- Isotretinoin has not been properly shown to be effective or safe.
- The Cumberlege Report of July 2020 shows that doctors and regulators have not listened to harmed patients, and even ‘gaslighted’ them, for decades.
- (a) Many of the Cumberlege findings and recommendations on conflicts of interest, and their disclosure, were the same as in the parliamentary Health Select Committee report of 2005,The Influence of the Pharmaceutical Industry. (b) My GMC complaints against three senior advisers to the MHRA, who were also part of the ‘expert’ group which produced an advisory report in 2014, which recommended no change to isotretinoin’s licensing, render that report unreliable.
- The Cochrane Review of 2018 found that RCTs show ‘no difference between therapies in decreasing the number of inflamed lesions’.
- Isotretinoin is a synthetic vitamin A analogue, with a poorly understood mechanism of action, but which appears to have a range of neurotoxic and other cytotoxic effects.
- There has been significant reporting of depression, psychosis, and sexual dysfunction since first licensed in the 1980s. By 2001, the FDA’s analysis of reports showed a six-fold increase in the rate of suicide, and a mandatory consent form was introduced in the United States. The MHRA should have done the same.
- In 2008, another study provided more support for the 2001 analysis.
- Since 2010, a deeply flawed study by Sundstrom et al has been used by Roche and the MHRA as evidence for a lack of causation of suicidality by isotretinoin. The MHRA has failed to take account of a major retraction by the Karolinska Institute, which renders all its published research, in the 5-10 years before 2013, unreliable.
- The 2014 ‘expert’ Report contains serious defects, in line with the multiple undeclared conflicts of interest (3b, above).
- UK dermatology has very poor leadership. In January 2020, one consultant dermatologist was still relying on a November 2018 article in the Daily Mail.
- Negligent failures of senior UK dermatologists, and senior MHRA doctors, are such that the MHRA should immediately suspend isotretinoin’s licence for the treatment of under-18s, and introduce a substantive consent form for all other patients.
Full document as sent to the MHRA on 21st July 2020:
2020 MHRA Isotretinoin Review [see letter of 26th August 2020, to MHRA, in response to pause of the Review]
Submission by Dr Neil MacFarlane MRCPsych, independent psychiatrist, GMC 3205688
21st July 2020
This work has been substantially informed by the previous and ongoing work of campaigners Sam Ward, Derek Jones, and many others.
1. Although I have not submitted that isotretinoin’s UK licence should be withdrawn for all age groups at this time, I state that I do not consider it to have been properly proven to be an effective or safe drug.
2. The recently published report of the Independent Medicines and Medical Devices Safety Review, First Do No Harm,[1] found multiple failures of medical doctors and regulators in relation to adverse events:
‘There is an institutional and professional resistance to changing practice even in the face of mounting safety concerns. There can be a culture of dismissive and arrogant attitudes that only serve to intimidate and confuse.’
‘Patients often know when something has gone wrong with their treatment. All too often they are the first to know. Their experience must no longer be considered anecdotal and weighted least in the hierarchy of evidence-based medicine.
The report’s nine recommendations include a compulsory public Register of Interests for medical doctors, the normalisation of audio/video recorded consent, a new ‘Redress Agency’, a new ‘Patient Safety Commissioner’, and reform of the MHRA.
Although the Review does not spell it out, it follows that because medical doctors take the lead in performing, publishing, and ‘peer reviewing’ the research on which MHRA licensing is substantially based, all published medical research must now be regarded as having further ‘risk of bias’ in favour of overstating efficacy and understating harms.
3. (a) First Do No Harm shows that the medical establishment and the MHRA failed to respond adequately to the parliamentary Health Select Committee report of 2005, The Influence of the Pharmaceutical Industry,[2] which found:
‘The influence of the pharmaceutical industry is such that it dominates clinical practice, to an extent that deprives it of independent and constructively critical feedback…’
‘…self regulation is not at present effective.’
‘The regulatory authority, which is responsible for controlling much of the behaviour of the industry has significant failings. Lack of transparency has played a major part in allowing failings to continue. The traditional secrecy in the drug regulatory process has insulated regulators from the feedback that would otherwise check, test and stimulate their policies and performance. Failure can be measured by the MHRA’s poor history in recognising drug risks, poor communication and lack of public trust. Regulatory secrecy also underpins publication bias, and other unacceptable practices.’
