Dr. Susan Jick, D.Sc., Roaccutane / Accutane

127 Lower Baggot Street,

Dublin 2,

Ireland.

Tel: +353-1-6612033

Fax: +353-1-6618107

Dr. Susan Jick, D.Sc.

Boston Collaborative Drug Surveillance Program,

Boston University School of Medicine,

11 Muzzey Street,

Lexington

Massachusetts, USA 02421

15^thAugust 2001

By Email: sjick@bu.edu and by Fax: 001-781 862-1680

Re: Isotretinoin Uses and Risk of Depression, Psychotic Symptoms, Suicide, and Attempted Suicide.

Arch Dermotol/Vol 136 Oct 2000

Dear Dr. Jick,

For the past four years I have been engaged with others in the investigation of depression, psychosis, suicide ideation attributed to the ingestion of Accutane/Isotretinoin. I have commissioned and financed studies some of which are ongoing. Some of these studies compare adverse reactions (ADR’s) for isotretinoin with ADR’s for antibiotics. I enclose copy of one of those studies, Appendix 1, published in the Journal of Pharmacy Practice, prepared by Dr. Middlekoop, which showed the following:

UK ADR Data (source MCA)

Drug	No. of Prescriptions	Psychiatric ADRs	Suicide	Suicide Attempt	Suicidal Ideation
Accutane¹	12,400	135	9	8	6
Minocycline	8, 802,900	45	0	0	0
Tetracycline	147, 237,000	32	0	0	0
Oxytetracycline	31,301,700	23	0	0	0
Doxycycline	13,650,000	22	0	0	0
Dianette	1, 214,600	5	0	0	0

¹Data for Accutane cut-off date July 1999

Earliest Reaction date February 15, 1983

Review on ADR’s for Isotretinoin/antibiotics recorded by other national agencies, including the FDA, found that the rate per 100K of ADR’s for Isotretinoin featuring depression/psychosis/suicidal thoughts and actions was more than 1,000 times greater than the combined ADR’s for Minocycline, Tetracycline, Oxytetracycline, Doxycline and Dianatte.

I am anxious to try and understand the reasons why your study contradicts adverse drug reaction reports for Accutane/isotretinoin, given that the drug has attracted the highest rate of ADRs featuring depression, psychosis, suicide, suicide attempt and suicide ideation, recorded by national health agencies in most countries and despite the fact that the number of people prescribed was miniscule compared to other prescription drugs. My colleagues and I are most anxious to fully understand the data and the validity of the conclusions referred to in your study. I would be most grateful if you would let me have the following information in respect of your study:-

1. Study Title

Page 1232 of your study indicates that the specific health disorders reviewed in your study were as follows:

· anxiety disorders, 61%,

· affective disorders, 6%

· noneffective disorders 3%

· mood disorders 29%

· Rounding diff 1%

Total 100%

Page 1233 states you used codes 296 to 301 of the ICD-9 codes recorded in the Saskatchewan (SH) database in respect of the above disorders and ICD-9 E codes from the accident field in respect of suicide or suicide attempt.

My understanding is that ‘code 300 - Anxiety’ in the SH data base mainly consists of agoraphobia with panic, agoraphobia without panic, adjustment reaction and that this classification ‘ Anxiety’ does not normally come within the definition of Depression or Psychotic symptoms. I am not aware of any studies suggesting that Accutane/isotretinoin specifically causes agoraphobia and anxiety and therefore it is not the issue. However, there are numerous independent published studies linking isotretinoin to depression, psychosis and suicide ideation/actions (see details on some of these published studies – Appendix 2). Published studies on depressive disorders based on the SH database exclude anxiety and other codes applied in your study. For example studies conducted by West et al[i] and Rawson N.S.B[ii] excluded codes 300.0-anxiety states, 300.1 hysteria, 300.2 phobic states and others but included 300.4 neurotic depression.

(i) Would you agree that the title of your paper could be considered most misleading and that the results of your study have been seriously distorted because of the inclusion of anxiety disorders, which accounted for 61% of the selected disorders that you decided to tabulate. (ii) Your population size re SH database was 20,895, of which 1777 patients were shown to have suffered one of the above disorders, 61% of which suffered anxiety (1083). Those 1083 were considered to fall within the category of ‘depression, psychotic symptoms’, which I think could represent a major falsification of your conclusions. Would you provide rates applicable where the 1083 cases of anxiety are excluded which I suggest would make your results more relevant. (iii) To clarify matters would you be willing to (a) provide the number of isotretinoin patients and the number of antibiotic patients recorded in respect of each of the codes (three digit SH codes and sub codes of each main code 296 to 301) in respect of the 1777 patients who suffered disorders and the specific 595 patients featured in Table 2 of you study (on which your conclusions are based).

