January 2, 2009

The way we’ve worked around this in Singapore, where it is indeed the case that HQ products require filing for NDA’s, is to use compounded formulas (either Kligman or Groot’s formulas).  For us here, this transfers the responsibility to the MD who is compounding the prescription and removes the local version of the FDA from responsibility. We also provide very small quantities of the cream to ensure there is regular oversight to the patient’s use of the cream and that it is used no longer than 2-3 months at one time.

On August 29, 2006, the FDA proposed restrictions on products containing the bleaching agent hydroquinone due to reported concerns about possible carcinogenicity and a link to ochronosis

 If implemented, the action would impose an outright ban on lower-strength (2%) over-the-counter products. But far more worrisome to dermatologists, who depend on such products to treat a variety of pigmentary disorders and post-inflammatory hyperpigmentation, would be a requirement that long-established prescription products be compelled to file new drug applications (NDAs). This could effectively eliminate all but one product — FDA-approved fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05% (Tri-Luma) — from the market until FDA approval conditions could be met.Could this be the beginning of the end for a product that has already been banned in Asia, Africa, Japan, the European Union and Australia?

An Optimistic Outlook

University of Miami Assistant Professor of Dermatology Heather Woolery-Lloyd, who specializes in pigmentary disorders, thinks not. She points to the product’s unparalleled efficacy and decades of safe use for both OTC and prescription products.

“The FDA is not likely to ban prescription hydroquinone. It has been widely and safely used in the United States for 30 to 40 years, and nothing else comes close to the effectiveness of prescription-strength hydroquinone. There are many products available, but nothing as efficacious.”

Her understanding is that the FDA may “grandfather in” existing products, but the worst-case scenario she imagines is “black-box labeling” that may alarm patients, and a temporary reduction in the number of products available while companies assess the feasibility of reapplication before undertaking expensive and time-consuming clinical studies and other FDA approval hoops.

But several of her colleagues, also dermatologists specializing in pigmentary disorders, are concerned about the very future of the agent that they all agree is unrivaled for the treatment of hyperpigmentation. They stress the considerable benefits of hydroquinone over risks they regard as questionable.

Hydroquinone Use in the United States

Dr. Susan Taylor, a Philadelphia dermatologist and the founding director of the Skin of Color Center at St. Luke’s-Roosevelt Hospital in New York does not feel the data used to question the safety of hydroquinone is compelling, especially in view of how it is used in this country compared to those in which it has been banned.

In Africa, she says, it is used in much higher concentrations, more often, and over larger areas, because the objective is overall skin lightening, whereas in the United States, the products are primarily used to lighten dark areas of the skin due to conditions including injury, rashes, acne and sun damage.

She considers the evidence of a link to cancer “quite weak”.

“The data on rats and mice cited by the FDA cannot necessarily be extrapolated to human data,” she asserts.

What’s more, she says, a link to cancer is not apparent in the very population that has experienced ochronosis.

“We have not seen a proliferation of various types of cancer from the African population, even among those who have used hydroquinone for 10, 20 or even 30 years and in high concentrations. Nor are there any data supporting human cancers in workers who are exposed to high levels of hydroquinone in film or lithography processing.”

Risks vs. Benefits

Fran Cook-Bolden, M.D., too, wonders if the FDA has not carefully enough considered the benefits of hydroquinone against the risks for patients whose conditions may well be considered more than cosmetic.

“As a dermatologist with a special interest in pigmentation disorders and a large practice (the majority with pigmentation concerns), my associates and I really do see the devastating effects of hyperpigmentation on our patients, from their ability to acquire employment and to succeed professionally to the effect on successful personal and social relationships.

So great is the need for effective treatment among those who need it most, it is her fear that they will turn to the most dangerous and unregulated market of all — the black market.

“Skin-lightening creams, which could contain high-potency steroids or mercury alone or in combination with high concentrations of hydroquinone, are readily available in many neighborhood markets and beauty supply stores,” says Dr. Cook-Bolden, Skin Specialty Group Director and Assistant Clinical Professor of Dermatology, Columbia University. “Horrendous side effects” from such substances, she says, could include “thinning of the skin, hypersensitivity, and can even result in neurological disorders as a result of high levels of mercury exposure with chronic use of many black market combination products.”

Lack of Other Viable Options

UCLA Dermatology Professor Pearl Grimes, M.D., is against both removal of OTC hydroquinone and the FDA proposal to require NDAs for prescription products.

“My experience as a dermatologist for the past 18 years is that hydroquinone is the most effective therapy we have for pigmentary disorders. Pulling it off the market would deny patients and lay people a safe and effective treatment,” says Dr. Grimes,  Director of the Vitiligo and Pigmentation Institute of Southern California.

Dr. Grimes offers a short list of alternatives such as azelaic acid, kojic acid, mequinol, and licorice, saying, “They have some efficacy, but they don’t work as well as hydroquinone. And that’s why after 50 years, it’s still the number-one seller in the United States.”

Long- and Short-Term Impact Of FDA REgulations

Noting that people of color tend to have more pigmentary disorders and hence need the medication more than Caucasians, Dr. Grimes is concerned about both short- and long-term ramifications of the FDA proposal.

“New drug applications are enormously expensive. For some companies it won’t be worth the expense. What’s more, those companies who choose to comply won’t be able to market these same drugs until the process is completed, meaning there could be a period during which there will only be this one drug on the market.”

And a single option, insists Dr. Grimes, is not enough. “When treating conditions such as melasma and post-inflammatory hyperpigmentation, there is no one drug that works for every patient and that’s why it is so important to have an array of products.

Product Safety

Calling herself “a purist about research”, Leslie Baumann, M.D., has mixed feelings about the FDA dust-up over hydroquinone. Like her colleagues, she considers hydroquinone “without equal” for treating hyperpigmentation and has few concerns about its safety.
She favors keeping the lower-strength OTC products on the market, but believes, partly as a matter of fairness, that the prescription hydroquinone providers should all be held to the same standard — a view she admits may make her unpopular with the drug companies, many of which she has worked with.

“I use both OTC and prescription hydroquinone on my patients and think it’s a really great ingredient. It would be a huge shame if taken off the market. However, the FDA is sending an inconsistent message if they remove OTCs for safety reasons but then allow prescription-strength products that have not undergone the rigors of a safety trial to stay on the market.”

“I think we should encourage companies to do research on their products and not penalize them for it,” she remarks. “I personally have performed safety and efficacy trials on Claripel and Tri-Luma, and I feel the other prescription brands should be held to the same standard.”

Denying Patients an Effective Treatment

The conclusion of this group of dermatologists differs markedly from the FDA proposal’s “tentative”conclusion that “the benefits of [over-the-counter] skin bleaching drug products are insignificant when compared to the potential risks.”

These dermatologists challenge the reasonableness of depriving patients of an effective treatment for disfiguring conditions that can be emotionally devastating on the basis of animal studies in which the product is not applied but ingested and on the experience of countries in which the product is used very differently due to different formulations and usage practices based on very different standards of beauty.