(b) The GMC is currently investigating my complaints against two senior members of the 2014 ‘Expert Working Group’ (EWG) into isotretinoin, including the senior experts on dermatology, and pharmacovigilance.[3] The complaints are mainly of failures to declare potential conflicts of interest in publications, and to the Committee on Human Medicines (CHM). They render the EWG’s 2014 Report unreliable.
The GMC has informed me that they have closed their investigation into the third senior member of the 2014 EWG, responsible for psychiatry. They have not fed back why they have done so, and I consider the complaints, which suggest ‘flipping’ of pharmaceutical industry and other funding with another senior colleague at the University of Edinburgh, to be extremely serious.
I submit that the MHRA had a responsibility to scrutinise declarations of interest in all ‘experts’ advising it, but failed to do so in 2014 and up to the present.
The MHRA has still not provided the names of the ‘experts’ who are advising it for the current Review, despite having been repeatedly asked by campaigners since 2019. It is understood that the ‘experts’ have had at least one meeting.
4. Roche, the original patent owner of isotretinoin, continues to claim that ‘millions of patients worldwide have benefited from taking the drug’.[4] But severe acne has a high rate of spontaneous improvement and remission, and the Cochrane Review of 2018 found that Randomised Controlled Trials (RCT’s, the ‘ideal’ method for testing efficacy of any treatment)[5] show ‘no difference between therapies in decreasing the number of inflamed lesions’.[6]
5. It has been known for hundreds of years that excess vitamin A can cause neuropsychiatric disorders.[7] Isotretinoin is a synthetic vitamin A analogue, with a poorly understood mechanism of action, but which appears to have a range of neurotoxic and other cytotoxic effects.[8]
6. There were many reports of depression and psychosis, following use of isotretinoin for acne, since it was licensed in the early 1980s. Sexual dysfunction was first reported in 1984.[9]A1994case series of sexual dysfunction pointed out that underreporting due to embarrassment is especially likely for that particular adverse effect.[10]
By 2001, the FDA’s analysis of reports showed a six-fold increase in the rate of suicide.[11] The FDA took the unusual step of mandating a four-page consent form for all patients.[12]
I submit that the UK drug regulator, headed by GMC-registered medical practitioners and therefore legally obliged to put ‘public health and safety’ first,[13] should have followed the FDA, and introduced a similar mandatory consent form in the early 2000s.
Since the 1980s, senior MHRA doctors, and dermatologists, have failed to ensure that proper research into the reports of depression/psychosis and sexual dysfunction was carried out.
7. In 2008, further support for the FDA’s 2001 analysis of suicidality came from a case-crossover study of patients hospitalised for depression (including psychotic depression) which found ‘the relative risk for those exposed to isotretinoin was 2.68 (95% CI = 1.10 to 6.48)’.
This relative risk may be an underestimate, because ‘Those who received an antidepressant in 12 months prior to the index date were excluded’, and it appears that no attempt was made to identify isotretinoin-treated patients who might have died by suicide, or other causes.
I submit that Dr Kent Woods (who is still on the GMC’s register),[14] CEO of the MHRA in 2008, missed a further opportunity, to protect the ‘health and safety’ of patients with acne, on publication of this study.
8. Since 2010, a deeply flawed study by Sundstrom et al has been used by Roche and the MHRA as evidence for a lack of causation of suicidality by isotretinoin.
The MHRA has failed to take account of a major retraction by the Karolinska Institute, which renders all its published research, in the 5-10 years before 2013, unreliable. There is also evidence for a Roche-specific serious risk of funding bias.
In addition, there are serious flaws within the Sundstrom et al paper, as published.
Sundstrom A, Alfredsson L, Sjolin-Forsberg G, et al. Association of suicide attempts
with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ
2010; 341:c5812
a. Unreliability of all published research from the Karolinska Institute, in the 5-10 years before 2013. Evidence for Roche-specific serious risk of funding bias.
Four of the paper’s five authors were primarily affiliated to the Karolinska Institute.[15] Two were dermatologists and one was a psychiatrist.