(iv) The study refers to disorders of depression or psychosis. How were patients who suffered more than one of the disorders previously outlined classified.

2. Suicides – SH

(i)Table 3 of your study shows the following data for suicide/suicide attempt:-

	All Subjects	Subjects with no Psychiatric History	Subjects with Psychiatric History
Nonexposed	17	8	9 (53%)
Current Isotretinoin	4	4	0 (0%)
Current Antibiotic	11	3	8 (73%)
Recent Isotretinoin	2	1	1 (50%)
Recent Antibiotic	3	2	1 (33%)
	37	18	19

The table is confined to those within the definition ‘Newly Diagnosed Depression or Psychosis’. What was the total number of suicides and suicide attempts recorded on the database in respect of the sample population of 20,895. How many suicides and how many suicide attempts related to isotretinoin users and how many related to Antibiotic users, how many had a previous psychiatric history. How many of the nonexposed had taken isotretinoin and how many had taken antibiotics.

(ii) Current Users are defined as ‘from date of first prescription through 3 months after receiving the last prescription’. Recent Users – ‘persons having received the prescription 4-6 months previously. Nonexposed Users – ‘all other time after receipt of the study drugs was considered (period beyond last prescription was 6 months)’.

It appears to be quite significant that none of the 4 isotretinoin users who committed/attempted suicide within the ‘current’ use definition had a history of depression (73% of the Antibiotic ‘current’ users and 53% of the non exposed ‘current’ users had a previous psychiatric history).

It is also perhaps significant that only 1 of the 6 combined ‘current ‘and ‘recent’ isotretinoin users (16%) had a previous psychiatric history compared with 64% for combined current and recent antibiotic users.

(iii) Table 3 of your study features data in respect of 37 or 38 patients recorded for suicide or attempted suicide in isotretinoin and Antibiotic exposure status (SH database). There appears to be a contradiction in numbers ---- M14, F 24, total 38 ---- previous depression/psychosis shows No.18, Yes 20, total 38 ---- Nonexposed 17, current Isotretinoin 4, current Antibiotic 11, recent Isotretinoin 2, recent Antibiotic 3, total 37, which please clarify.

3. UK Prescriptions for Isotretinoin

Pg 1233 of the study states "there were 340 isotretinoin users in the UK study who received 650 prescriptions". This is equivalent to 1.94 prescriptions per person. It is most unusual for isotretinoin users to have less than four prescriptions. In any statistics that I have seen the average number of prescriptions for isotretinoin was in excess of circa 5 (equivalent to 5 months treatment). Page 1232 provides details on SH isotretinoin users, which amounts to average of circa 4.93 prescriptions per patient[iii]. Therefore I would expect that the 340 isotretinoin users featured in your study in respect of the UK, would have received circa 1676 (340 x 4.93) prescriptions, which is a substantial discrepancy.

Would you be willing to recheck the UK data in order to clarify this matter. (The UK database appears to be driven by prescriptions/prescription numbers and therefore 650 prescriptions may represent 132 patients rather than 340). Either way it seems to me that this apparent significant discrepancy may well have caused distortions in your calculations and conclusions. Could you also provide a more detailed analysis between number of people/prescriptions.

Understatement in Number of Antibiotic Users

(a) The study indicates on page 1232 “There were 7,195 isotretinoin users in the SH data resource from 1983 to 1997” and that “there were 13,700 Antibiotic users”. The study indicates that some of the cases were excluded (for example cases with less than 6 months previous computer-recorded history and patients with less than 12 months post computer-recorded history). Please state how many actual patients were included which gave rise to the 1,777 patients with so called depression or psychos. Please state how many actual patients were included which gave rise to the 595 disorders featured in Table 2 on which your calculations and conclusions are based. Please state why such numbers were not disclosed in respect of the SH and the UK database.

