February 22, 2016
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 22, Rm. 5443 Silver Spring, MD 20993-0002
RE: Public Comments on Draft Guidance “Over-the-Counter Sunscreens: Safety and Effectiveness Data Draft Guidance for Industry” [Docket No. FDA-2015-D-4021]
Dear Ms. Hardin,
The following are the comments of the Public Access to SunScreens (PASS) Coalition, on the draft guidance entitled “Over-the-Counter Sunscreens: Safety and Effectiveness Data Draft Guidance for Industry” (the Guidance) published in the Federal Register on November 23, 2015, as required by the Sunscreen Innovation Act (Public Law 113-195). As a result of President Obama’s announcement of an Administration-wide initiative led by Vice President Biden to prevent and cure cancer at his last State of the Union address, making sure we get the final Guidance right is critical to ensure that Americans have access to the latest sunscreen technology to prevent skin cancer, the most common form of cancer in the United States.
Background on the PASS Coalition
The PASS Coalition is a multi-stakeholder coalition comprised of public health groups, leading dermatologists, sunscreen manufacturers, and concerned citizens. Our membership includes the leading advocates for skin cancer patients. The PASS Coalition formed to ensure Americans have access to the latest sunscreen technology to curb the skin cancer epidemic in the United States. The Coalition's mission is to work collaboratively with the FDA, the White House, Congress, health providers, consumer organizations and sunscreen manufacturers to establish a transparent review within a predictable timeframe for pending time and extent applications (TEAs) for over-the-counter (OTC) sunscreen ingredients. This comment letter represents the consensus view of the PASS Coalition, but does not necessarily indicate the view of each individual member.
A Moonshot to Prevent and Cure Cancer
Not long after his son died of cancer, Vice President Biden began calling for a “moon shot” to prevent and cure this disease. Addressing the prevention and cure of cancer became an official Administration priority when President Obama announced a new initiative lead by Vice President Biden to develop a strategy and lead this moon shot effort at his final State of the Union address before Congress. It is expected that the President will issue an executive order directing all federal agencies and departments to coordinate with the Vice President as a part of this cause.
One of the best ways to survive cancer is to prevent it in the first place. Since skin cancer is the most common cancer in the United States, ensuring that Americans have access to the latest skin cancer prevention technology should be a part of the moon shot initiative. This Guidance is critical to determining whether there will be a viable pathway for new skin cancer prevention technology to enter the US marketplace.
Public Health Effects of Skin Cancer
On July 29, 2014, the U.S. Surgeon General issued A Call to Action to Prevent Skin Cancer stating: "Even though most skin cancers can be prevented, rates of skin cancer, including melanoma, are increasing in the United States." According to the Surgeon General, nearly 5 million Americans each year are treated for skin cancer, making it the most common form of cancer in the United States. Treatments for skin cancer result in $8.1 billion per year in health care spending.
The alarming rate of skin cancer means that each year there are now more new cases of skin cancer than the combined incidence of breast cancer, prostate cancer, lung cancer and colon cancer. Melanoma, attributed primarily to UV exposure, is the most deadly form of skin cancer causing one death per hour in the United States. From 1975-2011, rates of melanoma in young men and women ages 20-39 years increased by 34% in men and by 84% in women.
Radiation from the sun includes both UVA and UVB rays and both UVA and UVB are responsible for skin cancer. UVA rays are the most abundant source of solar UV radiation at the earth's surface and penetrate beyond the top layer of skin, while UVB rays are less abundant at the earth's surface and penetrate less deeply into the skin. Further, UVA rays are prevalent year- round, while UVB rays are most prevalent in summer and during the middle of the day. According to the latest science, while UVB rays are the main cause of sunburn, UVA rays are the primary cause of premature skin aging.
The most effective way to address the risk of skin cancer is prevention including the regular use of sunscreen, covering up with clothing, hats and sunglasses, and seeking shade. Broad spectrum sunscreens including effective protection against both UVA and UVB, are key mechanisms to prevent sunburn, skin damage and skin cancer. Unfortunately, there are few broad spectrum sunscreens on the market in the US.
The Surgeon General's Call to Action states that the government must work with businesses, health care systems, educational institutions, community organizations and citizens to address skin cancer as a major public health problem. The Call to Action concludes with this powerful recommendation: “We must act with urgency to stop the ever-increasing incidence of skin cancers in the United States.” Rapid implementation of the Sunscreen Innovation Act (the Act) and ensuring that Americans have access to new sunscreens is an important first step.
