FOI release

Freedom of Information request on enquiries regarding Isotretinoin including ADR information (FOI 21-024)

Published 24 March 2021

Our Ref: FOI 21/024

Thank you for your email dated 12th January 2021, where you asked for information regarding isotretinoin under the Freedom of Information Act. You requested the following information for the medicine isotretinoin:

• Under the FOI act I would like information on all isotretinoin deaths and homicides, acts of violence and cases of all aspects of sexual dysfunction and infertility? Including the murder of a dermatologist in the US and any court cases where Isotretinoin was implicated.

• Please include information relating to the death of Lata Ferma and let me know if Rafiq Rasheed was ever treated with isotretinoin by Dr Ferma? (India - but relevant information relating to UK safety)

• I know how to access the yellow card data analysis but I have been informed by one of your staff that the information is not always correct.

• I would like world stats if you have this information and or an explanation as to why the MHRA wouldn’t have this information as it does have a direct impact on patient safety?

• Failing to provide world stats I would like you to provide all European stats – I have not been able to access this information despite following the links.

• Failing inability or unwillingness to provide the above information please provide UK information.

• I would specifically ask that you separate and provide all the requested information relating to the dates: Sept 2019 – Jan 2021?

• Please provide me with all information relating to clinical study reports from the clinical trials on Isotretinoin submitted to the MHRA from the pharmaceutical industry – pre and post authorisation.

• I would like to know when the MHRA were first made aware of Isotretinoin induced suicide with no warning signs.

• Roche US were sued between 2002 and 2009 for the suicide of a young male who committed suicide with no warning signs. Did Roche inform the MHRA about this and if not should they have.? If Roche failed to inform the MHRA about suicide without warning did the MHRA learn of it independently?

• Have the MHRA at anytime considered, researched, requested info from Pharmaceutical companies or other institutions , had any meetings to discuss – Isotretinoin induced suicides with no warning signs? Please provides all dates.

Please see the below our response to your request which addresses each of your points in turn.

Under the FOI act I would like information on all isotretinoin deaths and homicides, acts of violence and cases of all aspects of sexual dysfunction and infertility? Including the murdered of a dermatologists in the US and any court cases where Isotretinoin was implicated. Please include information relating to the death of Lata Ferma and let me know if Rafiq Rasheed was ever treated with isotretinoin by Dr Ferma? (India - but relevant information relating to UK safety.

I would like world stats if you have this information and or an explanation as to why the MHRA wouldn’t have this information as it does have a direct impact on patient safety?

Failing to provide world stats I would like you to provide all European stats – I have not been able to access this information despite following the links. Failing inability or unwillingness to provide the above information please provide UK information.

The MHRA does not hold details of worldwide suspected adverse reactions. The Marketing Authorisation Holders (MAH) have a regulatory requirement to hold details of all reported suspected adverse reactions. Cumulative figures are provided in the Periodic Safety Update Reports (PSURs) submitted by the MAHs. Since 2012, MAHs have submitted their PSURs to a repository held by the European Medicines Agency (EMA).

Information on adverse drug reactions in India or the US would be held by the MAH and the regulatory authority in the country where the suspected side effect occurred. The MHRA is aware that a report has been submitted for a homicide in the USA relating to the death of a dermatologist, however, we do not hold the case report. The MHRA is not aware of a case report for Rafiq Rasheed and it is not clear from the publicly available information whether Rafiq Rasheed was treated with isotretinoin.

Reports of suspected adverse reactions reported in Europe are held within the EudraVigilance database by the European Medicines Agency (EMA). As the MHRA does not hold this data, it cannot be provided under FOI. You may wish to request the information directly from the EMA under FOI.

We have therefore provided information for the UK.

Please refer to the table below for the total number of UK spontaneous suspected Adverse Drug Reaction (ADR) reports received for deaths, homicides, acts of violence and sexual dysfunction/infertility in association with isotretinoin. Reports were extracted using the Medical Dictionary for Regulatory Activities (MedDRA) and the search criteria used is detailed below Table 1. Table 1 shows the total number of reports received for each group as well as the number received by the MHRA between September 2019 and January 2021.