(b) The ratio of patients prescribed isotretinoin in the treatment of acne compared to patients prescribed antibiotic in the treatment of acne tends to be more than 1:50 (for every one person prescribed isotretinoin there are about 50 people prescribed antibiotics in treatment of acne). Even if I take a ratio of 1:50, I would expect than in the 15 years covered by your study (1983 to 1997), there would be at least 350,000 patients on the SH database who had been prescribed antibiotic in the treatment of acne (7,195 isotretinoin users by 50 times). As previously outlined, page 1232 of your study states “There were 7,195 isotretinoin users in the Saskatchewan data resource and there were 13,700 antibiotic users, 43% were male and 75% were female……most patients with acne treated with antibiotics received tetracycline (64%), followed by erythromycin (22%), minocycline (10%), Doxycycline (5%)”. I respectfully suggest that the number of people that you say are recorded for antibiotic treatment is substantially understated. If the number of patients prescribed antibiotic for acne, recorded on the SH data base in the period covered by your study is even 350,000, then the number disclosed by you viz 13,700 represents a major understatement (350,000/13,700). I must confess that this potential discrepancy is quite alarming. My fear is that you took or were given the 1,771 case disorders and the 595 case disorders as representing the total number of the specified disorders recorded on the SH database in respect of patients using isotretinoin and antibiotic in the treatment of acne. That you were given or assumed that the total number of people prescribed antibiotics for acne recorded on the database was 13,700 (instead of circa 350,000). Could you please clarify all matters previously outlined and provide a detailed analysis, including SH case reference numbers, if possible, in order to clarify this issue.

Person-Years

(i) The tables in your study, summarised below, measured the specified health disorders as a factor of person years.

Person-Years

	Category	Depression/Psychosis	Suicide/ Suicide Attempt
1.	Nonexposed	11655	13894
2.	Current Isotretinoin	3469	4003
3.	Current Antibiotic	9324	11051
4.	Recent Isotretinoin	1455	1678
5.	Recent Antibiotic	4303	5133
	Total person years	30206	35759

Table 2 clearly relates to 30,206 patient years, however, the same table analyses that number as - male 1,438 and female 15,468, total 16,906. Could you please clarify this apparent discrepancy.

(ii) My understanding is that person-years is a measurement combining persons and time used as a denominator in person-years incidence –(for example 300 person years could be equivalent to 300 people over 1 year, or 100 people over 3 years, or 600 people over 6 months).

The review of adverse reactions recorded for medications is normally by reference to the number of adverse events/number of people prescribed (for example rate of X case reports of psychosis per 100K people in respect of isotretinoin, compared with Y case reports of psychosis for antibiotic per 100K). I appreciate that person years is sometimes applied in medical statistical analysis.

(iii) Please state the number of persons in respect of each of the five categories above, to include the number of people for each of the categories above, featured in Table 2 and Table 3, as I would like to do some further calculations that may be of extreme significance:-

(iv) Please provide the individual calculations used in the figures previously outlined (number of persons/individual units of time).

Number of Events (SH database)

(i) Appendix 3, attached is a summary of the key figures featured in Table 2 and Table 3 of your article.

Even if the 1,777 recorded events relate to 20,895 (which is most unlikely for reasons previously outlined), this would be equivalent to 8,504 cases of depression/psychosis per 100K. The ratio of 8,504 per 100K, appears to be substantially more than the ratio applied in other population groups in respect of depression/psychosis. For example, Canadian statistics for 1997 indicate circa 17.1 cases per 100k for psychoses, neurotic disorders, personality disorders and other non-psychotic mental disorders. Can you please explain this discrepancy given that your study purports to measure depression/psychosis. Is this major distortion due to the inclusion of terms that do not come within the accepted terms, which define depression or psychosis.

(ii) Could you provide details on the total number of so called depression/psychosis recorded on the SH database (for example per year/per age group), analysed by each SH code and sub code. This would be most helpful in assessing overall statistics compared with the numbers applied in to your study.

(iii)Table 3 re: suicides/suicide attempt provides data on the number of subjects that had no psychiatric history. Could you please provide information on the number of subjects that had no psychiatric history (prior to taking isotretinoin and separate numbers on prior to taking antibiotics) in respect of the total population 20,895, in respect of the 1,777 and also in respect of the 595 featured in Table 2.

(iv)Table 2 under isotretinoin and antibiotics users shows that there were 61 ‘current’ isotretinoin users and 25 recent isotretinoin users, total 86. Data shown at the bottom of table 2 shows 93 ‘current’ isotretinoin users and 34 recent isotretinoin users, total 127. Could you please explain the apparent discrepancies between the figures previously outlined.

(v)To what extent were records of psychiatrists used or included in the SH and UK database.

7. UK database

I note the figures set out in Table 4 and 5 in respect of the UK database viz.

