Isotretinoin and Safety – Destiny or Mirage?

On January 22, Britain’s Medicines Regulator convened a meeting on consent to Isotretinoin (Accutane, Claravis), whose dynamics map straight onto Prima Facie.

Families whose children died from Isotretinoin triggered suicide, or whose sexual function is potentially wiped our forever have clamored for reform for over a decade. In 2023, MHRA rewrote the Rules of Evidence on consent and were reporting on progress.

In 2020, concerned parents in the US got FDA to put a Black Box Warning on Merck’s Montelukast (Singulair) for neuropsychiatric effects.

Doctors in the US and dermatologists in the UK complained. The new warnings were not ‘evidence-based’ by which they meant not based on controlled clinical trials (RCTs) linking suicidal, sexual or neuropsychiatric hazards to Isotretinoin or Montelukast.

The US families kept lobbying and in 2023 New York’s Attorney General wrote to FDA stating that the flood of mental health problems linked to Montelukast, particularly among children, was growing not diminishing. What did FDA propose to do about this? Nothing it seems.

The fact that FDA and MHRA bowed to family pressure is momentous. But it doesn’t solve our drug assault problems. These are not something regulators can solve.  We need to tease out the different elements involved and nail down who needs targeting for what.

World Leading?

MHRA say the 2023 Risk Minimization Meeting led to agreement on these points.

1. Better information
2. Better monitoring of mental health and sexual hazards
3. Better Consent to benefits and hazards
4. Better Communication re hazards
5. Better Knowledge of what is happening on the ground.

They have since introduced Risk Management Materials

• A patient card
• Consent forms acknowledging risk
• Specific Pregnancy Warnings
• Prescriber and Pharmacist involvement
• Counselling re hazards requirement
• Assessment and monitoring of hazards requirement
• Initial prescriber should have relevant expertise requirement
• First appointment should be face to face

In 2023, MHRA required two Independent doctors to approve prescriptions for under-18s. As dermatologists never disagree, this has been dropped.  MHRA now say people should have access to a second opinion.

In association with the British Association of Dermatologists (BAD), MHRA have put Audits in place, and have had 358 audit responses which they say show positive changes

In association with BAD and ‘comms’ companies, MHRA supported the production of an Isotretinoin Video to explain the hazards (BAD call side effects) and when Isotretinoin should and should not be used. The Video Transcript is here.

MHRA have also produced a Drug Safety Update article.

MHRA view what has been done as the best safety system there is internationally.

Valid Consent or Drug Assault

Harriet Vogt, RxISK’s communications (‘comms’) consultant, has views on the BAD video. There is a contrast between Benefits and Hazards.  Benefits sound close to invariable.  Hazards are translated into Side Effects which are mentioned as possible but rare.  There is no hint Isotretinoin can have sexual or suicidal Hazards. If anything in these nameless areas should happen – the hint is your mental make-up is the likely source not the pill.

There is a wishy-washy hint sexual dysfunction may continue after stopping but no mention your ability to make love may be wiped out forever. Faced with a choice between mentioning risks of death and having a cheery soundtrack – the soundtrack seems to have sounded more sound.

Response:  MHRA haven’t offered thoughts on what they think of this video – other than saying it was put together by experts.

The video reflects the views of many good dermatologists that the benefits of Isotretinoin have been so convincingly linked to isotretinoin that they accept hazards need to be mentioned but they do not want to deter people from seeking treatment.  It is not clear any ‘good’ dermatologist has met a case of suicidality or sexual dysfunction they convincingly link to Isotretinoin.

Q and A Involving Families

1. Where is the Research on what can happen and is happening?

• MHRA mentioned an ‘Acne Isotretinoin Dosing’ trial

This is not unimportant. Doses have been far too high in the past but the questioner almost certainly meant research on suicide and sexual issues.

2. The warnings are small print, is this right?

• MHRA say warnings about Hazards are primarily down to the doctor to mention.

MHRA don’t do Black Boxes the way FDA does

3. Are Dermatologists assessing Hazards?

• MHRA suggest the Audit suggests they are. The video says Nurses may ask about your ‘mood’ and it is important you mention changes.

Can dermatologists or nurses do more than a superficial check?

4. What is being done to treat the profound injuries caused?

• MHRA advise consulting your doctor/clinic nurse.

Nothing.

5. Dermatologists or nurses are supposed to Monitor – Then what?

• MHRA indicate that is down to the doctor/nurse

Nothing.  Dermatologists have no experience managing these states.

6. Second Opinion?

• MHRA say this is lieu of a second independent view before starting treatment

Do Injuries after starting treatment warrant a second opinion?

7. What is being done about Disability Payments

• MHRA say disability payments are not their department

8. Can MHRA decide if the Drug is causing a problem or not

• MHRA say if you have problems you can consult the Samaritans

Samaritans are prohibited from linking a problem to a drug – from practicing medicine.

MHRA or NHRA

This Q and A precis misses the disappointment, close to disgust, of family members asking questions apparent in a parallel set of back and forth emails among listeners.

There was a mismatch between the good job MHRA believe they are doing and families who saw a NHRA (No Help Regulatory Agency) in action. Families used words like whitewash, gaslighting and conspiracy.

This gulf illustrates public, medical and political misunderstandings about the role of regulators – See Are Healthcare and Science Compatible. And perhaps MHRA misunderstanding of or failure to communicate their role clearly to families.

MHRA washed their hands of drug induced injury and disability questions. In terms of their job description, this was correct. It is not clear if their job description means they can’t name resources able to help on these points.

Part of the problem is families, patients, and increasingly doctors delegate narcissism to FDA/MHRA, as the Freudians used to say, or fetish MHRA/FDA, as social scientists often say.  We do not see this.  Nor apparently do regulators – Narcissistic Doctor Disorder.