The Karolinska appears to have had a strong relationship with Roche, relative to other pharmaceutical companies, over the last decade. The database of the independent trial registry ICGGCP.net lists the Swiss company as a sponsor or collaborator for more than sixty clinical trials,[16] while the UK-based GSK appears ten times less frequently.[17]
The Karolinska also has a close relationship with the Anglo-Swedish company AstraZeneca, including the ‘Astrazeneca Clinical Pharmacology Unit’, which appears to date back to 2002 or earlier.[18] In 2010 the company was fined in the US after ‘illegal marketing’ of its best-selling antipsychotic drug quetiapine (Seroquel), for indications including anxiety and depression: ‘In addition, the company recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct…also…AstraZeneca violated the federal Anti-Kickback Statute by offering and paying illegal remuneration to doctors it recruited to serve as authors of articles written by AstraZeneca and its agents about the unapproved uses of Seroquel.’[19]
In 2011 the Karolinska was reported as planning to ‘commercialise research and development’ over the following decade, with a particular emphasis on the pharmaceutical industry.[20]
Seven researchers involved in clinical research at the Karolinska, conducted in 2011-13, were found ‘responsible for scientific misconduct’ in 2018.[21] An ‘additional 31 authors’ were ‘blameworthy for their contributions to the articles, however not responsible for scientific misconduct’. The Karolinska president requested that six published journal articles be retracted. An ‘action plan’ for ‘the prevention of scientific misconduct’, was considered necessary to remedy the ‘deficiencies’ in the Institute itself, and in Swedish research more widely.[22]
b. The paper was excluded in the 2018 Cochrane Review’s assessment of ‘Frequency of serious adverse effects’. However, Cochrane follows an overly stringent approach to non-RCT evidence of harms which also excludes Azoulay, 2008.
Historically, many treatments with low efficacy and/or serious adverse effects have been discontinued or restricted without RCT evidence. Tobacco’s use as a treatment mostly declined through non-systematic clinical observations on efficacy,[23] and then its causation of cancers was demonstrated by case-control studies. Professor Dr David Healy FRCPsych has written extensively on how patients and the public have been systematically misled about adverse events of drugs in recent decades, particularly by misinformation about RCTs.[24]
c. Specific criticisms of the paper.
i. There was no control group, or blinding, which would have ensured that over- and/or under-identification of suicides and attempts occurred equally within treated and untreated subjects: ‘…we compared the study cohort with the general population, enabling an estimate of relative differences in the occurrence of suicide attempts between the study population and the background population.’ […] ‘The expected number of suicides came from mortality data for the entire general population…’
ii. The‘Discussion’ section begins with a rhetorically loaded statement about the number of ‘person years’ of treatment and follow-up, but says nothing about statistical power (later, under ‘Limitations’, it is stated ‘…the statistical precision was low’), and then proceeds to a false statement about suicidality [my emphasis]: ‘This retrospective cohort study of 5756 patients treated with isotretinoin for severe acne encompasses more than 17000 person years of observation before treatment, 2900 person years on treatment, and 87000 per- son years of follow-up thereafter.’
‘The data support our hypothesis that severe acne, regardless of exposure to isotretinoin, carries an increased risk of attempted suicide. The point estimates of the standardised incidence ratios rose gradually from three years before treatment through to the year immediately before treatment. However, none of these point estimates was statistically significant.’
If the ‘point estimates’ of suicide attempts were not significantly different from the general population, then ‘the data’ do not support the ‘severe acne…carries an increased risk of attempted suicide’ hypothesis.
The false statement is repeated two paragraphs later: ‘Considering the increasing risk of attempted suicide during the years before treatment…’
And again, under ‘Limitations’ (p.7): ‘The standardised incidence ratios were clearly rising before treatment…’ [my emphasis].
iii. Buried in the Discussion is this statement about female patients: ‘…the standardised incidence ratio for repeated attempts increased among female patients eight years after treatment.
Figure 3 shows that this increase was not statistically significant. However, two graphs on suicide attempts, in both sexes combined and in males only (figures 4-5), might suggest an attempt to distract from this female-only data.
A late increase in suicidality in female patients would be compatible with a mechanism of some suicidality being caused by permanent sexual dysfunction, rather than a more direct causation via depression/psychosis. Female patients might take longer to become aware of SD.
