FDA's Nonprescription Drugs Advisory Committee voted unanimously April 15 to recommend approval of Galderma Laboratories L.P.'s first-in-class OTC switch of adapalene gel 0.1% acne treatment.

During the meeting in Gaithersburg, Md., each of the 16 panel members said yes to FDA's two questions put to votes:

Has the safety of adapalene gel 0.1% for OTC use for the treatment of acne been adequately demonstrated?
The sponsor proposes OTC use of adapalene gel 0.1% for the treatment of acne in consumers 12 and older. Does the totality of the data support the use of this product OTC?

The latter addresses what traditionally has been the indication for OTC acne treatments.

The US subsidiary of French pharma Galderma SA submitted its supplemental new drug application for the switch in September. If approved by FDA, the product, to be marketed as Differin Gel, would be the first OTC drug available in the US that contains adapalene, a member of the retinoid class.

While the drug's demonstrated safety profile as an Rx ingredient was affirmed unanimously by panelists – with Ohio State University associate pharmacy professor Maria Pruchnicki characterizing Galderma's case as "very compelling" – more of their discussion focused on a question raised by FDA but not subject to vote.

The issue before the panel was whether the product should be labeled with a warning advising women who are pregnant or breastfeeding to consult a healthcare professional prior to use.

In a March 2013 meeting before Galderma Labs filed its sNDA for the potential switch, staff from FDA's Division of Nonprescription Drug Products advised the firm to conduct studies including label comprehension, self-selection, actual use and a pharmacokinetics assessment under maximal usage conditions, or Maximal Usage Trial (MUsT).

The division said it requested label-comprehension testing on warnings against use in pregnancy and for sun avoidance. FDA expressed concerns about teratogenic and carcinogenic potential identified in animal studies and post-marketing experience for adapalene and other retinoid category drug products.

In its briefing document, Galderma Labs stated that FDA's current OTC label warning for pregnant and breastfeeding mothers is required only for drugs intended for systemic absorption, unlike topical Differin Gel. However, the firm proposed to include the warning – “if pregnant or breastfeeding, ask a health professional before use” – on the Differin Gel label.

"This well-established language appears on many OTC medications today. While the proposed [Drug Facts label] includes this language, the data demonstrate no meaningful incremental risk if Differin Gel is used during pregnancy," the firm said.

Galderma Labs also pointed out that animal and clinical pharmacokinetic studies for the ingredient indicate a "clinically important safety margin for risk with topical use, under normal or maximal use conditions."

FDA's briefing document and agency officials in their presentations did not question the potential for safe OTC use of adapalene 0.1% gel, but noted concern – based on Galderma Labs' studies conducted for the sNDA – about breastfeeding or expecting mothers accurately determining whether they should use the product.

DNPD said Galderma Labs' study did not "demonstrate that pregnant or breastfeeding women could adequately self-select to use the product."

General And Targeted Studies

Galderma Labs included 515 subjects 12 and older (304 females and 211 males) in the general population cohort of its label comprehension study and 130 participants (61 females and 69 males) in the low health literacy cohort.

Primary And Secondary Communications Objectives

The study had two primary communication objectives related to important warnings and directions and 10 secondary objectives conveying important considerations regarding use of OTC adapalene gel 0.1%:

Primary objectives:

1. Do not use: On damaged skin (cuts, abrasions, eczema, sunburned)

2. Directions: Use once daily

Secondary objectives:

Use of the medication:

1. For the treatment of acne, clears up acne pimples and acne blemishes, helps prevent new acne pimples and acne blemishes from forming

When using this product:

2. Avoid unnecessary sun exposure, including tanning beds, and use a sunscreen when going outdoors (only tested the “including tanning beds” portion of this warning since all other wording is currently used on OTC acne medications)

Irritation (redness, itching, dryness, or burning):

3. Is more likely to occur in the first few weeks of use

4. Is more likely to occur if using more than one topical acne medication at a time

5. Moisturizers may be used to relieve dry skin

6. During the early weeks of use your acne may appear to worsen before it improves. This is not a reason to stop using

7. Do not use wax to remove hair in the areas where the product has been applied

Stop use and ask a doctor:

8. If irritation becomes severe

Directions:

9. Ages 12 and older

10. Under 12 years of age, consult a physician

Additionally, the firm said in its briefing document that "despite the totality of the evidence supporting safety if used during pregnancy," it conducted a targeted self-selection study with females ages 13 and older on the effectiveness of the OTC warning statement for pregnant or breastfeeding women proposed for the Differin Gel label.