MHRA are a bureaucracy. They are not a Patient Safety Body (PSB) or scientists. Their minimal input to safety is linked solely to the words in a drug’s label – and as far as they are concerned the words have changed.

Doctors are the safety professionals. They decide whether a drug has the capacity to cause a problem and has or has not caused the problem in the case of a particular patient.  Doctors used to be able to force companies to update drug labels accordingly but their powers to do so are now limited by medical journal unwillingness to publish reports of Hazards for fear of company lawsuits – see Silencing Doctors Silencing Safety.

On top of that, medical insurers advise doctors against making a link between a medicine and hazards – Making Medicine Great Again.

In the case of cross-boundary hazards like suicidality or permanent sexual dysfunction, the most dermatologists can be expected to do is recognize there might be a problem. They should make a referral at that point just as a psychiatrist or genito-urinary specialists would if a patient came back with a rash after starting a treatment. No one would want a psychiatrist managing skin issues,

With a rash or photos, a psychiatrist or family doctor cannot readily deny the problem exists but in the case of suicidality, homicidality or persistent sexual dysfunction there is nothing to show or take a picture of.  Some of the experiences are so disturbing that the doctor has to open the door to hearing about them in order to make it possible for us to talk about them – See Guilty until Proven Innocent. Psychiatrists have been shamefully poor at this.

There is no hint MHRA or dermatologists have any feel for this aspect to the problems Isotretinoin poses.  In failing to recognize the complexity involved, dermatologists are failing patients. It is not the role of regulatory bureaucrats to lead professionals.

Disabilities and Research

The recognition of disabilities and questions of disability payments also hinges on this point.  Regulators do not advise on whether a disability exists that might warrant support with benefits.

Disabilities are a job for a doctor, who may be convinced their patient has a real and enduring disability and be willing to report that opening the door to seeking a benefit.  The next step is a Disability Benefit Application – which goes to a board on which there are doctors and lawyers.  For a missing leg, this is easy.  For enduring sexual dysfunction claim, a board, or politicians may say “Yes, but if we grant this are we opening the door to a flood of applications based on people’s say so?  We will review this when there is a reliable test to confirm the disorder”.

Having said this, the system manages to hand out disability payments for ADHD and mood disorders without a test to show they are real.

This brings the question of research into the frame.  There is effectively no research going on to test for the existence of SSRI/Isotretinoin/Finasteride induced suicidality or sexual dysfunction that is likely to lead to a Test or Treatment soon.  If we get a Test or Treatment it will be by accident.

Regulators have no role in doing or commissioning research that might remedy this situation.  The most they can do is note Hazards in drug labels. This you’d imagine should lead to research but hasn’t and seems increasingly less likely to lead to progress.

The only progress in these areas has come from the efforts of affected individuals or their families.  This is likely to remain the case.

The Art of the Possible

For people with drug-induced injuries or bereaved families, regulators like MHRA or FDA look the obvious port of call.  And Isotretinoin families in the UK and Montelukast in the US have taken the regulators out of their comfort zone, which may bear long term fruit for all of us.

In the short term, we all can do with a degree of thinking outside the box by folk with Skin in the Game.

Inquests are an important venue. Coroners have no box to tick to say a prescription drug caused a death. Families have no reason to think they need a lawyer going to inquests but they stand no chance without both a lawyer and an expert.

The Death of Stephen O’Neill (see also The Perfect Killing Machine) and Thomas Kingston – see Tangled up in Bureaucracy – bring the points home.

Stephen’s problems began with doxycycline a drug often given for acne, which can cause suicide and the suicides it causes have been weaponized to defend against the idea Isotretinoin is uniquely bad (it is worse than doxycycline).  His inquest led the NICE Guidelines apparatus to agree that their guidelines are based on a ghostwritten often fraudulent literature – The NICE Before Xmas.

In Thomas Kingston’s case, the Coroner wrote to the Royal College of Psychiatrists and General Practitioners which may have played a part in MHRA setting up a working group like this successful dermatology one – that will likely also be regulatorily perfect but frustrating for anyone interested in patient safety.

These bodies, along with the BAD guys, who are supposed to keep us safe will of course say they can’t go against MHRA labels or NICE Guidelines.

It is also worth engaging with journals like BMJ (and BMA) who opened the door to dermatologists dismissing the 2023 warnings on Isotretinoin.

Engaging with medical insurers who warn doctors at inquests not to link suicides to a drug a patient was on is also worth doing – See Will Medical Insurers Stop Killing People.

There is a further limitation to MHRA’s abilities to contribute to safety that the families of those who have committed suicide or now have permanent sexual dysfunction or other problems linked to Isotretinoin (or finasteride or SSRIs) do not take into account when calling for more stringent precautionary measures on labels along with calls for the drug to be removed from the market.

No Drug is an Island.  Any precedent established with one drug risks toppling over into all other drugs. Companies have armies of lawyers lined up monitoring every change in a dot on an i or cross on a t in order to exploit it.

In addition to that even FDA’s Bazooka – Black Box Warnings – are now widely viewed as and ignored by doctors as May Contain Nuts labels. Companies have colonized doctors in ways very few doctors can spot. Doctors see themselves practicing according to the evidence.

Words and labels and guidelines are not what keep us safe.  What keeps us safe are the judgement calls we as patients make and the judgements our doctors make. We are safest when these coincide. In efforts to keep us safer, well intentioned people, including doctors, have put ever more words in place in the form of guidelines etc. These have given us an increasingly Unsafe Safety System – see also and Unsafe Safety at FDA.

We lack a Patient Safety Body – that we agree really does have our safety at its heart.  What would such a body look like?  What might a video it made look like?