Since 2002, eight new sunscreen ingredients have been submitted for review under the FDA’s Time and Extent Application (TEA) process. FDA still has not made a final decision on a single sunscreen ingredient through the TEA process, even though some have been waiting for as long as 14 years. Meanwhile, these ingredients have been widely available in Europe, Asia, and Central and South America for decades.
That’s why the PASS Coalition supported enactment of the bipartisan Sunscreen Innovation Actby the Congress and rapid implementation of the Act by the FDA. Clearing the sunscreen applications backlog will ensure that Americans have greater access to broad-spectrum sunscreens, which provide better protection against both UVA and UVB rays. Congress intended for the Act to establish a transparent and predictable review process including timelines for review of new and currently pending sunscreen ingredients to ensure that new sunscreen products available to consumers all over the world would also be available in the US to address the skin cancer epidemic.
Independent Scientific Review of FDA’s Proposed Orders
In 2015, the PASS Coalition contracted with two independent scientist to review FDA’s proposed orders for the eight pending sunscreen ingredients. The purpose of the independent scientific review was to provide the Coalition with an analysis of FDA’s actions and to help the Coalition develop recommendations for an appropriate testing regimen based on the risk profile of the pending sunscreen ingredients and the growing incidence of skin cancer. The independent scientists reviewed the FDA feedback letters/proposed orders, the minutes from the NDAC Advisory Committee meeting in 2014, and recent letter correspondence. The conclusions and recommendations made by the independent scientific review are the authors’ own. The authors have submitted the paper for publication in a peer-reviewed journal.
The bios for the two independent scientific reviewers are:
- Edward Sargent, Ph.D., M.P.H., Owner/Managing Director at EV Sargent LLC. Dr. Ed Sargent, who has over thirty-four years of experience in the field of toxicology, is the owner and managing director of EV Sargent LLC, a healthcare and toxicology consulting and research firm. Prior to founding EV Sargent LLC, Dr. Sargent worked as the senior director of toxicology at Merck for twenty-five years. Dr. Sargent earned a Ph.D. in toxicology from New York University and a Master of Public Health, with a specialization in environmental health, from Yale University School of Medicine.
- Jeffrey B. Travers, M.D., Ph.D., F.A.A.D., Professor and Chair, Pharmacology & Toxicology Professor, Dermatology, Wright State University. In addition to serving as Professor and Chair of the Department of Pharmacology & Toxicology, Dr. Travers is a Professor of Dermatology and also holds a part-time 5/8th Staff Physician position at the Dayton VA Medical Center. Dr. Travers earned both his M.D. and Ph.D. in pharmacology from The Ohio State University. A practicing dermatologist-scientist, Dr. Travers oversees an NIH- and VA-funded research program centered on photobiology and skin cancer.
The independent review by Drs. Sargent and Travers concluded that the FDA’s proposed safety and effective data requirements, the topic of this draft guidance, are not supported by internationally recognized standards. However, there is a path forward where appropriate testing and safety thresholds can be developed that balance benefit and risk by factoring in the benefit of more effective sunscreens versus the risk of skin cancer. The feedback from the independent scientific review is described in the specific comments below.
The Act required FDA to issue draft and final guidance on the safety and effectiveness data to be used in the agency’s review of new sunscreen ingredients. The final guidance is required under the Act by November 26, 2016.
Our specific comments follow.
The Coalition supports an appropriate testing regimen that ensures consumers receive timely access to new safe and effective sunscreen ingredients to prevent skin cancer. FDA’s structured approach to benefit-risk assessment in drug regulatory decision-making includes a strong consideration of the impact a new drug can have on its intended patient population. A benefit- risk assessment for sunscreens – one that takes a balanced approach – is crucial. Given the epidemic of skin cancer and melanoma in the United States, FDA should balance the benefits that new sunscreen ingredients will deliver by enabling new broad spectrum sunscreens that prevent the known risk of sun exposure against the potential and theoretical safety risks of these new sunscreen ingredients. The consideration of potential risks should take into account that each of the ingredients seeking to get to market was determined by FDA to be eligible for the TEA pathway because of its safe use in at least 5 countries for at least 5 years prior to the eligibility determination. Since its eligibility determination, each of these ingredients has gains an additional 6-12 years of market experience in even more countries with no evidence of lack of safety or failure of efficacy.