Although the number of suicides identified was small, their time course was also compatible with this (p.4): ‘One man committed suicide during treatment and two within one year after treatment. The first woman who committed suicide did so six years after treatment.’
iv. No explicit mention of sexual dysfunction.
v. “After 1986-7, dermatology clinics could prescribe isotretinoin without an individual application for each patient. We could not collect the identities of all patients treated at such clinics. These unidentified patients would, however, be a source of bias only if the frequency/pattern of suicide attempts can be assumed to be distinctly different in that “lost population”. We cannot conceive of a mechanism to justify such an assumption.’ (p.7, my emphasis).
There are at least two readily ‘conceivable mechanisms’. It is likely that the pre-1986-7 patients had more severe acne. If very severe acne does, in fact, lead to significant suicidality, which isotretinoin then reduces in some cases, then the failure to identify patients with milder acne who had been treated would lead to an underestimate of isotretinoin-caused suicidality in the whole treated group.
It is also possible that, after 1986-7, dermatologists were less diligent about entering patients with milder acne into the ‘register’, if they were aware that prescribing to such patients was contrary to official guidance.
vi. The way that Figs 1-3 are plotted, with continuous lines rather than ‘error bars’ for each point, is potentially confusing and appears not to be in line with usual 2010 practice.
9. The 2014 EWG Report contains serious defects, including the failures (a) to properly scrutinise Sundstrom et al 2010, (b) to evaluate the FDA’s findings on suicide, and Azoulay et al 2008, (c) to consider sexual dysfunction (which was first reported in 1984) at all.
The 2014 report failed to consider research by US psychiatrist Dr Doug Bremner MD, of Emory University, including his functional brain imaging studies which support direct causation of neuropsychiatric disorders by isotretinoin, which were summarised in ‘Retinoic Acid and Affective Disorders: The Evidence for an Association’. J Clin Psychiatry. 2012 Jan; 73(1): 37–50.
It also failed to consider the actions of Roche, and Roche-funded Dr Charles Nemeroff MD, which Dr Bremner outlined in his book The Goose That Laid the Golden Egg: Accutane, the truth that had to be told, in attempting to discredit Dr Bremner and his research.[25] The deeply corrupt Dr Nemeroff[26] is notorious within world psychiatry for being sacked by Emory after failing to disclose 2 million dollars of pharmaceutical company funding, despite having given a specific undertaking to do so.
10. A senior UK dermatologist told me, in January 2020, that he/she does recognise that isotretinoin causes depression. It was also that dermatologist’s practice to advise all patients (male and female) about the possibility of permanent sexual dysfunction, and to recommend a November 2018 article in the Daily Mail.[27] That 2800-word piece highlighted individual experience of neuropsychiatric effects and sexual dysfunction, published case reports, and recent research suggesting ‘yellow card’ reports to the MHRA and FDA might lead to considerably lower estimates of adverse events than regulators previously thought.[28]
I submit that, at the most senior level, the UK dermatology establishment, and in particular Dr Tony Bewley MRCP, the co-chair of ‘Psychodermatology UK’,[29] who is currently under investigation by the GMC (see 3b, above), has failed to ensure that pharmacovigilance and research have been properly communicated to patients.
11. I submit that negligent failures of senior UK dermatologists, and senior MHRA doctors, are such that the MHRA should immediately suspend isotretinoin’s licence for the treatment of under-18s, and introduce a substantive consent form for all other patients, until adequate research on efficacy and adverse effects, and remediation of professional standards in UK dermatology, has been demonstrated.
Dermatologists have claimed that acne increases suicidality, but have failed to develop educational and public relations approaches to mitigate the stigmatising appearance of acne, as they have with vitiligo and psoriasis. I am not aware of any case reports or case series reporting acne to be physically life-threatening. Given all the contextual factors, it is reasonable to conclude that under-eighteens informed by current UK dermatology about the benefits and risks of isotretinoin, even with the new mandatory consent form, cannot be ‘Gillick competent’ in any meaningful sense.
Given the Cochrane finding of lack of evidence for efficacy, the wide range of evidence for serious and frequent adverse events, and the burial of those adverse events over decades, it is very likely that the current availability of isotretinoin, even under specialist dermatology prescription, causes net deficits in mental and physical health in the population as a whole. Therefore there is a wider public health interest in steps which would be likely to lead to substantially less prescribing.
