A “Precedent-Setting” OTC Switch – And A Case Study In Disregarding FDA’s Advice

Galderma’s OTC switch application for the acne therapy Differin (adapalene 0.1% gel) cleared an important milestone with a unanimous vote in favor of approval from an FDA advisory committee April 15. FDA urged the committee to consider the application as “precedent setting” given the theoretical risk of teratogenicity – but one committee member was more worried about the bad precedent of approving an application for a sponsor that didn’t do a label comprehension study they way FDA requested.

When FDA Nonprescription Drug Products Division Director Theresa Michele introduced the agenda for the Nonprescription Drugs Advisory Committee’s April 15 meeting, she wanted the panel to carefully consider a “precedent-setting” application.

Galderma Laboratories Inc.’s proposed OTC switch application for the acne therapy adapalene 0.1% gel (marketed as Differin in the Rx setting) would be a first-in-class therapy and the first NDA-approved acne formulation in the OTC setting. (FDA allows five ingredients to be marketed for acne OTC under the monograph process.)

More importantly, Michele noted, it “would be the first time we’ve considered placing over-the-counter a product that does have a significant toxicology signal for teratogenicity.”

Differin is a retinoid, chemically-related to isotretinoin (Accutane) – an oral acne therapy marketed with an extensive (and controversial) pregnancy prevention program. Differin has no proven link to fetal abnormalities, and FDA agrees that there is a significant margin between doses that may be teratogenic in animal models and the maximum exposure likely for humans using a topical gel.

Still, Michele urged the committee to weigh carefully how much reassurance it would need to say the product is okay for OTC use.

“As a general philosophy, products for over-the-counter use are expected to have a very high bar for safety,” she noted. Given the teratogenicity signal, “what we are asking you to weigh is where do you set that bar? What is an appropriate level of risk in the over-the-counter setting given the absorption profile we see for adapalene?”

That set a high bar for the sponsor indeed. However, Galderma’s own development plan arguably made the bar higher still: the company decided not to follow FDA’s advice in designing a labeling comprehension trial to test whether pregnant women would appropriately follow instructions to consult a physician before using the therapy.

FDA’s briefing documents for the meeting presented the issue succinctly and starkly: “it is apparent from the data provided by the sponsor that if adapalene were available OTC, the product would be used by pregnant women due to the low perceived risk of OTC products in general and topical products in particular. “ Thus, FDA told the committee, “the primary consideration for this application is whether the benefits of OTC availability outweigh any potential risk for teratogenic effects on the developing fetus. “

By a 16-0 vote, the committee agreed they do. In doing so, they suggested something like enthusiasm for the precedent: voicing strong opinions that animal studies using much higher exposures than are seen (or even possible) with a topical gel are essentially irrelevant to safety in humans. (Also see "Galderma's Acne Drug Switch Gets Unanimous NDAC Support" - Pink Sheet, 25 Apr, 2016.)

While FDA approval is not a foregone conclusion, it sure looks like FDA is indeed ready to approve a retinoid acne therapy for OTC use. And the agency may not stop there.

What Should The Label Say?

On the key question of safety in pregnancy, the committee also voted unanimously (16-0) that the drug is safe for OTC status, despite concerns about potential teratogenicity in the retinoid class to which adapalene belongs. The safety vote reflected a strong view from the committee that the risk with adapalene is low at any dose, and inconsequential in the context of a 0.1% topical concentration.

While the committee was unanimous in their opinions that use of the 0.1% concentration of Differin gel is safe in pregnancy, they were divided on whether and how the label should discuss the risk. That remains the key issue for FDA and Galderma to resolve.

There was no formal vote on the question of labeling for pregnancy risk. However, the committee was about evenly split on how to handle the issue. At one end of the spectrum, several committee members –including the reproductive specialists invited as guest members—argued that the conclusion that the product is unlikely to pose any risk in pregnancy argues against any warning statement whatsoever. At the other end of the spectrum—including many of the permanent members of NDAC—the view was that consumers should be informed of the teratogenicity risk with the class and provided with useful information to make an informed decision.

The one point of agreement was that the proposed label—with a boilerplate statement that pregnant or breastfeeding women should consult a physician—is not the right approach. Panelists also shared a concern that the wrong approach could lead to needless anxiety or fear in pregnant women, and potentially decisions to terminate pregnancies based on a largely non-existent risk of adverse fetal outcomes.

