-incided with decision by the French Government Health Agency on the 3rd March 1997 to apply suicide warnings on label packaging for Roaccutane, because of the studies and adverse reaction reports from Roaccutane which were of grave concern to the French Authorities (referred to later in this submission).
Appendix 10 sets out a critical review of the above article. The review also highlights how the article relates to a study of 16 patients referred to the General Infirmary at Leeds and Lasercare Care Clinic, who are subsequently known to have committed suicide. The article makes references to 16 patients having been reviewed. Case details are only shown in the article in respect of 9 patients i.e. patients numbered one to eight and patient number 10. It is significant that only one of the cases disclosed related to a patient with acne and it is also significant that no disclosure is made with regard to the medication prescribed to the patients reviewed.
This article is widely quoted as giving support to a proposal that people with acne have a greater propensity to suicide. Roche feature the article extensively in defence of submissions that Roaccutane causes depression. Yet, only one of the 16 patients reviewed in the article was receiving treatment for acne. The patients featured include a 51 year old person with a ten year history of severe manic depressive psychosis who was receiving treatment for psoriasis, a 57 year old woman with delusions of parapsytosis and a long history of alcoholism and depressive illness, a police officer who had scabies and was undergoing a laminectomy for chronic back pain, a 50 year old female with threadveins on legs who attempted to kill her son with a bomb which was unsuccessful, a 26 year old unemployed woman with complaints of excessive facial hair and thinning of scalp which patient had past history of violent behaviour and threatened to kill her dermatologist, a 34 year old with facial burning and excessive redness had dysmorphovia, a 73 year old male well with systematic sclerosis, a 71 year old male with psoriasis etc.
Promotion of increased use of Roaccutane in the treatment of mild/moderate acne:-
Appendix 11 sets out a selection of articles by Professor Cunliffe and colleagues at Leeds, including others, whereby the author's promote increased use of Roaccutane for the treatment of mild and moderate acne.
For example, the article titled ' Current Indications for Isotretinoin as a treatment for acne vulgaris, author's Goulden, Cotterill, Layton, and Cunliffe (of Leeds) refers to a survey conducted at Leeds Infirmary which showed that 74 % of patients treated with Roaccutane had mild or moderate acne (this is despite the fact that the license is restricted, as previously outlined, and therefore Roaccutane was being prescribed outside the license conditions).
Another article for Roaccutane treatment guidelines (by Cunliffe) states " all physicians used oral Isotretinoin in patients with moderate acne that had failed to respond to long-term antibiotics". The article states that the U.K. and Italy, such places represented the greatest number of patients so treated, " the U.K. at 74 - 76% and Italy at 50%.
These articles illustrate that Cunliffe and his colleagues at Leeds were actively engaged in encouraging use of Roaccutane outside the licensed conditions.
It is also significant that none of the Cunliffe/Leeds articles referred to in Appendices 7 to 11 make any reference whatsoever to psychiatric side effects, despite the fact that such side-effects had been well publicised as referred to in point 5 of this submission.
Professor Cunliffe Attendances at Conferences to promote Roaccutane on behalf of Roche It has been established that Professor Cunliffe attended a number of conferences each year, including World Health/Dermatotology Conferences where he made presentations promoting Roaccutane, on behalf of Roche. These presentations presented slides, promotional materials, data and statistics produced by Roche. The presentations by Professor Cunliffe made no reference whatsoever to psychiatric or other serious side effects of Roaccutane. Professor Cunliffe obtained fees and expenses from Roche in respect of such presentations. It appears that Professor Cunliffe may have some form of contract with Roche for many years to cover his presentations on behalf of Roche in different countries at different events.
7. Investigations on side effects of Roaccutane commissioned by the Norwegian Health Authorities 1990/1993
In or about 1990/1992, the Norwegian Health Authority became concerned with regard to the number of C.N.S. and psychiatric disorders associated with the ingestion of Roaccutane which received significant media coverage during that time. A Roaccutane Patient Association was set up in Norway in 1990, founded by 30 Norwegian people who had been prescribed Roaccutane and who had suffered severe physical and psychiatric disorders. Many of these patients had to be referred for psychiatric treatment arising from the side effects suffered from ingestion of Roaccutane.