Table 4 –

Isotretinoin Users - 340

Antibiotic Users - 676

Total 1016

Table 5 (UK data on which study based)

	Total	Isotretinoin	Antibiotics
Nonexposed	27	4	23
Current Isotretinoin	3	3	-
Current Antibiotics	32	-	32
Recent Isotretinoin	2	2	-
Recent Antibiotics	11	-	11
Total person years	75	9	66

(i) Please state the total number of patients who featured depression or psychosis in respect of the 1,016 UK study population. Table 5 indicates that 75 patients suffered depression who fell within the definition shown in table 5 viz. "newly diagnosed depression or psychosis by exposure status, age and sex".

(ii) In the SH data there were 1,777 cases of so called depression/psychosis based on a study population stated at 20,895. It is noted that 595 of the 1,777 cases fell within the ‘newly diagnosed’ definition (circa. 33%). If that statistic applied to the UK data, it would mean that the total number of so called depressions in respect of the UK study population of 1,016, would be circa 3 times more than 75 cases viz circa 225 cases. 225 cases of so-called depression/psychosis in a population of 1016 would be equivalent to 25,098 per 100k. Perhaps you might let me have your comments on this. This may be a further example of major distortions in the data applied in your study.

(iii) Please state the number of patients on isotretinoin and the number of patients on antibiotics who featured depression/psychosis in relation to the full UK study population and also in relation to the 75 featured in Table 5.

(iv) The data in respect of the UK includes the following:

Prescription drug	Total Number of Patients	Number of Depression/Psychosis cases(within definition of tables)	Percentage
Isotretinoin	340	9	2.6%
Antibiotics	676	66	9.8%

Total	1016	75	7.38%

I appreciate that the 1016 patients generated more than 75 disorders on basis that the table only shows disorders for a stated category of patients. However, leaving that aside the above ratios in respect of the UK appears to contract the SH findings and defy ADR data. Could you please provide information on the number of patients/number of cases of depression /psychosis person-years in respect of the UK study similar to that sought in connection with the SH study.

(v) Please provide information for the UK database featured in your study similar to that requested under each heading in respect of the SH database

8. Miscellaneous

(i) On what approximate date were the results of your study or preliminary findings of your study first known to Roche employees/executives. Could you please state what stage your study was at in November 1998.

(ii) I note that your co-author for the study was Dr. Kremers, Global Drug Safely, Roche, Basel, Switzerland. Would you please provide details on the extent to which Roche furnished information/data, the extent to which Roche computers/Roche software was used in collecting, recording, reviewing, analysing or otherwise processing the data, which formed the basis of your study/data featured in tables etc.

(iii) I note your paper discloses that Roche are one of the pharmaceutical companies who finance your organisation (the Boston Collaborative Surveillance Program, Boston University School of Medicine). Proper disclosure has now become an accepted practice and for that reason, would your organisation be willing (a) to disclose financial contributions made by Roche to the said organisations in each of the years from 1996 to the present date and (b) other studies or assignments undertaken or in hand on behalf of Roche either directly or indirectly.

(iv) I note various press releases and press statements attributed to you when the study was first published in October 2000. Reuters Health quote you as stating “people who take acne medication are more likely to be depressed than others. Therefore people who take acne medication are also at increased risk of depression/suicide because they have acne and not because they use accutane”. This would appear to be inconsistent with your findings which indicate that 5 out of 6 isotretinoin users who committed /attempted suicide had no prior psychiatric history. It would be inconsistent with your UK data which showed that the incidence of depression for isotretinoin users (2.6%) was less than the incidence of depression for antibiotic users (9.8%). The Reuter report also states that the authors note that the conclusions drawn from the study are in agreement with the results shown by prior research. Your study results are not consistent with other independent published studies, some of which are listed in Appendix 2. (a) Have you reviewed the Roche or any other ADR database for isotretinoin and compared with antibiotics in treatment of acne. (b) Are you aware that isotretinoin causes pseudotumor cerebri/hypercranial tension and a number of specific central nervous systems disorders which are not disputed by Roche. I enclose a copy of published study featuring survey of dermatologists, which indicated that 72% of patients treated with accutane/isotretinoin had mild or moderate acne. Would you be willing to disclose whether you carried out any overview with regard to ‘isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide’.

I should be very grateful if you would let me have response at your earliest convenience.

Yours sincerely,

Liam Grant

Enc.

By Email: sjick@bu.edu and by Fax: 001-781 862-1680

Arch Dermotol/Vol 136 Oct 2000

Nonexposed

Category

Table 4 –

Total