Galderma reported that 74% of the 293 pregnant or breastfeeding women who completed the targeted study stated that they would ask a health professional prior to using Differin Gel. The firm noted that with a 68.4% lower bound of a two-sided 95% confidence limit, the self-selection rate for the general population did not meet the primary endpoint of 95%.

DNDP echoed that conclusion in its briefing materials as the potential basis for concern.

"This suggests that a substantial proportion of pregnant or breastfeeding women would not consult a healthcare professional before using the product," the division stated.

In their debate, several NDAC members, including dermatologists, suggested removing the label warning because the ingredient has been shown safe for pregnant women since becoming available Rx in 1994.

Other members said women who are pregnant should be informed to ask about the drugs they use, and several recommended making the warning more detailed than proposed.

Victor Wu, a physician and an assistant professor at the George Washington University School of Medicine, summed up the question when he called it a "tricky one."

While including the warning in the product's Drug Facts label could cause the "unintended consequences" of some women choosing unnecessarily not to use the drug, omitting the warning would prevent women from being informed that they may want to learn more about the ingredient, said Wu, who also is medical director for clinical transformation at Evolent Health in Arlington, Va.

Anthony Scialli, a physician and a specialist in reproductive and developmental toxicology and obstetrics and gynecology, said warning labels "create adverse effects on their own" and OTC adapalene gel 0.1% does not need a warning for women who are pregnant.

The director of the Reproductive Toxicology Center in Washington said he would not advise a pregnant woman against using adapalene gel 0.1% and he expects the warning would not prompt many to consider not using the drug to treat acne.

"There's no question that regardless of the labeling, pregnant women will use this product and others like it," he said.

Committee Chairwoman Christianne Roumie supports the warning's use. "Removing this from the label doesn't give anybody any information," noted Roumie, an associate professor of internal medicine and pediatrics at Vanderbilt University's Institute for Medicine and Public Health and a physician at a VA hospital in Nashville.

Galderma Labs is proposing for Differin Gel a new OTC indication – “clears up acne pimples and acne blemishes" – but that issue was not a matter for discussion at the NDAC meeting because new efficacy data for adapalene gel 0.1% was not part of the firm's sNDA for the switch.

FDA expressed other misgivings about Galderma's targeted self-selection study, including that it enrolled only two adolescents.

Additionally, only 91 (37%) of the 242 females in the firm's general-population cohort for the self-selection study were pregnant (80 pregnant and 11 both pregnant and breastfeeding). The remaining majority were breastfeeding but not pregnant.

"This is a significant issue with the study, because in development discussions regarding the labeled statement, FDA had focused its concerns on pregnant women. The relatively small sample size of pregnant women in the study leads to difficulty in drawing conclusions from age analyses of this subgroup in the general population," DNPD stated.

The division noted in its briefing document that Galderma Labs is proposing for Differin Gel a new OTC indication – “clears up acne pimples and acne blemishes." However, discussion of the labeled indication was beyond the scope of the NDAC meeting because new efficacy data for adapalene gel 0.1% was not part of the firm's sNDA for the switch; the committee discussed efficacy only in relation to the benefit-risk determination for the drug as OTC.

Galderma Labs has removed from the proposed label a statement it included in its label-comprehension study, that the drug “helps prevent new acne pimples and acne blemishes from forming,” FDA said.

Galderma's Acne Drug Switch Gets Unanimous NDAC Support

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