Appendix 12, is a copy of article published in the British Journal of Dermatology (1994) 131,360-363 entitled ' Long Term Safety of Isotretinoin as a treatment for acne vulgaris ' The article was written by Goulden, Layton and Cunliffe, Department of Dermatology, General Infirmary at Leeds (accepted for publication on the 6th December 1993). The article assesses " possible long term side-effects of Isotretinoin Therapy in 720 patients."
The article states the following:
"The media, however, have recently published the cases of 21 Norwegian patients who are claiming to experience persistent and severe long-term side effects following a course of Isotretinoin. These are reported to have started two or more years after treatment and include numerous symptoms, some of which also occurred during treatment, such as, arthrilgia, myalgia, malaise, headache and nausea, as well as a variety of other symptoms including memory loss and insomnia. Many of the patients claim their symptoms are so severe that they are unable to work …."
The Cunliffe/Leeds article is apparently based on follow up of 720 patients who allegedly attended at Leeds. The analysis shown of those patients are as follows:
Number of years after the cessation of treatment
Our committee collected documentation from the UK showing the number of tablets and also the number of people prescribed Roaccutane in the period from date of introduction in or about 1982/1983 to the present date. The number of people prescribed Roaccutane in the early and mid-1980s in the U.K. was negligible.
The article was submitted for publication in 1983. The 121 referred to above, would have completed the Roaccutane between 8 and 12 years previously i.e. completed Roaccutane treatment sometime between 1981 and 1985. Roaccutane was not on the market in 1980 to mid 1983 and the number of people prescribed Roaccutane between the date of introduction to 1985 was negligible. It is interesting how Professor Cunliffe and his colleagues could have obtained data on ex-patients within a matter of months, covering a span of 12 years.
We believe that results presented in some of the published articles by Professor Cunliffe/Leeds, including the above, are fictitious.
We obtained information from patients who suffered severe physical and psychiatric side effects from Roaccutane who were prescribed Roaccutane by Professor Cunliffe/Leeds at the pre-trial studies. We have also obtained copies of the most incomplete records in respect of patients treated with Roaccutane at Leeds.
Study commissioned by the Norwegian Health Authority:
At the end of the 1980s, reports were delivered to the Norwegian Adverse Reaction Committee ("Bivirkningsnemda") containing suspected long- term side effects of Roaccutane. This experience was reported in a preliminary form at the 18th World Congress of Dermatology in June 1992. The Norwegian Health Authorities wanted an assessment of the reported side effects by an independent, non-Norwegian group of experts. Via contact with the Swedish Medical Products Agency (MPA) a commission consisting of two dermatologists (Liden and Vahlquist), one rheumatologist (Woolheim) and one representative of the MPA (Wiholm) was appointed. Cunliffe is quoted as stating at the 1992 Conference that " Long Term side effects of Roaccutane do not exist."
The Commission was asked to evaluate 30 Norwegian adverse reaction reports registered in respect of Roaccutane between 1986 and 1992 and to perform investigations which were considered necessary to clarify the issue. Among these were 20 patients who complained of persistent central nervous system symptoms such as tiredness, sleep disturbances, depression, headaches, vertigo, impaired memory, 16 had persistent musculoskeletal symptoms (myalaga, arthralaga, muscular tiredness etc.). Professor Cunliffe/Leeds University was appointed to participate in the study.
In due course, a report was formulated and submitted in 1993 (appendix 13). The report covers 11 pages plus appendices. A substantial part of the report refers to investigator number five (Great Britain) who is Professor Cunliffe and his colleagues at Leeds. The report states: -
" This is a unique study from one of the leading centres in the World where acne has been the main scientific interest since about two decades, i.e. the Department of Dermatology, the General Infirmary of Leeds. Over the years a whealth of data has been collected, including information regarding long- term adverse effects of Isotretinoin. These data now have been compiled and are presented in a preliminary manuscript. Our committee got permission to refer the main results of this manuscript, written by Dr. Goulden, Layton and Cunliffe. It describes the long- term safety of Isotretinoin in 720 acne patients followed for 12 years post treatment. Each patient was seen at follow up visits with four to six month intervals. At each visit the patients were asked to report any symptoms experienced since the previous visit, then directly asked to report any symptoms related to skin, eyes and joints (No question on depressive, CNS or similar side effects). For each report a possible side effect severity was assessed, investigation where appropriate was carried out and treatment if necessary documented."