Reproductive Toxicology Center Director Anthony Scialli made the strongest case for removing the pregnancy warning altogether: “I am not at all concerned about the teratogenicity of retinoids as a group. In fact I think it is rather unfair to characterize a whole group of molecules at different doses as being teratogenic, that kind of generalization just leads to trouble,” he said. “If a woman asked my advice on use of the product during pregnancy, I’d tell her, ‘Go right ahead.’”

Kaiser Permanente Dermatologist and temporary committee member Kenneth Katz shared Scialli’s sentiments, and argued that any warning label would in fact do more harm than good. “It raises questions about how women will feel once they realize they have been using a product that bears that label… I don’t think the teratogenicity concerns are substantial, so why have the label there? I think it just creates problems for the consumers and their physicians later on down the line.”

“I think that all of us strive to practice evidence based medicine and I think that we saw how the committee felt about the safety of this product,” Katz said. “If I had to stick to evidence based medicine or reflexive evidence based caution, I think we should move more toward evidence based medicine. If we are comfortable with the safety profile, we should put our nickel down on that.”

Committee chair and Associate Professor of Pediatrics at Vanderbilt Christianne Roumie argued the opposite side, noting that because adapalene is in the retinoid class, there are bound to be questions raised for some consumers about potential risks in pregnancy.

Roumie explained that, rather than remove the warning, she would “make it stronger.” She noted that there is plenty of information online about the potential risks of retinoids in pregnancy, and that consumers are bound to have questions as a result. She agreed with Katz that the boilerplate language is inadequate, and that the default reaction of most clinicians contacted by a patient will be to advise them to discontinue use in pregnancy.

Thus, she argued, the label should explain the basis for the concerns about retinoids and communicate the rationale for concluding that adapalene is safe for use in pregnancy. “I think more knowledge is more power for the patient.”

Galderma’s Effective Reframing Of The Issue…

Michele’s framing of the meeting as “precedent setting” posed a tough challenge to Galderma. The company, however, did a good job of reframing the “precedent-setting” nature of the application in a more reassuring light, including an effective summary presentation by former FDA Dermatology Division Director Jonathan Wilkin.

He stated his enthusiasm for the “first OTC acne therapy approved and regulated by FDA under an NDA.” In addition, he noted that retinoids are already widely available over the counter in the form or Vitamin A based dietary supplements and “retinol” creams. Differin, he said, would thus be the “first retinoid” approved for OTC use with studies showing “a substantial safety margin.”

However, the company’s fundamental challenge remained: Galderma’s own studies suggested many pregnant women would disregard instructions to consult a physician. That left the company to argue that, in fact, there is no risk of teratogenicity with the marketed formulation.

Thus, this became an OTC switch application that pivoted on non-clinical teratogenicity data – yet another unusual aspect of the review noted by Michele in her intro. FDA’s presenters suggested that, based on animal models, the margin of safety with the proposed OTC formulation was quite large: about a 70-fold difference between the dose associated with risk in teratogenicity models and the maximum absorbed dose seen in pharmacokinetic studies of the gel.

Reproductive specialist Scialli argued that analysis essentially showed no risk of teratogenicity. “If [adapalene] didn’t look like trans retinoic acid we wouldn’t even be having this conversation,” he said. He argued that the animal models only reinforce the truism that “the dose makes the poison” and that any drug could produce fetal malformations at a high enough dose.

While the committee ended up agreeing with the sponsor that there is no serious risk of teratogenicity, FDA may find it harder to shrug that issue off, particularly since the agency had specifically asked the company to do studies to test the ability for pregnant women to appropriately self-select against using the product.

…But “Boilerplate” Approach May Still Backfire

Galderma explained to the committee that it opted not to test the proposed label advising pregnant and breast-feeding women to consult a physician because it is standard labeling included in FDA templates for OTC products.

FDA, however, repeatedly noted that the agency does encourage sponsors to test comprehension of even well-established labeling in cases where the warning is particularly important for safe use of the product.

FDA’s summary of the regulatory history for the OTC product includes several notations of agency recommendations to focus on the teratogenicity risk in label comprehension studies and self-selections studies, and to provide data about reproductive counseling practices in the prescription setting. At several points in the document, FDA offers a tone of disappointment that Galderma did not look more specifically at the pregnancy risk, including when the agency notes in the risk/benefit summary that “the sponsor did not investigate whether strengthening the proposed Drug Facts Label or other labeling options for adapalene OTC would change this consumer perception.”

The agency made clear to the committee that it needs to assume that pregnancy exposures will be very likely in the OTC setting as a result.