1 MedDRA (Medical Dictionary for Regulatory Activities) is a clinically validated international medical terminology dictionary. There are five levels to the MedDRA hierarchy, arranged from the broadest grouping to the most specific terms. Thus System Organ Class (SOC), which is the broadest grouping, is divided into High-Level Group Terms (HLGT), which is divided into High-Level Terms (HLT), then Preferred Terms (PT) and finally Lowest Level Terms (LLT) which are the most specific and of which there are more than 70,000 terms.

Table 1: Number of UK spontaneous Adverse Drug Reaction (ADR) reports received for deaths, homicides, acts of violence and sexual dysfunction/infertility in association with isotretinoin

Number of UK spontaneous Adverse Drug Reaction (ADR) reports

	In Total	Received between Sept 2019 – Jan 2021
Reports with a fatal outcome	99	17
Homicide*	0	0
Acts of violence**	6	0
Sexual dysfunction and infertility***	148	34

PT: Homicide *PT: Violence related symptom or LLTs: Violence, Violent, Violent behaviour, Violent dreams, Violent ideation or Violent thoughts ** HLGT: Sexual dysfunctions, disturbances and gender identity disorders or Sexual function and fertility disorders

When considering the Adverse Drug Reaction (ADR) within the response, it is important to be aware of the following points: • A reported reaction does not necessarily mean it has been caused by isotretinoin, only that the reporter had a suspicion it may have. The fact that symptoms occur after use of a medicine, and are reported via the Yellow Card Scheme, does not in itself mean that they are proven to have been caused by it. Underlying or concurrent illnesses may be responsible and such events can also be coincidental. • It is also important to note that the number of reports received via the Yellow Card scheme does not directly equate to the number of people who suffer adverse reactions and therefore cannot be used to determine the incidence of a reaction or compare the safety profile of different medicines. ADR reporting rates are influenced by the seriousness of ADRs, their ease of recognition, the extent of use of a particular medicine, and may be stimulated by promotion and publicity about a drug. Reporting tends to be highest for newly introduced medicines during the first one to two years on the market and then falls over time. • It is also important to note that the received date may not reflect when the ADR occurred. Cases can be submitted at any time and may include historic cases.

A data lock point of 4th February 2021 has been used to generate the figures provided within the response.

‘I know how to access the yellow card data analysis but I have been informed by one of your staff that the information is not always correct’

Please accept my apologies if you have received incorrect information from one of MHRA staff. The information available on our interactive Drug Analysis Profiles (iDAPs) is regularly updated to reflect up to date information, however there is a delay of around 1 month between receipt of a report and when it appears on the iDAPs page. Information displayed in the iDAPs is always accurate at the time it is uploaded. The figures on the iDAP may change over time if duplicate reports are identified and subsequently merged or if further reports are received. iDAPs are a useful tool allowing users to view all adverse reactions reported for a particular drug substance and also filter the reports, so the charts and tables display subsets of the data, such as limiting to the type of reaction reported. There is guidance at the bottom of each iDAP page around the interpretation of this information provided on the website which is important to read and understand.

‘Please provide me with all information relating to clinical study reports from the clinical trials on Isotretinoin submitted to the MHRA from the pharmaceutical industry – pre and post authorisation.’

Please find attached the following clinical reports that were submitted in 1982 and 1983 to support the initial applications for the brand leader Roaccutane 2.5 mg, 5 mg, 10 mg and 20 mg Capsules (PL 00031/0157-0160):

1. FOI 21024 Redacted Clinical Study Reports (Parts 1-5) submitted with initial appls_Roaccutane 2.5 mg_20 mg Caps PL 0157-0160_fxd.pdf
2. FOI 21024 Redacted Additional clinical reports (concerning bone toxicity serum lipids and CNS toxicity)_Initial appls Roaccutane 2.5 mg_20 mg Caps PL 00031_0157-0160_fxd.pdf
3. FOI 21024_Additional clinical study report Roaccutane and Oral Contraceptive Steroids_ Initial appls_Roaccutane 2.5 mg_20 mg Caps PL 00031_0157-160_fxd.pdf

Clinical trials are generally not conducted after a medicine is authorised, however, other types of studies may be undertaken to evaluate specific issues or safety concerns. If further information is needed, please provide further information regarding the types of studies, time period or the area of concern to help narrow the search. A manual review of all record would exceed 24 hours of work allowed under the FOI request.