The report then proceeds to effectively incorporate the data contained in the Professor Cunliffe/Leeds published article referred to in appendix 12.
The report states the following:
The authors (Goulden, Layton and Cunliffe) emphasise that the reported persistent adverse experiences were all mild or had other explanations than adverse drug effects. "Since no control material is available, it is impossible to evaluate the causal relation between the merging symptoms and the treatment."
Our investigations to date in respect of Norway:
We received a considerable amount of documentation on the situation in Norway, including information with regard to the number of trips made by Professor Cunliffe to Norway during the time when the increased publicity/media attention was focused on psychiatric side effects suffered by patients in respect of Roaccutane.
We believe that there is very strong evidence to indicate that Professor Cunliffe at the behest of Roche, produced the article entitled ' Long term safety of Isotretinoin as a treatment of acne vulgaris.' That the sole purpose of producing this article was to dampen, diminish, and neutralise the adverse publicity in Norway and effectively to dismiss the complaints expressed by a number of Norwegian people who suffered severe side effects from Roaccutane. We also believe that the data and tables referred to in the article are fictitious.
We should point out that certain of the other parties who participated in the compilation of the report submitted to the Norwegian Authority are the subject of separate investigations.
8. French Health Authority investigation leading to Suicide Warning for Roaccutane introduced on the 3rd March 1997
The French Government Health Agency introduced increased label warnings for Roaccutane on the 3rd March 1997. A study took place in France from 1992-1996, on the association of depression with Roaccutane/Isotretinoin. The results of this enquiry were presented at the 3rd forum of the National and Provincial Journal of Dermatology at Mount Pelier on the 14th / 17th March 1996. The new warning on the information leaflet introduced by the French authorities on the 3rd March 1997 stated " in rare occasions, neuro-psychological problems have been recorded, behavioural difficulties, depression, convulsion and suicide attempts (Appendix 14 sets out copy of the French warning). It should be noted that in 1992 the French label warning expressly featured depression as a side effect of Roaccutane.
It is essential that the part played by Professor Cunliffe and his colleagues at Leeds University in relation to attempts by Roche to suppress, diminish or prevent the French authorities from introducing the increased label warning for Roaccutane be fully documented, including the various representations, attendances by Professor Cunliffe in efforts to avoid the application of the increased warning in France.
There is evidence that Cunliffe, in response to request by Roche, published the article 'Suicide in Dermatological Patients' referred to in Appendices 9 and 10 as a direct response to the increased pressure placed on Roche in the years up to the date when the increased label warning in France featuring suicide as a possible side-effect was first introduced on 3rd March 1997. It is more than just a coincidence that the Cunliffe Article was published on the 19 March 1997, being the same month when the French Health Authority included suicide as a potential side effect of Roaccutane.
A review of the financial transactions between Professor Cunliffe and Roche at dates coinciding with the French, Norwegian and other studies is essential.
9. Increased label warnings for Roaccutane featuring severe psychiatric disorders, suicide, suicide attempt, suicide ideation
Appendix 15 sets out increased label warnings for Roaccutane applied in the U.S., U.K. and other countries in 1998.
Appendix 16 sets out copy of report produced by Dr. T.V. Middelkoop entitled Roaccutane/Isotretinoin - review of psychiatric adverse reactions (dated August 1998).
Appendix 17 (click here) is copy of published articles by Dr. Middlekoop published in the Journal of Pharmacy Practice vol. Xiii, No. 5/October 1999.
By letter dated 30/07/1998 Roche disclosed that there were 40,000 adverse drug reaction reports for Roaccutane/Isotretinoin held on the Roche data base at May 1998. Over 20,000 adverse drug reaction reports were disclosed on the World Health Organisation data base in respect of Roaccutane at September 1997.