In the study of label comprehension, the primary objective tested among the 586 respondents ages 12-70 was the instruction to “use once daily,” and the secondary objective was to test “Do not use on damaged skin.” The study succeeded on those terms. “Unfortunately,” FDA added in the briefing documents, “warnings regarding use in pregnancy and sun avoidance (other than tanning bed use) were not tested, which substantially limits the utility of the study.”

The self-selection study indicated that pregnant women would indeed disregard the warning. Among pregnant subjects, “70% of women (LCB 58.7%) said they would ask a doctor before use”—but 30% said they would not, FDA noted. “Rationales given by subjects for incorrect self-selection suggest that women believe that topical products cannot hurt a developing infant and that OTC products are safe to use during pregnancy. In addition, a subgroup (N=15) stated that they did not see the warning on the label.”

Galderma’s actual use study similarly demonstrates the likelihood of use during pregnancy: “Fourteen subjects chose to use the product while pregnant or breast feeding,” FDA said. “Similar to the self-selection study, the stated reasons for this suggest that women perceive a low risk with topical products, lack of perception of the seriousness of the warning, or not seeing the warning.”

Limits To The Precedent

As the meeting played out, FDA did not press the committee to demand more studies from Galderma, with the agency seemingly willing to accept the view that—for this particular product—the risk of teratogenicity is remote enough that it can in essence be disregarded.

However, the agency also signaled that other sponsors should not assume they can follow Galderma’s approach.

During the discussion, when it was clear that the application was headed toward an approval vote, Michele came back to the notion of the precedent-setting nature of the decision. She acknowledged the committee’s vote that the bar for safety had been cleared in this case, but asked the committee to offer thoughts on “where the bar should be set” for future applications where teratogenicity is a concern.

The executive secretary cut off that discussion by reminding Michele that the conflict-of-interest screening for the committee was focused on a specific application and not a “general issue.”

However, it seems safe to assume that FDA is thinking ahead to potential switches of other retinoid therapies, including Valeant Pharmaceuticals International Inc.’s Retin-A/Renova (tretinoin) franchisewhich has long been discussed as a logical OTC candidate – and a case where the active ingredient (tretinoin) has been shown to be teratogenic in oral form.

Galderma’s decision to rely on boilerplate language and a reassuring margin of safety, in fact, limits the precedent setting nature of the approval: at least at the advisory committee level, this is a safe product for OTC use in pregnancy, and therefore not setting any new boundaries for OTC status.

Other therapies with greater risks, however, may need to apply different approaches and hope to capitalize on the agency’s NSURE initiative (Nonprescription Safe Use Regulatory Expansion).

FDA announced the NSURE effort at the start of the Obama Administration, driven in part by the identification OTC switches as an opportunity to reduce costs for insurers in the market expansion contemplated by the Affordable Care Act.  The focus of the initiative is on applying new technologies and commercial strategies to allow for OTC availability of therapies that may not fit the traditional expectation of a nearly risk-free profile in the absence of physician and pharmacy oversight. (Also see "Reinventing OTCs: FDA Seeks New Models; Stakeholders Urge Renewed Focus" - Pink Sheet, 3 Apr, 2014.)

While the initiative raised hopes for a wave of new switches, there have been few signs of tangible progress to date, and the likelihood is that FDA won’t even issue a formal NSURE proposal before the Obama Administration ends.

Still, anti-acne treatments like Retin-A are widely considered the low-hanging fruit for Rx-to-OTC switches, given the long history of OTC treatment of acne and the overall margin of safety inherent in topical formulations. Galderma’s application may not trigger the need for stronger controls to limit access by pregnant women – but a follow-up application may.

And at least one member of the advisory committee—who joined the vote in favor of setting the precedent of approving a potential teratogen for OTC use—nevertheless voiced concern about seeming to approve the precedent of a sponsor failing to do label comprehension studies requested by FDA.

“The safety of this drug with all of the information provided to us certainly makes it a very compelling ‘yes,’ I don’t think anyone here on the committee is in doubt of that,” Ohio State Associate Professor of Clinical Pharmacology Maria Pruchnicki said.

However, “I’m not sure that [failing to study specific pregnancy labeling] is a good precedent for others to follow. If the FDA is requesting more information, I personally would like to see that information, and I do think we, in terms of the process or in terms of the totality of data, in other situations would need more to make that assessment.

She drew an analogy appropriate to the April 15 meeting date. “It’s a little bit like having to fill out the tax form even though you don’t need to send in any money at the end of the day, you still have to go through the process, the IRS doesn’t give you the bye,” she said. “So I would just state that even though in this case it was fine because the sponsor felt like it was really safe, I would like to see the proof in the pudding.”