See Sex, Drugs and Bureaucrats for the start of this correspondence. You will need both posts to understand next weeks Suicide, Drugs and Bureaucrats.
Thank you for your letter of 31st January 2020 regarding SSRIs and PRACs latest recommendation on the risk of persistent sexual dysfunction after treatment with serotonin and noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). I am sorry to hear about the suffering of your patients and would like to reiterate EMA’s commitment to public health and that it does everything it can to ensure that medicines are as safe as possible.
You are dissatisfied with the outcome of the assessment and state that patients with Post SSRI Sexual Dysfunction (PSSD) “had hoped for more than the very minimal set of words”. We are sorry that you feel this way. Please note that the wording of the product information reflects the outcome of the assessment. The issue will of course remain under review and the wording of the product information will be updated as necessary to accurately reflect any new knowledge of this risk.
We would like to clarify that sexual dysfunction is a well-known side effect described in the product information of SSRIs. For example, for the antidepressant Cymbalta, sexual dysfunction was highlighted in the product information when it was first authorised in 2004 and was extensively discussed in the initial assessment (report available here:
Please also note that the guideline on clinical investigation of medicinal products in the treatment of depression
(https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigationmedicinal-products-treatment-depression en .pdf)
specifically states that investigators should pay “special attention to the effect on sexual function and libido”. PSSD has not been recognised before and the reasons are described in your letter but are also linked to their late onset making detection in an RCT setting difficult.
You challenge in your letter the way medicines are regulated. We would like to take this opportunity to clarify a few issues:
In line with current legislative requirements, EMA’s role is to establish full benefit-risk analyses for medicines. In order to do this EMA looks at all the evidence submitted to establish the benefits as well as the risk profile of a given medicine. Only if the benefits outweigh the risks for a given medicine can EMA recommend a medicine for marketing.
Like all medicines regulators worldwide, and in line with the principles of evidence-based medicine, EMA considers RCTs to be the gold standard for measuring medicine effects in most cases and provides guidance on their use to support licensing applications. For further information you may wish to consult the above-mentioned guideline which describes how this applies to antidepressants. It is not the case, as you claim, that a randomised controlled trial deliberately only looks at a particular benefit and ignores any side effects. RCTs are explicitly set up to investigate safety as well as efficacy and EMA assessment reports include extensive information on the safety profile of each medicine — indeed, it would scarcely be possible to provide a benefit-risk assessment if we did not require evidence on the risks to be collected. In this context the guidelines on clinical investigation also identify the specific side effects that should be monitored in clinical trials.
As for any clinical trial there is a legal obligation for companies to report all suspected side effects. For further information on the safety monitoring during clinical trials please refer to the following link:
https://ec.europa.eu/health/documents/eudralex/vol-10 en and in particular
htts://ec.europa.eu/health/sites/health/files/files/eudralex/vol10/2011 c172 01/2011 c172 01 en.pdf
Once authorised, the benefit risk balance of medicines is always monitored and confirmed through regular benefit risk analyses (so-called PSURs – https://www.ema.europa.eu/en/human—renulatory/nost-authorisation/pharmacovigilance/periodic-safety-undate-reports-psurs).
It is not only during clinical trials that side effects are closely monitored. Companies must always report any side effects that occur with a medicine worldwide, which are then analysed by regulators as part of their regular safety monitoring of medicines as mandated by legislation (Art 23 (2) of DIR200 1/83/EC).
We therefore strongly encourage you and affected patients to notify side effects to the relevant national competent authorities so that the reports can be taken into account for the safety monitoring of these medicines.
Please note that EMA, in collaboration with EU Member States, will continue to monitor sexual disorders as it does for all safety issues in general. EMA will take necessary action in case a new safety issue is identified. This may include a further update of the product information or other regulatory action. You can find more information about pharmacovigilance in the medicine lifecycle on EMA’s website:
https ://www.ema .europa.eu/en/human-regulatory/overview/pharmacovigilance
Finally, regarding your point on the redaction of personal data, please note that this is done to protect patients’ privacy, in line with current EU law which we are obliged to follow just like any private company or public institution. We would like to clarify that deleting personal patient data does by no means impact the causality assessment.
I assure you of EMA’s unwavering commitment to safeguard public health, and to do all it can to ensure that medicines are as safe as possible and that side effects are identified and assessed continuously, before and after marketing authonsation. In this context EMA acknowledges that despite many approved antidepressants (most of them approved many years before EMA came into being) and a reappraisal of the role of medicines vis-à-vis other treatments such as psychotherapy, there is still a need for new medicines with better efficacy and improved safety profile in patients with depression.