The published study referred to in appendix 17 showed the following ADR reports in respect of the United Kingdom -
UK Data:
Professor Cunliffe and his colleagues at Leeds would have been familiar with adverse drug reaction reports in the U.K. for the six prescription medications principally used in the treatment of acne. They would also have had access to the M.C.A. who had readily available data on the number of prescriptions for these medications prescribed by U.K. hospitals. The statistics speak for themselves.
Professor Cunliffe and Leeds ignored the above statistics. Instead, they adopted the Roche P.R. stance that acne causes depression and that ADR reports for Roaccutane are simply a reflection of depression in the general population. These statistics are even more chilling when it is a fact that less than one in ten serious ADR's are ever reported or formally recorded.
Following the introduction of increased label warnings for Roaccutane, featuring psychiatric disorders and suicide ideation, we were informed that certain dermatologists were making representations that Professor Cunliffe was working on a survey which would prove that Roaccutane did not or could not cause depressive symptomatology. We received copies of the enclosed leaflet (appendix 18 (click here)) from a number of patients who had suffered psychiatric disorders from Roaccutane and who stated that they had received the leaflet referred to in appendix 18 from the prescribing dermatologists after the increased label warnings had been introduced. These patients stated that the prescribing dermatologists had actually quoted Professor Cunliffe in reassuring the patients that Roaccutane did not and could not cause depressive side effects despite the fact that suicide featured as a possible side effect on the label warning, when the leaflet was being distributed.
It will be noted that the leaflet contains the names of Dr. Gawkrodger, Dr. Tony Chu (consultant dermatologist, Hammersmith Hospital) and Bill Cunliffe (Professor in Dermatology, Leeds General Hospital).
Tony Chu has a long association with Roche in an independent capacity and also as one of the founder members of the Acne Support Group established in the United Kingdom. Since making the submission Dr. Gawkrodger appeared on BBC Radio 4 program on 20/02/01 on behalf of Roche to defend Roche statement that the drug does not cause depression.
We initially made enquiries with The Irish Medicines Board in order to investigate who produced the leaflet referred to in Appendix 18. We subsequently obtained a letter from Roche dated 6th September 1999 which stated, " that the leaflet was neither instigated, nor produced, by Roche."
We require an explanation with regard to whyProfessor Cunliffe decided to produce, print and circulate the leaflet. We also raise the question as to why Professor Cunliffe, after the introduction of increased label warnings featuring severe psychiatric illness including suicide/suicide attempt attributed to the ingestion of Roaccutane, could be so irresponsible as to participate in the production of a leaflet which effectively was circulated in order to dismiss the increased label warnings that had been applied by U.K. Medicines Control Agency. We suspect that Roche engaged Professor Cunliffe to produce the leaflet.
Appendix 19 is a copy of the presentation presented by Gawkrodger (Sheffield) at the British Association of Dermatology annual meeting, referred to in the leaflet. The leaflet states that the said report showed that prior to Roaccutane 16% of patients had clinical depression which disappeared at the end of a course of Roaccutane. The leaflet also states that " this data is very similar by Layton 1997 which showed a much greater improvement in the psycho-social skill aspects of acne sufferers after Roaccutane, as compared with oral antibiotics. Dr. Gawkrodger appeared on BBC Radio 4 program on 20/02/01 on behalf of Roche to defend Roche statement that the drug does not cause depression.
Appendix 20 is copy of FDA public letter of warning issued to Roche after introduction of increased label warnings in the US in March 1998. The FDA forced Roche to withdraw adverts which claimed that Roaccutane can stop emotional suffering, depression and poor self image.
Roche would have been subjected to the same restrictions in the United Kingdom. However, they appear to have used the services of Professor Cunliffe to produce the leaflet and other similar tactics to get home a message that Roaccutane was a safe drug and which effectively dismissed the increased label warnings that had been applied. A 1997 Layton published article indicated that Roaccutane effectively reduces depression and was identical to the representations made in the Roche U.S. adverts which the FDA forced Roche to withdraw in 1998.
