Sunscreen: FDA Reviewed Applications for Additional Active Ingredients and Determined More Data Needed

Using sunscreen as directed with other sun protective measures may help reduce the risk of skin cancer—the most common form of cancer in the United States. In the United States, sunscreen is considered an over-the-counter drug, which is a drug available to consumers without a prescription. Some sunscreen active ingredients not currently marketed in the United States have been available in products in other countries for more than a decade. Companies that manufacture some of these ingredients have sought to market them in the United States by applying to add the ingredients to the sunscreen monograph, which lists ingredients that can be used in sunscreens without FDA's premarket approval. FDA reviews the applications and corresponding safety and effectiveness data for the ingredients.

The Sunscreen Innovation Act includes a provision for GAO to examine FDA's implementation of the act. This report examines (1) the extent to which FDA implemented requirements for reviewing applications for sunscreen active ingredients within mandated time frames, and (2) the status of the sunscreen applications. GAO reviewed FDA regulations and guidance documents, Federal Register notices, and FDA and sponsor documents for all eight sunscreen applications. GAO also interviewed FDA officials; sponsors of sunscreen applications; and stakeholders with interests in sunscreen, including health care providers, researchers, and industry groups. Stakeholders were selected based on knowledge of the monograph process and sunscreen active ingredients. The perspectives of these stakeholders are not generalizable.

The Food and Drug Administration (FDA), within the Department of Health and Human Services, implemented requirements for reviewing applications for sunscreen active ingredients within time frames set by the Sunscreen Innovation Act, which was enacted in November 2014. For example, the agency issued a guidance document on safety and effectiveness testing in November 2016.

As of August 2017, all applications for sunscreen active ingredients remain pending after the agency determined more safety and effectiveness data are needed. By February 2015, FDA completed its initial review of the safety and effectiveness data for each of the eight pending applications, as required by the act. FDA concluded that additional data are needed to determine that the ingredients are generally recognized as safe and effective (GRASE), which is needed so that products using the ingredients can subsequently be marketed in the United States without FDA's premarket approval. To make a GRASE determination, FDA requested that the application sponsors provide additional data, including human clinical studies, animal studies, and efficacy studies.

Sponsors of some of the sunscreen applications and some stakeholders GAO interviewed questioned FDA's requests, stating, for example, that the agency's recommended absorption test has never been conducted on sunscreen ingredients and there is a lack of knowledge on how to conduct it. At the same time, other stakeholders support the additional testing FDA requested. FDA reports that the increase in the amount and frequency of sunscreen usage, coupled with advances in scientific understanding and safety evaluation methods, has informed the agency's perspective that it needs additional data to determine that sunscreen active ingredients are GRASE. However, none of the sponsors reported current plans to provide the requested information—that is, they are either still considering whether to conduct the additional tests or they do not plan to do so. They cited the following reasons:

Return on investment. The testing FDA requested is extensive, would cost millions of dollars, or take several years to conduct, according to sponsor representatives. Some stakeholders and sponsor representatives said that sponsors are currently working to develop newer sunscreen ingredients and are therefore reluctant to invest in the testing FDA requested for the older ingredients covered by the pending applications.

Alternatives not accepted. Some sponsor representatives and stakeholders said that when they proposed alternative testing methods for absorption, for example, the agency rejected the alternatives.

Animal testing. One stakeholder and some sponsor representatives reported concerns about the effect that the animal testing requested by FDA may have on companies' marketing of sunscreen products worldwide. Additionally, one stakeholder and representatives from one sponsor expressed concern that sunscreen manufacturers may face backlash from animal rights groups and shareholders if animal testing is conducted.

The Department of Health and Human Services provided technical comments on a draft of this report, which GAO incorporated as appropriate.

With nearly 5 million people treated each year, skin cancer is the most  common form of cancer in the United States and rates are rising. To help  reduce the risk of skin cancer, the U.S. Surgeon General and other  authorities recommend using sunscreen in conjunction with other  preventive measures. Given this recommendation, there is interest in  ensuring Americans have access to the most effective sunscreen  products. Furthermore, authorities encourage people to apply sunscreen  liberally and frequently when out in the sun; and Americans are using  sunscreen more often and in larger quantities than in the past. However,  heightened concerns about possible adverse effects from absorbing  sunscreen ingredients through the skin have accompanied this increase  in sunscreen use.

