Descovy, Truvada And The Politics Of PrEP

US FDA's advisory committee review of Gilead’s Descovy for pre-exposure prophylaxis of HIV wasn’t exactly free of controversy. But the meeting sure went more smoothly than the first PrEP review seven years ago.

When the US Food & Drug Administration’s Antimicrobial Drugs Advisory Committee met on 7 August to review Gilead Sciences Inc.’s Descovy for pre-exposure prophylaxis of HIV (or PrEP), FDA Division of Antiviral Products Deputy Director Jeffrey Murray noted that it was only the second application for PrEP to come before the agency.

The first, he reminded the panel, was a May 2012 review of related compound: Gilead’s Truvada. Like Truvada, Descovy is a combination of emtricitabine with a pro-drug of tenofovir; the pro-drug differs in the two formulations.

“Some of you may have been here in 2012,” Murray observed dryly. “I know I was.”

It would be hard to forget being there. The 2012 meeting ended in positive votes to recommend approval for Truvada, but only after a grueling marathon of a review that made national headlines.

The meeting took place in a climate of considerable media attention, with an unusual range of advocates all urging rejection of the application – some on moral grounds painting Truvada as a drug to enable a lifestyle they object to; some on public health grounds as likely to backfire by reducing proven-effective strategies like condom use; and some from HIV advocates frustrated by Gilead’s past pricing practices. It was the rare application that prompted billboard ads at bus stations in the Washington, DC area.

FDA knew the Truvada review would be a long day, and blocked out 8 am-6:30 pm for the review. But the meeting dragged on well into the evening. The panel voted to recommend approval of the application – but then agonized over the appropriate mechanisms to assure appropriate prescribing.

The committee finally adjourned at 8:30 pm without even discussing the final two of the four questions posed by FDA. (Also see "Truvada PrEP REMS Needs More Work, FDA Panel Says" - Pink Sheet, 14 May, 2012.)

Times Have Changed, And Changed Dramatically

So it might have seemed like a bold scheduling decision for FDA to start the Descovy meeting at 8:30 am (a half hour later than most committees convene) and plan to wrap up at 4:30 pm.

But times have changed, and changed dramatically. FDA itself noted the change ahead of the meeting in conflict-of-interest waivers to allow two members (Brigham & Women’s Lindsey Baden and Case Western’s Barbara Gripshover) to participate in the review.

As part of the waiver process, FDA has to assess the level of “sensitivity” around the topic, and the agency made the case that this time would be very different.

“This topic is not considered to be sensitive as the Division with responsibility for review of this product does not expect that the meeting is likely to receive significant public interest, (non-trade) press interest,” the agency said, “nor is it considered highly controversial given that the newsworthy and controversial issues of PrEP were fully addressed 7 years ago at the time of the initial approval of Truvada. PrEP has now been widely embraced as part of a public health strategy to reduce new HIV infections. In addition, Descovy is already approved for the indication of HIV treatment.”

It is indeed true (and even remarkable) how completely the arguments against PrEP on medical/moral grounds have dissipated in such a short period of time. The embrace of PrEP is exemplified by the Trump Administration’s announcement of a plan to expand PrEP use to help eradicate HIV in the US, including negotiating a substantial product donation agreement with Gilead. Sometimes, it seems, scientific evidence does carry the day.

Pricing Issues Are Still Present

That said, the background controversy over Gilead’s pricing and commercial activities remains – and arguably made it a stretch for FDA to say it would not be “sensitive.”

After all, the product donation agreement was followed up in the House of Represenatives with a hearing into Gilead’s pricing of Truvada, the potential that it might attempt to replace the brand with Descovy, and the role of taxpayer funding in the PrEP use. (Also see "Drug Pricing Hearing Takes A Partisan Turn As Gilead’s O’Day Holds His Own " - Pink Sheet, 17 May, 2019.)

The concerns about “product hopping” have also been raised with FDA directly in the pending application: two advocacy groups (the Treatment Action Group and the PrEP4All Collaboration) challenged the sNDA publicly in a letter to the FDA Antiviral Drugs Division within 10 days of Gilead’s submission of the application.

The advocates’ concerns about the potential for Gilead to paint Descovy as a “superior” PrEP option carried over into the committee discussion, with a clear message that the company not be permitted to “oversell” the new formulation. (Also see "Gilead’s Marketing Of Descovy For HIV Prevention Should Not Suggest Superiority To Truvada" - Scrip, 9 Aug, 2019.)

FDA Got The Committee Chair It Wanted

Still, the conflict of interest waivers were important not just in correctly predicting a lower profile meeting. They also disclosed the very narrow focus FDA intended for the conversation – whether Gilead’s study conducted exclusively in men and transgender women could support an indication that includes cis-gender women.

That topic generated plenty of passionate commentary about the “failure” in the study design – but also pre-supposed the overall approvability of the application. (Also see "Gilead, US FDA Ponder Innovative Designs For Descovy HIV Prevention Study In Women" - Pink Sheet, 12 Aug, 2019.)

Indeed, the committee voted overwhelmingly in favor of approval of the PrEP indication for men, before splitting almost down the middle (10-8 against) on whether to include women in the label as well. (Also see "Gilead's Descovy HIV Prevention Indication Should Exclude Women, US FDA Advisory Cmte. Says" - Pink Sheet, 7 Aug, 2019.)

And the waivers also meant that Baden was eligible to chair the meeting. As chair of the committee since 2015, Baden has shown an ability to be unfailingly polite, articulate and fair in his summaries, and firm in moving the discussion along in a timely fashion without shortchanging participation by other members.

As FDA put it in the waiver, Baden “has vast experience running complex meetings which would be complementary to new and less experienced members attending the meeting. Recently, he successfully chaired two complex meetings for the Division of Antiviral Products, one for smallpox and one for rabies. He not only guided the meetings, but also raised important issues that were necessary to fully understand the Division’s concerns. Without his extensive background, the Division would not have received the advice that was critical for drug development in these serious and life-threatening infectious diseases.”

FDA is surely right that the second PrEP review would never have been quite as big a deal as the first. But it also surely helped to have a tightly focused topic up for discussion and an experienced, effective chair to run the meeting.