11. Previous submission made to the Leeds Teaching Hospital/University/General Infirmary at Leeds
Appendix 21 (click here) contains references to the previous submission made by Mr. [Name blanked out]to Leeds Hospital/University/General Infirmary at Leeds.
12. Manner in which General Infirmary at Leeds are dealing with genuine enquiries from patients who suffered severe psychiatric disorders arising from ingestion of Roaccutane
As previously outlined, we are in touch with a large group of people from most countries where Roaccutane was sold over the past several years, including people who suffered severe physical and psychiatric disorders from the ingestion of Roaccutane. We are also in contact with a group in excess of 200 people in the United Kingdom who claim to have suffered severe disorders from the ingestion of Roaccutane.
Many people in the United Kingdom who suffered serious side effects sought medical details from the prescribing doctor/prescribing hospital, such as medical records with regard to their attendances for the prescribing of Roaccutane, seeking copy of blood tests on basis that a blood test is a requirement before and during treatment on Roaccutane and also seeking other general information on their medical records held by the prescribing doctors/prescribing hospitals.
It would not be an understatement to say that the General Infirmary at Leeds have been uncooperative and in fact, perhaps, obstructive with regard to the provision of basic information to patients prescribed Roaccutane who suffered side effects from the drug. Where information was provided, such information was extremely deficient. Hopefully, the attitude of the General Infirmary at Leeds will now change and a policy decision at Board Level will be made to provide all information, records, data, copy of blood test results, all medical records etc, to U.K. patients or representatives of patients who request such information. Records obtained from patients who participated at the Roche pre-trial studies, at Leeds, and who suffered severe short and long-term effects need to be investigated and reviewed.
13. Matters requiring independent investigation in respect of Professor Cunliffe and colleagues of Professor Cunliffe/General Infirmary at Leeds/University of Leeds
(I) That Professor Cunliffe knowingly and wilfully, colluded with the manufacturers of Roaccutane/Accutane, Roche/Hoffman La Roche, in a course of action that concealed the known serious physical and psychiatric side effects of Roaccutane.
(II) That Professor Cunliffe generated published studies and engaged in actions with the collusion of Roche, which had the sole or principal aim of diluting, negating, diminishing and concealing the known serious side effects of Roaccutane.
(III) That even after the increased label explicit warnings applied for Roaccutane in the U.S. throughout the 1980's, in France on 3rd March 1997 and applied in other countries in the early part of 1998, [Name blanked out] continued to publish studies and participated in the preparation of leaflets solely or mainly aimed at diluting, negating, diminishing and concealing the known serious side effects reflected in the increased label warnings inserted in the packaging for Roaccutane.
(IV) That Professor Cunliffe, and the Dermatology Dept. of Leeds Hospital and Leeds University, engaged in practices which seriously put at risk patient safety. Not alone the safety of patient's attending at Leeds but also, arising from published studies, so effectively used by Roche in the promotion of Roaccutane, put at risk the safety of patients in every country which sold Roaccutane/Accutane.
(V) That throughout a period of almost 20 years, Professor Cunliffe at Leeds were in receipt of fees, financial and other benefits from Roche which they failed to disclose either in published studies, attendances at Dermatology Conferences in countries marketing Roaccutane, where they lectured on the safety of Roaccutane and promoted increased use of Roaccutane outside the license and for younger and older patients.
(VI) That Professor Cunliffe produced published studies based on fictitious or partly fictitious data.
(VII) That Professor Cunliffe was motivated by financial or other benefits obtained by him from Roche/Hoffman La Roche and/or connected companies.
Requirements:
1. We require disclosure on all financial and other benefits made by the manufacturers of Roaccutane to the individuals and institutions referred to in point 2 of this submission in respect of each of the years from 1979 to date viz. Professor Cunliffe and [3 Names blanked out], General Infirmary at Leeds, University of Leeds and associated organisations.
2. Such documentary and other evidence to verify the payments and other benefits previously referred to.
3. Disclosure on the identity of the two persons appointed by Leeds to review previous submission. Details on the investigation carried out by the said parties.
