Last Wednesday, I had a letter from Michael Davis, the Acting Director of FDA’s Center for Drug Evaluation and Research.
It wasn’t a complete surprise to get a letter. I’d written to Dr Davis 3 weeks beforehand about MedDRA codes for PSSD and about PSSD more generally. But his letter was not a response to mine.
Dockets
Dr Davis’ letter was about Docket No. FDA-2018-P-4088.
The figures 2018 after FDA in the title refers to something submitted to FDA in October 2018 – 3 months short of 8 years ago.
The submitted something was a petition to FDA that ‘formally requests that the FDA update the safety information and warnings on the prescribing labels for isotretinoin (commonly known by brand names like Accutane) to include a warning about the potential risk of developing long-lasting or permanent sexual dysfunction and erectile dysfunction’. [1, 2]
Eight years comes very close to a record for time-taken by FDA to respond to a petition. The only petition that beats Docket 2018-P-4088 that I am aware of is FDA-2018-P-1846, which was submitted in May 2018.
P-1846 is also a RxISK petition requesting persistent sexual dysfunction warnings for PSSD on prescribing labels.
Eight years is not just a record for length of time, on paper it breaches regulations. FDA have to respond to petitions in a timely fashion. Timely may be codified but it used to loosely mean responding within 2-3 years at the most.
FDA came close to responding in a timely fashion, apparently by rejecting the petition(s). Their hand was stayed for some reason.
Eight years opened a door to PSSD-Network (not RxISK) taking a Legal Action against FDA. A technicality allowed FDA to get this dismissed but in the meantime it generated a lot of useful publicity for PSSD.
Last week’s letter grants the Isotretinoin petition in part and denies it in others. For more on what was accepted and will change and what has been denied, see a RxISK post – probably FDA Responds to Isotretinoin Petition – that will appear later this week.
There will in short order also be several other posts linked to these developments.
Lengthy though it is, it is probably worth reading Dr Davis’ Letter if only to see if you can spot what it is about it that has us figuring it raises several substantial issues quite apart from what it accepts and what it denies.
See Davis to Healy.
Overplaying our Hand?
P-1846 was submitted to both FDA and EMA and later to Health Canada. EMA, Health Canada and other regulators like the TGA in Australia made moves to change their prescribing labels and mention (in small print) the possible persistence of sexual dysfunction after treatment stopped.
(Actually, we’ve just heard that a PSSD sufferer from Romania, liaising with the PSSD-Network, has found her efforts to get her PSSD recognized has led the Romanian authorities to discover that not all companies have complied with EMA’s 2019 notice to include mention of PSSD in drug labels).
Our hope in submitting the petitions was that inclusion in prescribing labels would give people with PSSD and Post-Retinoid Sexual Dysfunction something to point to when being gaslit by their doctors (neurologists in particular).
We almost certainly overplayed our hand. The ask was for prominent, even Black Boxed, warnings.
There are many decent people in the Isotretinoin and Finasteride communities who want these drugs banned. It is easy to understand this point in the abstract but even more so if a family member has been affected. Drugs that can cause suicide and persistent sexual dysfunction are problematic enough, if they are being used to treat life-threatening conditions, but difficult to justify keeping on the market without at the very least prominent warnings, if they are given for what can be termed cosmetic indications.
Recognition of the problem, however, has been another motive for many to get PSSD and PRSD recorded in prescribing labels. Any mention in the label gives the person affected a better footing in their dealings with doctors. Black Box Warnings might sound like they should do a better job for this purpose than some small print tucked away, but these days many doctors view Black Box Warnings as May Contain Nuts labels – something close to irrelevant.
In a close to unbelievable situation like our current dismissal of warnings, is it a good strategy to push for the two black-birds in the bush at the risk of losing a bird in the hand which regulators might be almost forced to concede if the ask is pretty modest?
Recognition of the problem will assist efforts to get MedDRA and other coding systems to embrace these conditions and will also facilitate academic publications. Formal recognition can be expected to increase the likelihood of research input that may help us understand what is going on in these medically mysterious conditions. Tardive Dyskinesia, the first drug-induced and post-treatment enduring dysfunction, was recognized 65 years ago but remains a mystery.
There is a Nobel Prize to be won here and, of course, a $100K RxISK Prize, but without a clear endorsement that these are real conditions rather than a concern of fringe groups, Prizes are not going to have the hoped for incentive force.
A Regulatory Crisis
Why an 8 year delay? Michael Davis’s letter sheds some light on this – hence our challenge to you to read it, even though you might find it somewhat mind-numbing. Skim-reading it (like someone with ADHD) rather than focusing on the minutiae (like someone with ASD) – See ADHD and ASD on RxISK – might put you in a better place to spot what has me anyway excited.
There is lots more to come about this letter – starting later this week on RxISK.
See also
- Isotretinoin and Consent
- Finasteride and Consent
- Bad Trips on SSRIs
- No Sex We’re on SSRIs
- Good Trips on SSRIs
This is what I had to do when I won the British Overseas Trade Board prize for report writing.
Explain, repeat, explain repeat, double-down, repeat, repeat again. It is a formulaic process which I got a handle on and when I sent in my report, I thought they would think I was having a laugh. But no, the letter to my boss, head of Worldwide Marketing, said it was the best report they had ever seen.
I just picked out a few bits, that RxISK is now on the radar of the FDA. ‘through a web portal entitled “RxISK’
Repeat, explain, repeat, explain, repeat again…
Application holders have an opportunity to object to such labeling and may enter into discussions with the Agency to reach agreement on whether the labeling for the drug should be modified to reflect the new safety information.27 FDA has the authority to issue an order requiring that the safety labeling changes be made.28
From our review of the materials identified above, including those submitted with your Petition, we have not identified reasonable evidence of a causal association between isotretinoin and the sexual dysfunction adverse events identified in the Petition during isotretinoin use; thus, inclusion of such information in the WARNINGS AND PRECAUTIONS section of labeling of isotretinoin products is not warranted.
Second, among the literature reviewed were two publications on which you are a co-author that you cited in the Petition as evidence of a causal association between sexual dysfunction and isotretinoin use.48,49 Because of serious limitations in the methodology of these studies as described below, they did not provide interpretable data from which any causal relationships between the sexual dysfunction adverse events reported and isotretinoin use could be identified. Specifically, these two studies were not adequately designed to provide interpretable data on the relationship between isotretinoin and any of the sexual dysfunction adverse events evaluated. They were uncontrolled, retrospective, observational studies relying on patients’ online self reports of sexual dysfunction submitted through a web portal entitled “RxISK.”50 The studies’ authors collected data online, without examining or treating the patients who responded to queries on the web portal. Given the limitations of the assessment methods, the investigators could not adequately assess for the presence of other potentially confounding risk factors for sexual dysfunction (e.g., depression, anxiety, refractory acne or other medical conditions, psychosocial stressors, relationship factors). Furthermore, the studies did not use validated assessments of sexual function, and investigators conducted directed queries using specific adverse event terms, which can stimulate, influence, and bias adverse event reporting and data collection. The studies’ authors stated that they performed causality analyses of these reports based on patient responses to structured questions, but did not provide more detailed information about any of the specific structured questions or directed queries. In addition, as noted by the authors in one of the studies, the RxISK website includes numerous articles describing “enduring sexual dysfunction” attributed to the use of a variety of drugs, including isotretinoin, which could introduce bias by potentially stimulating the reporting of sexual dysfunction adverse events.5
For the reasons outlined above, your request that FDA require the addition of information on the risk of sexual dysfunction adverse events to the WARNINGS AND PRECAUTIONS section of labeling is denied.
We have concluded, however, that the evidence of risk of erectile dysfunction, decreased libido, vaginal dryness, and decreased vaginal lubrication that may continue after discontinuation of the drug warrants inclusion in isotretinoin product labeling in the ADVERSE REACTIONS section.
As such, you have not provided, and FDA has not otherwise identified, any basis to require the addition of information in isotretinoin drug product labeling on sexual dysfunction adverse events that worsen or first emerge after drug discontinuation.
Accordingly, we deny your request that FDA require the addition of a BOXED WARNING on the risk of sexual dysfunction adverse events that persist, worsen, or emerge after discontinuation of the drug to the labeling for isotretinoin products.
Repeat, repeat again, ‘through a web portal entitled “RxISK’
Didn’t spot it David. A bit of conceptual shenanigans in “definitely” and “definitively”, but they did give a pittance and not nothing.
A bit of news on the finasteride front: Donald Trump has long been known to use it to preserve his orange mane. In prior years it had always been included in his publicly released medical reports. But not anymore, it seems:
https://www.independent.co.uk/news/world/americas/us-politics/trump-hair-loss-drug-medical-report-b2990662.html
Press coverage mainly focused on the question of “well then, what else might be missing?” It was noted that the drug was “linked to an elevated risk of depression,” but PSSD and other risks were not mentioned. The White House replied that nothing “clinically relevant” had been omitted from its report, and told commenters to shut up.
But hey, any glimmer of public notice is welcome …
Well, I read the letter that took 7. 75 years to arrive last night. Mind-numbing to the point of being almost comedic – I had to lie down and regularly found myself pressing a palm to my brow – involuntarily. Have mercy, Dr Michael C Davis, please have mercy.
And then he did – on lucky page 13:
‘For the reasons outlined above, your request that FDA require the addition of information on the risk of sexual dysfunction adverse events to the WARNINGS AND PRECAUTIONS SECTION OF LABELING IS DENIED.
However, although we did not find reasonable evidence of a causal
association to justify the inclusion of information in the WARNINGS AND PRECAUTIONS section of labelling, we have determined that the following sexual dysfunction adverse events supported in the post marketing setting WARRANT INCLUSION IN THE ADVERSE REACTIONS SECTION OF LABELING FOR ISOTRETINOIN PRODUCTS: ERECTILE DYSFUNCTION, DECREASED LIBIDO, DECREASED VAGINAL LUBRICATION, AND VAGINAL DRYNESS…’
…We have concluded, however, that the evidence of risk of erectile dysfunction, decreased libido, vaginal dryness, and decreased vaginal lubrication THAT MAY CONTINUE AFTER DISCONTINUATION OF THEDRUG WARRANTS INCLUSION IN ISOTRETINOIN PRODUCT LABELING IN THE ADVERSE REACTIONS SECTION.’
Marvellous – congratulations all – so the FDA has ordered the symptoms of enduring PRS to be included in the small print. Any size print is a triumph. I’m guessing that this could have been the protracted hiccup in the PSSD negotiation? And assuming that a letter from you to that effect will have winged or be winging its way to that jolly chap, Michael C, already.
I’m sure I’ve missed myriad subtleties that you will have eagle eyed. Advice to others attempting this regulatory Matterhorn – read it from the back.
I’m pretty sure that was not the hiccup. A letter saying thanks has gone. And another letter about a hiccup.
D
I missed the brief – ‘what it is about it that has us figuring it raises several substantial issues quite apart from what it accepts and what it denies.’ Too much speed-reading and then a numbed mind.
On reflection– obvious to you for decades – the letter is by way of an extremely long and detailed confession – the system is geared to harm patients more than protect them.
Top tier evidence of causation is ‘RCTs’, so largely marketing to heighten perceived benefits and bury harms. Maybe unethical, but not an unexpected commercial object8ve. Second tier evidence of causation is case reports and pharmacovigilance from a voluntary, inadequate, laggardly adverse event reporting system. Hence the average 30 year time lag between first reports and begrudging system recognition of harms.
Awaiting your clever stiletto work on this – and more correspondence. But my simple diagnosis is- intractable hiccups – a medical emergency.
Intractable Hiccups is a marvellous description of the problem we have. It’s not just a medical emergency – it’s what in bigger picture terms might be called a metamedical emergencies
A number of linked things came to light with this FDA response. There are at least two posts on their way to lay these out – one of which will need have Intractable Hiccups in there
D
The first time I read it, I picked up on them stating about general population dysfunction and applying it, when at least in my view, they already lessened that with stating “the reports featured young, overall healthy men and women without specifically stated additional risk factors for sexual dysfunction”.
I was also thinking along the lines of FAERS data also being online self reported, that they imply self reported online data to be of lesser value, while most of their own data may be that as well.
Then I saw the comment from Harriet about missing the brief, and realised you were asking for something different, so re-read it, and think the answer you were looking for was actually super simple and I was overthinking.
“a boxed warning is ordinarily used when:… There is a serious adverse reaction16 that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring,
avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation)”
A boxed warning may still be possible, if there is a proven way to reduce or prevent it from happening. Which I think might have been the answer you were looking for.
The wording for reference 16 states that “a persistent or significant disability/incapacity” is part of the allowing criteria for that section. Its already there, “persistent disability”. Need to find a way to reduce or prevent it to get it on the box going by what they gave. In reality, I don’t think it is that easy, there are so many external factors that would make getting a post-cessation study almost impracticable for the evidence required that they accept.
I might be completely wrong, atleast that is how I have taken it in reference to “what it accepts and what it denies”.
M
Thanks for this. See the new post on RxISK.org – there are going to be follow up posts in response to this petition and the PSSD post which is still awaiting a decision
D