Please note that the documentation is historical and variation applications may have been submitted subsequently to update some of the information included.

Please also note that the documentation has been redacted under Section 40 (Personal information), Section 41 (Information given in confidence) and Section 43 (Commercial Interests) of the Freedom of Information (FOI) Act. Disclosure of information subject to Section 40 (Personal information) would be an infringement of personal data. Section 40 (Personal information) is an absolute exemption and no consideration of the public interest is required.

Section 41 (Information given in confidence) is an absolute exemption and no consideration of the public interest is necessary, except to state that the release of this information withheld under this section of the FOI Act would be considered an actionable breach by the MHRA.

We have redacted some parts of the attached documentation under Section 43 (Commercial Interests) of the FOI Act because the release of all, or part of, the information would, or would be likely to, cause harm to the third party’s commercial interests. Section 43 is a qualified exemption and a consideration of the public interest should be made. In this case we have not identified any issues which would benefit the public as a whole by this being brought to their attention.

I would like to know when the MHRA were first made aware of Isotretinoin induced suicide with no warning signs.

The first report of suicide suspected to be associated with isotretinoin was received through the Yellow Card scheme in 1993. Adverse drug reactions are categorised using MedDRA (Medical Dictionary for Regulatory Activities), a clinically validated international medical terminology dictionary. This does not distinguish different subcategories of suicide, such as suicide with no warning signs, as these are not recognised as a separate medical conditions.

The risk of suicide was added to the product information in 1998 and has been kept under review. Psychiatric adverse reactions including suicide are currently being considered by the Isotretinoin Expert Working Group. Please find more information about the group and the public consultation it is conducting here: https://www.gov.uk/government/consultations/isotretinoin-call-for-information-to-be-considered-as-part-of-an-expert-review It is important to note that Yellow Card reports may not include all of the information about a patient’s medical history, risk factors or potential triggers to establish whether or not there were warning signs before their death.

The warnings in the product information reflect what is known and currently state: “Some people have had thoughts or feelings about hurting themselves or ending their own lives (suicidal thoughts), have tried to end their own lives (attempted suicide), or have ended their lives (suicide). These people may not appear to be depressed.”.

Although the current warning in the product information notes that patients may not have symptoms of depression prior to their suicide, the Isotretinoin Expert Working Group will be considering the warnings and whether these need to be updated.

Roche US were sued between 2002 and 2009 for the suicide of a young male who committed suicide with no warning signs. Did Roche inform the MHRA about this and if not should they have.? If Roche failed to inform the MHRA about suicide without warning did the MHRA learn of it independently?

No, Roche did not inform the MHRA about the legal action in the USA but there is not a regulatory requirement to submit this information. Marketing authorisation holders have an obligation to provide a summary of adverse drug reactions associated with their products in periodic safety update reports. The MHRA is aware of the class action legal cases in the USA via media coverage.

Have the MHRA at anytime considered, researched, requested info from Pharmaceutical companies or other institutions, had any meetings to discuss – Isotretinoin induced suicides with no warning signs? Please provides all dates.

As explained above, ‘suicide with no warning signs’ is not recognised as a specific subcategory of suicide. The overall risk of suicide has been closely monitored by the MHRA and is part of an ongoing review by the Isotretinoin Expert Working Group. I hope the information provided is helpful, but if you are dissatisfied with the handling of your request, you have the right to ask for an internal review. Internal review requests should be submitted within two months of the date of this response; and can be addressed to this email address.

Yours sincerely, FOI Team, Vigilance and Risk Management of Medicines Division