Dear Professor Rasi
Your February 26th letter elegantly slips by the points raised. Let me reframe them.
What else would it take to get genital numbing added to the label?
Your letter doesn’t take up the risk-benefit challenge posed to you. I’d appreciate any input on the origins and meaning of this term that EMA can offer. As mentioned, Dr. Jordi Linares placed great, almost sole, weight on RCT data when making a risk benefit assessment, but the effects of SSRIs on sex and the ability of RCTs to make effects like these to disappear almost entirely seem to blow a hole in that strategy.
I was involved in several industry cost-benefit analyses in the early 1990s. It was wonderful to be able to “prove” drugs like the SSRIs that cost 50 times more than imipramine, or risperidone which was 100 times more expensive than chlorpromazine, were actually saving money. It all depends on the data and assumptions you feed into the system. None of the SSRI modelling fed in figures of 5-10% of the population being hooked on them of the contribution this might make to declining birth rates in certain ethnic groups.
I’m sure that at some level you must see that it’s not realistic to view risk-benefit analyses as involving anything other than a baptizing of a new drug with a sprinkling of fairy dust.
On a wider front, it was clear in the RCTs used for licensing SSRIs there were more suicidal acts and both suicides and deaths on active treatment than on placebo in the subset of trials shown to regulators. I think it was right to license SSRIs, but I am flummoxed by your suggestion that the data allowed you to license them on the basis of a risk benefit analysis. Perhaps you can explain?
Licensing, with an acknowledgment of hazards that ensured clinical discretion would be brought to bear on when to use these drugs and how to respond in the event of an apparent hazard, would have been appropriate. But one of the first uses of risk-benefit terminology by regulators was in 1991 when FDA, faced with concerns about Prozac and suicide, opted not to warn stating this might put people off seeking a benefit.
This approach puts doctors in the firing line if they exercise clinical discretion or stick to their guns that SSRIs can and do make patients suicidal. People with PSSD can also tell you what it’s like to be ridiculed and referred for counselling or treated as lepers by doctors who, understandably, in the absence of a warning figure regulators like EMA endorse their denying that PSSD can be triggered by treatment.
Whenever there is a dispute about issues, an operational approach – like your supposed risk-benefit analysis – can look appealing. But, unless agreed to by all sides of a dispute, operational approaches are amoral. They do not take right and wrong or human suffering into account. Were any PSSD sufferers contemplating suicide to take a comparable risk-benefit approach, they might well consider it would be of greater benefit to other PSSD sufferers to take a suicide bomb into the offices of a major regulator than to kill themselves in a manner that disturbed as few others as possible. This would be immoral, however, and few people ever take an approach life this without the shield of a bureaucratic apparatus.
I hope you hear a call on your humanity here rather than a call to beef up the security of your building. I am confident that those with PSSD will act with humanity but less confident that regulators will.
I attach a letter from Nicola Blackwood, then in Britain’s Dept of Health to Wera Hobhouse MP, in response to a letter occasioned by one Ms Hobhouse’s constituents who has PSSD. This offers a galling example of politicians regurgitating stuff fed them by regulators that leads to patients and doctors being dismissed by people who know nothing.
Faced with an issue like PSSD, politicians say they are critically dependent on advice from regulators (MHRA now in Britain) and the framers of guidelines (like NICE). NICE and MHRA have made it clear in correspondence with me that it’s not their job to sort out issues of access to clinical trial data or police the ghostwriting of the medical literature. In a good example of the Deep State that fuels populist rage, both MHRA and NICE on one side and politicians on the other hide behind risk benefit mumbo-jumbo, which, deployed in sonorous tones like the Wizard of Oz once used, they hope will stop awkward questions.
It also leaves doctors, who in 1962 were thought to be a critical part of the regulatory apparatus, behind. Regulatory bureaucrats were supposed to listen to people like me but, when it comes to matters like this, doctors are like salt that has lost its saltiness – good for very little. They act like politicians who wait on bureaucrats to tell them what’s what.
I hope you do not find the tone of this letter too hostile. I blame my profession more than I blame you. I worry that our failure to recognize our role means that pretty soon we will survive in name only, effectively practicing as middle managers ensuring that nurses and others keep to guidelines and the labels of drugs regulators have approved – I initially said authorised.
I hope you appreciate the date of this proposal.
Yours sincerelyShare this: