It’s Not 2003 Anymore
Why the Latest Prescription Dry Eye Drops Are Less Likely to Be Blockbusters
2003
The year is 2003, and after a bruising dialog with the FDA, Allergan’s dry eye drop Restasis is finally approved. Over the next 20 years, Restasis will generate billions of dollars in revenue for Allergan, making the company a stock market Big Pharma darling.
The Restasis Story is worth reviewing, because Big Pharma learned from Allergan’s mistakes. We can see this in the design of a recent phase 3 clinical trial for a novel dry eye drug, in particular the choice of vehicle eye drop and the outcome measures.
If you want to geek out, the entire Restasis drug approval package is available here:
Restasis Drug Approval Package
The original clinical trials were, of course, vehicle controlled. This means that some study patients received an eye drop identical to the product later marketed as Restasis, and others received an identically packaged eye drop that contained all the same ingredients except cyclosporine (which was the active ingredient being evaluated).
The two primary outcome measures for the study were interpalpebral (between the eyelids) corneal and conjunctival staining, and the Ocular Surface Disease Index (OSDI) score. Oopsies for Allergan, one study showed no difference in either outcome measure between Restasis and the vehicle eye drop at any time point. The other study showed statistically significant differences at some time points but not all of them. In particular, there was no difference in OSDI scores between Restasis and the vehicle at month 6. The statistician (God love her) concluded that these two clinical trials “…did not prove adequate evidence for the efficacy of cyclosporine 0.1% and 0.05%.”
As in, Do Not Approve.
Allergan lost its mind, thrashed its data, and eventually received approval for Restasis based on the fact that it increased Schirmer test scores in about 15% of study patients. You heard me, 15%.
The statistician wrote a great summary of the amended FDA approval submission, best paraphrased as “You’re shitting me, right?” Her language is so beautiful that I quote it in full below:
Since the subpopulation was selected unblindedly after the original studies, the interpretability of the analysis result is questionable. Without a pre-specified clinical criteria, a subpopulation could be selected in numerous ways and it would not be surprising to find a subpopulation with significant results even when a drug is not effective.
It didn’t matter. Restasis was approved. The horse was out of the barn and running hard.
In 2003 dry eye patients had very few treatment options. Lower potency topical steroids like loteprednol weren’t on the market yet. Artificial tears were limited and primitive. Most eye care providers paid little attention to Meibomian gland function unless the patient had frequent styes, thus many patients with evaporative dry eye disease were under-managed. Blepharitis was something that happened to eyelashes, not the ocular surface. Contact lenses, and contact lens cleaners, weren’t the greatest (remember thimerosol?).
Along comes Restasis, which offers to improve those un-improvable dry eye patients we all had piling up in our practices. And it did.
Except, it didn’t. But it did. Because the vehicle was a pretty darned good dry eye drop in and of itself. This OTC eye drop was briefly marketed as Refresh Endura before someone in the Allergan C-suite slapped their forehead and realized how stupid it was to manufacture your own competition. Refresh Endura was discontinued in the US around 2008.
Thus Restasis became a blockbuster drug for Allergan, because eye care providers prescribed it for anyone with dry eye symptoms and it was freakishly expensive. We’re talking billions and billions earned. Restasis was such a luscious peach that Allergan engaged in anticompetitive behavior to keep generics off the market for several years longer than usual (the first generic was not approved until 2022). I was startled to find that the FDA felt the need to do a news release on this. (I think Luscious Peach would be a good name for a race horse. What do you think?)
By the way, Allergan has been hit with class action lawsuits over its anti-competitive behavior, the total fines of which are much less than Restasis earns in a year. Although I have to hope that the legal fees hurt in principle.
2023
Anyway back to now…. Earlier this year, Xdemvy (for Demodex blepharitis) and Miebo (for evaporative dry eye disease) received FDA approval. Are these the next blockbuster prescription eye drops? Should we all buy Bausch & Lomb stock?
You might be saying to yourself, “Now there are many good treatments for dry eye disease, targeted at the actual underlying problem(s) like Meibomian gland dysfunction or aqueous deficiency. So Miebo and Xdemvy aren’t going to get the same traction as Restasis, which was the only prescription option in 2003.”
You’re right. But not for the reasons you think.
One reason why Miebo isn’t going to take the race is because an increasing number of eye care providers provide cash-pay office procedures to treat Meibomian gland dysfunction (such as LipiFlow and IPL). After dropping big change on these devices, I can’t see them being happy to give B&L a slice of their profit pie. This is particularly true if Miebo is expensive (which it will be), because then patients will choose to do one, not both: Miebo drops, or office procedures. And if the cost of the Miebo is about the same as the office procedures, and it works, then those patients go away forever. But the finance charge on the equipment remains.
It reminds me of the early days of laser vision correction. Optometrists were seriously not keen on LVC because every happy LVC patient was one less patient getting an annual exam, glasses and a year’s supply of contact lenses. The LVC billboard crowd cured this referral reluctance through co-management, which was basically a kick-back scheme from MDs to ODs. Or they just gave kick-backs. Bausch & Lomb has almost no way to financially entice doctors to prescribe Miebo, because there is a chunk of new-ish Federal law that makes those enticements 100% reportable, and in some circumstances illegal.
So Miebo is in competition with cheaper, effective treatments for Meibomian gland dysfunction. But more importantly, it is in competition with the bottom line for any “dry eye specialist” eye care provider who offers in-office Meibomian gland treatments.
Xdemvy might have some good laps around the track, especially because I expect it will be prescribed whenever a patient has even 1 collarette, or potentially the slightest bit of lash debris at all. However, Xdemvy is one of those “single cycle” drugs which either works or doesn’t work. If the patient doesn’t have demodex, Xdemvy won’t help. If the patient does have demodex, Xdemvy kills it in 6 weeks and you’re done. Since demodex infestation messes with your Meibomian glands, there is also the same competition with in-office procedures that Miebo faces. The more expensive Xdemvy is, the less likely a patient will use the medication and also swing by the office for an IPL treatment while they’re waiting for it to work. [If I had demodex I would take oral ivermectin, which would cost me about $20 and kill the demodex on the rest of my body too.]
What I wish I could believe, but I don’t believe, is that eye care providers have learned from our collective Restasis experience. The Restasis approval allowed Allergan to rape and pillage the pockets of patients for almost 20 years, by requiring them to buy cyclosporine (which did nothing for 85% of them) in order to use Refresh Endura. Eye care providers were accessories to the crime, because without a doctor writing a prescription, Allergan had no power.
It is possible that a certain generation of ophthalmologists – my generation – recalls Restasis with bitterness and views all new prescription drugs in the dry eye space with extreme cynicism. Or maybe that’s just me. I have no clue about the younger generation, except to say that they have been much more protected from the depredations of drug reps so there is reason for slight optimism.
Optometrists have had prescription-writing privileges for some time now. Optometry has always had a stronger business orientation than ophthalmology, so the sale of cash-only in-office tests and treatments doesn’t conflict with the profession’s self-image. I hope that as this profession matures in the medical management of eye disease, it collectively becomes more cautious and discerning regarding the adoption of new drugs and other treatments.