Isotretinoin’s PIL and SPC must also be substantially updated, to include the ‘very poor’ evidence for efficacy as found by Cochrane. At the time of writing this submission, the MHRA had failed to provide its latest pharmacovigilance data to campaigners, so it is not possible to outline what the new mandatory consent form, PIL and SPC should state about adverse effects. The MHRA should immediately provide a response to, and clarification of, the 2018 Daily Mail piece (see 10, above) which some UK dermatologists appear to be resorting to as a form of patient communication, given the absence of leadership by Dr Bewley (who should currently be suspended by the GMC, in my opinion, while they continue to investigate him).
[1] https://www.immdsreview.org.uk/downloads/IMMDSReview_Web.pdf (8th July, 2020)
[2] https://publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/4212.htm
[3] https://drnmblog.wordpress.com/2020/06/30/a-senior-psychiatry-adviser-to-the-mhra-and-two-other-senior-medical-advisers-are-being-investigated-by-the-gmc-following-my-complaints-about-undeclared-conflicts-of-interest/
[4] https://www.bbc.co.uk/news/health-47952076
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665449/pdf/9468688.pdf (1998)
[6] https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009435.pub2/full p.3
[7] P Lips, Hypervitaminosis A and Fractures, N Engl J Med 2003; 348:347-349
[8] https://rarediseases.info.nih.gov/diseases/517/fetal-retinoid-syndrome
[9] N P Bruno, B E Beacham, J W Burnett. Adverse Effects of Isotretinoin Therapy. Cutis, 1984 May; 33(5):484-6, 489. According to JD Bremner, Kirsty Shearer, P McCaffery, Retinoic Acid and Affective Disorders: The Evidence for an Association. J Clin Psychiatry, 2012 Jan; 73(1): 37–50: ‘In patients treated with high doses (>.75 mg/kg/day), 7% reported insomnia, 22% fatigue, 11% headache, 7% weight loss, 2% impotence, and 9% loss of libido, while no subjects with untreated acne reported these side effects.’
[10] R Coleman, D MacDonald ‘Effects of isotretinoin on male reproductive system’ Lancet 1994 344: 198
[11] D K Wysowski, M Pitts, J Beitz. An Analysis of Reports of Depression and Suicide in Patients Treated With Isotretinoin. J Am Acad Dermatol 2001 Oct;45(4):515-9
[12] https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18662s051lbl.pdf pp.29-32
[13] ‘Public health and safety’ is paraphrased from the Medical Act, 1983.
[14] https://www.gmc-uk.org/doctors/1523728
[15] https://www.bmj.com/content/bmj/341/bmj.c5812.full.pdf
[16] https://ichgcp.net/clinical-trials-registry/research/list?research%2Flist=&term=karolinska+roche
[17] https://ichgcp.net/clinical-trials-registry/research/list?term=karolinska+gsk
[18] https://www.ncbi.nlm.nih.gov/pubmed/11882056
[19] https://www.justice.gov/opa/pr/pharmaceutical-giant-astrazeneca-pay-520-million-label-drug-marketing
[20] https://sciencebusiness.net/news/75207/Karolinska-to-set-out-10-year-plan-for-commercialising-R%26D%2C-after-raising-%E2%82%AC63M-
[21] https://news.ki.se/seven-researchers-responsible-for-scientific-misconduct-in-macchiarini-case
[22] https://ki.se/en/about/action-plan-following-the-investigations-of-the-macchiarini-case?_ga=2.171951840.1164596494.1572363305-994540990.1570266979
[23] Medicinal uses of tobacco in history https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1079499/
[24] The Decapitation of Care: A Short History of the Rise and Fall of Healthcare (2020) Samizdat Health Writer’s Co-operative ISBN-10: 1777056500 ISBN-13: 978-1777056506
[25] ISBN-10: 0990865037 ISBN-13: 978-0990865032
[26] See item 18 in https://drnmblog.wordpress.com/2019/05/22/prescribed-harm-manifesto-learning-disability-and-autism-now-included/
[27] https://www.dailymail.co.uk/health/article-6431453/Thousands-prescribed-Roaccutane-theres-disturbing-evidence-leave-men-suicidal.html
[28] Y M Alatawi, R A Hansen, Empirical Estimation of Under-Reporting in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) Expert Opin Drug Saf 2017 Jul;16(7):761-767 https://pubmed.ncbi.nlm.nih.gov/28447485/
[29] https://www.psychodermatology.co.uk/about-us
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