4. The immediate appointment of an independent group/committee, consisting of legal, medical and other persons who ideally should be previously disclosed and approved by our committee, to investigate all of the matters referred to in the submission. Such parties must have no prior connection with Leeds Dermatology Department, prescribing of Roaccutane, or the manufacturers of Roaccutane.
5. A protocol to be produced in advance setting out terms of reference, the powers conferred on the investigating committee together with an undertaking by Leeds that the full unedited text of interim reports and final reports/conclusions shall be made available to us within a specified period.
6. Disclosure on the findings of the auditors appointed by Leeds to investigate the financial matters referred to in the submission.
7. Disclosure on the extent to which the underlying data featured in the several published studies by Professor Cunliffe, his colleagues at Leeds, shall be independently examined in order to determine whether such data is based wholly or partly on fictitious records, incomplete records, and/or data produced by Roche. Whether articles and tables of data are a true reflection of the data in respect of patients treated at Leeds.
8. A comprehensive investigation on Professor Cunliffe and [3 Names blanked out] in respect of their financial involvement with Roche. The extent to which Roche used these parties to precipitate published studies that were aimed or intended to be used to neutralise the serious side effects attributed to Roaccutane and to promote increased sales.
9. To investigate the authenticity of each of the circa 60 published articles by Professor Cunliffe and his associates in respect of Roaccutane/Isotretinoin and related topics.
10. To investigate the survey conducted by Professor Cunliffe at Leeds which purported to show that 74% of U.K. dermatologists prescribed Roaccutane for moderate and mild acne, in contravention of the license conditions that applied and to determine whether such study was based on fictitious or partly fictitious data.
11. To immediately provide an agreed independent party or organisation with a copy of the data recorded by Professor Cunliffe in respect of pre-trial studies. To obtain affidavits from those who participated in those studies as to whether data was misrepresented or manipulated. To make public full details on the 3 patients who suffered severe side effects in 1982 which 3 patients were excluded from the study results, as previously referred to.
As you know, I made my initial submission in May 1998, which is more than 2 years ago. In correspondence Leeds representatives refused to identify the two consultants engaged by Leeds Teaching Hospital to investigate the matters referred to in my previous submission. Also, Leeds representatives refused to meet with me or representatives of my committee and also refused to allow me meet with the two consultants. At this point, I would ask that you set out a time scale in which you intend to provide a full and detailed response to this submission. On the last occasion, you dealt with the detailed submission in a one paragraph response. You failed to make any reference whatever to any of the matters referred to in the submission, which is entirely unsatisfactory.
I trust you will let us have a detailed response as soon as possible.
Committee Chairman Roaccutane/Accutane Action Group,
127 Lower Baggot Street,
Dublin 2,
Tel: 353 1 6612033,
Fax: 353 1 6618107
Dated 4th August 2000
10th May 1998 Submission submitted to Leeds Hospital (PDF 9 pages 809KB)
5th August 1999 Letter from by Leeds Hospital (PDF 1 page 132KB)
1st December 1999 Letter from Leeds Hospital (PDF 2 pages 192KB)
3rd August 2000 from Leeds Hospital (PDF 3 pages 513KB)
4th August 2000 Submission submitted to Leeds Hospital
26th January 2001 from Leeds Hospital (PDF 5 pages 506KB)
A number of the forms listed above are stored in PDF format. To view them you must have Adobe's Acrobat PDF Reader.
AppealWe appeal to any patients or medical person who was involved in any studies on Roaccutane/Isotretinoin at Leeds Hospital or Leeds University or such studies under the control or direction of Professor W.J. Cunliffe to please make contact with our organisation. A procedure is in place which shall ensure absolute confidentiality. We also appeal to any medical person who was involved in any studies on roaccutane/isotretinoin at Leeds Hospital or Leeds University or such studies under the control or direction of Professor W.J. Cunliffe to please make contact with our organisation. A procedure is in place which shall ensure absolute confidentiality. |
We can be contacted in any of the following ways:
Roaccutane Action Group 13, Upper Fitzwilliam Street Dublin 2, IRELAND |
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