The PASS Coalition appreciates that the FDA has issued this guidance and is attempting to balance benefit and risk when determining the appropriate safety and effectiveness data manufacturers must provide. Nonetheless, in our view the approach proposed falls short. By calling for manufacturers to complete new tests prior to marketing – including tests never before used on sunscreen ingredients, tests required by no other countries and for which there is no agreed-upon protocol – the FDA’s proposal may simply continue to deny Americans access to the latest skin cancer prevention products available throughout the rest of the world.
According to the Guidance, its recommendations “are designed to ensure that FDA’s GRASE determinations for OTC sunscreen active ingredients under the SIA...reflect current scientific knowledge and patterns of nonprescription sunscreen use by consumers”. (Guidance, page 2). The Guidance also notes that FDA balances the role sunscreens play in decreasing skin cancer risks with the “public health importance of providing an adequate safety margin for active ingredients... versus the risks.” (Guidance page 4). FDA goes on to say it considers “both the circumstances under which OTC sunscreen products are intended to be used by consumers and current scientific knowledge and assessment technology.” (Guidance page 4).
We respectfully disagree that the proposed approach meets these criteria.
Maximal Usage Trial (MUsT)
Specifically, the FDA relies on a Maximal Usage Trial (MUsT) as part of its clinical pharmacology/bioavailability assessment. The Guidance says that “sponsors of sunscreen active ingredients provide data from a MUsT to support an adequate assessment of safety.” (Guidance, page 7). In addition, FDA defines maximum use in the case of sunscreen to mean that the ingredient being tested should be used on “nearly all” of the body surface area. (Guidance page 8).
However, a literature search performed by independent scientists commissioned by the PASS Coalition found that the MUsT has little history of use and completion of the test will likely take over a year. In addition, it has never been used for sunscreen ingredients. There is no established protocol for using the MUsT on sunscreen and no baseline for how a sunscreen should perform under the MUsT. In contrast, there are numerous internationally recognized tests that have been used on sunscreen ingredients, have established testing protocols and have yielded significant data on safety and effectiveness. results for sunscreens. Therefore, to propose, as this guidance does, that sunscreen ingredient manufacturers perform a MUsT without an appropriate safety threshold that reflects the risk profile of the products will unnecessarily delay access to new sunscreen ingredients without a sound scientific basis.
We are also concerned that FDA suggests the MUsT “[should be] conducted in subjects with the disease of interest". This implies that the MUsT model should be tested on individuals with dermal conditions, specifically skin cancer. This statement should be removed from the guidance as it is not appropriate for sunscreens. This criterion is meant for drugs treating specific conditions. Preventative drugs such as sunscreen do not treat a disease state so using health volunteers is more appropriate. Therefore, we suggest replacing with “the MUsT is conducted in healthy subjects.”
Body Surface Area
American consumers do not apply sunscreen to “nearly all” of the body surface area. Therefore, 70% of body surface area is the more appropriate testing surface.
Number of Subjects
Given that significant nonclinical data are available indicating that dermal absorption of sunscreen is low, 10 to 15 healthy adult volunteers is sufficient to confirm the lack of dermal absorption when applied under maximum use conditions.
Number of Formulations
Moreover, FDA recommends that the MUsT be conducted under maximal use conditions employing a “minimum of four” formulations containing the new sunscreen active ingredient as the only active ingredient to support the GRASE determination. (Guidance page 7). We are concerned that requiring tests employing at least four formulations will also delay access to important new drugs without a commensurate increase in public health protection.
In addition, the testing of 4 different formulations in the MUsT is neither necessary nor customary. Multiple formulations are usually screened in vitro prior to any clinical testing. As an alternative, if a MuST is required, we recommend testing ofa representative formulation of that to be marketed. These may be formulations with single or multiple active ingredients.
Safety Threshold: 0.5 ng/mL
In addition, in the Guidance, FDA applies a new and arbitrary scientific standard regarding carcinogenicity and toxicity tests. Specifically, FDA says it expects that systematic carcinogenicity studies would be required to support a GRASE determination for a sunscreen active ingredient if an adequately conducted human pharmacokinetic MUsT results in a steady state blood level greater than or equal to 0.5 ng/mL even when an adequately conducted toxicology program does not reveal any other safety signals for the ingredient or any known structurally similar compound indicating the potential for adverse effects at lower levels. (Guidance page 9). Subsequently, the guidance also relies on the 0.5 ng/mL standard regarding absorption levels shown in a MUsT related to toxicity. (Guidance page 10).
However, based on the independent scientific review performed by the PASS Coalition, a blood level of 0.5 ng/mL is not a recognized standard and is not an appropriate standard to use in this context. The 0.5 ng/mL standard is based on the principle that this level would approximate the highest blood level below which the carcinogenic risk of any unknown compound would be less than 1 in 100,000 after a single dose. The 1 in 100,000 excess cancer risk is the internationally recognized standard – not the 0.5 ng/mL – and it yields a 1.5 μg/day threshold of toxicological concern for impurities in new drugs which has also become an internationally recognized standard.
That is, according to the accepted international standard, ingesting or absorbing less than 1.5 μg/day of a chemical of unknown carcinogenic potential will not pose an appreciable risk of cancer. There are no data in any FDA or International Conference on Harmonization (ICH) guidelines (the regulatory guidelines adopted by the US, EU and Japan) which correlates the 1.5 μg/day standard to a threshold blood concentration or suggests that 0.5 ng/mL is the standard for safe absorption of sunscreen ingredients. In fact, the scientific literature supports a standard higher than 0.5 ng/mL as the threshold of concern for sunscreen ingredients. While we support FDA’s establishment of a threshold for absorption, the 0.5 ng/mL standard proposed by the agency is not justified and is lower than the absorption rate FDA used when approving a sunscreen through the New Drug Approval (NDA) process.1
Based on the PASS Coalition’s independent scientific review, it is more appropriate to use a range of 10 to 100 ng/mL as a safety threshold. Under 10 ng/mL would be considered not to be absorbed systemically and no further testing is required. Levels greater than 10 ng/mL would need to be evaluated against results of nonclinical toxicology tests to determine a margin of safety. If the margin of safety is not satisfactory then further testing is needed.
Thus, the testing regimen outlined in the draft guidance does not “reflect current scientific knowledge” or appropriately balance risk and benefit. Sunscreen ingredients can be found to have safe levels of absorption even if these rates are greater than 0.5 ng/mL.
The PASS Coalition was created with the singular focus of ensuring Americans have access to the latest sunscreen technology to curb the skin cancer epidemic in the United States. We are eager to work collaboratively with the FDA to ensure patients have access to safe and effective, broad spectrum OTC sunscreen ingredients. We believe that:
Internationally accepted testing protocols should be accepted instead of MuST. The focus by FDA on the MUsT instead of internationally accepted testing protocols has unnecessarily delayed the consideration of sunscreen ingredients because the MUsT has never been conducted on any sunscreen ingredient and no safety protocol for the design, conduct and interpretation of a MUsT for sunscreen ingredients exists.
If FDA insists that a MUsT is the appropriate pathway, the agency must establish safety protocols and an appropriate safety threshold that reflects the risk profile of the products.
It is more appropriate to use 70% body surface area as the appropriate testing surface since American consumers do not apply sunscreen to “nearly all” of the body surface area.
An interpretation of evidence of dermal absorption must be based on a reasonable and scientifically supportable threshold, not the current recommended threshold of 0.5 ng/mL.
Based on the PASS Coalition’s independent scientific review, it is more appropriate to use a range of 10 to 100 ng/mL as a safety threshold. Under 10 ng/mL would beconsidered not to be absorbed systemically and no further testing is required. Levels greater than 10 ng/mL would need to be evaluated against results of nonclinical toxicology tests to determine a margin of safety. If the margin of safety is not satisfactory then further testing is needed.
Given that significant nonclinical data is available indicating that dermal absorption of sunscreens is low, a MUsT limited to no more than 10 to 15 healthy adult volunteers is sufficient to confirm the lack of dermal absorption when applied under maximum use conditions.
The PASS Coalition remains willing to work collaboratively with FDA to develop an appropriate testing regimen for new sunscreen ingredients – that will ensure safety while balancing the need for new and effective sunscreens to combat the ever-increasing risk of risk cancer. We look forward to future dialogue with the Agency to accomplish that goal.
The Public Access to SunScreens Coalition
1 Letter from L’Oreal USA to FDA (July 17, 2015), available at http://www.regulations.gov/contentStreamer?documentId=FDA-2008-N-0474- 0034&attachmentNumber=1&disposition=attachment&contentType=pdf
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