Some sunscreen active ingredients not currently marketed in the United  States have been available in products in other countries for more than a  decade, and companies that manufacture some of these sunscreen  ingredients have sought to bring these ingredients to the U.S. market. In  the United States, sunscreen is considered an over-the-counter (OTC)  drug, which is a drug available to consumers without a prescription. The  Federal Food, Drug, and Cosmetic Act authorizes the Food and Drug  Administration (FDA), an agency within the Department of Health and  Human Services, to ensure that OTC drugs, such as sunscreens, are  safe and effective in order to be marketed in the United States. There are  two routes that can be used to market an OTC drug:

One route is through FDA’s OTC monograph process, which focuses  on the conditions, such as active ingredients, dosage forms, and  labeling for OTC drug products. Under the OTC monograph process,  FDA reviews active ingredients and other conditions to determine  whether they are generally recognized as safe and effective (GRASE)  for use in an OTC drug, such as sunscreen. If FDA finds an active  ingredient to be GRASE for use in a particular category of OTC drugs,  OTC drug products that contain such ingredients do not need  individual preapproval from FDA to be marketed, assuming  compliance with applicable regulations.

The other route is through the new drug application (NDA) process,  under which FDA determines the safety and effectiveness of an  individual drug product. FDA must review and approve an NDA before  a product can be marketed.

For active ingredients that have previously been marketed only in other  countries or in drug products individually approved for the U.S. market  through an NDA, FDA’s time and extent application (TEA) process  provides a pathway for FDA to determine whether an ingredient is  GRASE and can be marketed under the OTC monograph process. To be  eligible for review under the TEA process, an active ingredient must be  shown to have been marketed for a material time and material extent in  an OTC product, as described in FDA regulations. Once the agency  determines that a TEA is eligible for review, sponsors—such as the  manufacturers of these ingredients—and other interested parties may  submit safety and effectiveness data for FDA to review and make a  GRASE determination.

Sponsors submitted TEAs for eight sunscreen active ingredients between  2002 and 2009. Amid concerns that these TEAs had been pending with  FDA for several years, Congress enacted the Sunscreen Innovation Act  (SIA) in November 2014. SIA altered the process FDA uses to determine  whether a sunscreen active ingredient is GRASE and established time  frames for the agency’s review. The act also included requirements for  the agency related to this new process, such as developing guidance.  Additionally, the act included a provision for GAO to report on FDA’s  implementation of the act. This report examines  1.  the extent to which FDA has implemented requirements for reviewing  applications for sunscreen active ingredients within mandated time  frames, and  2.  the status of FDA’s review of applications for sunscreen active  ingredients.

This report also describes information about the steps FDA has taken to  review TEAs for non-sunscreen active ingredients. (See app. I.)

To examine the extent to which FDA has implemented requirements for  reviewing applications for sunscreen active ingredients (sunscreen  applications) within mandated time frames, we reviewed the Federal  Food, Drug, and Cosmetic Act (as amended by SIA), applicable FDA  regulations, and agency guidance related to the TEA process and  sunscreen active ingredients. We also reviewed agency documentation  regarding SIA implementation, such as a May 2016 report to Congress  required by SIA, and interviewed agency officials.

To examine the status of FDA’s review of applications for sunscreen  active ingredients, we reviewed documentation associated with each  sunscreen application from regulations.gov and FDA. This documentation  included the TEA submitted by each sponsor of a sunscreen active  ingredient, Federal Register notices of eligibility, feedback letters, and  minutes from meetings between FDA and sponsors, when applicable. We  also reviewed applicable FDA regulations and guidance, and interviewed  FDA officials. Additionally, we interviewed representatives from five  sponsors, which represent all eight sunscreen applications submitted to  FDA (all of which were submitted prior to the enactment of SIA). We also interviewed nine stakeholders with interest in sunscreens, including  industry groups, researchers, and health care providers. We identified  stakeholders through our interviews with and review of key documents  from FDA, sponsors, and other stakeholders. We selected stakeholders  knowledgeable with the OTC monograph process for sunscreen active  ingredients, including stakeholders who commented on FDA draft  guidance and participated in FDA advisory committee and SIA  implementation meetings. These selected stakeholder organizations  provided their own insights on these issues, and their perspectives are  not generalizable.

To examine the steps FDA has taken to review TEAs for non-sunscreen  active ingredients, we reviewed SIA, applicable FDA regulations and  guidance, and other relevant documentation associated with the non- sunscreen TEAs. We also interviewed FDA officials and representatives  of the sponsors associated with the six non-sunscreen TEAs submitted  prior to the enactment of SIA in 2014.

We conducted this performance audit from December 2016 to November  2017 in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.

How Sunscreen Works  Most sunscreen products work by absorbing,  reflecting, or scattering sunlight. Sunscreen  contains chemicals that interact with the skin  to protect it from ultraviolet (UV) rays. UV rays  are an invisible form of radiation from the sun,  tanning beds, and sunlamps that can  penetrate the skin and change skin cells.

The most common kinds of skin cancer, including the deadliest kind of  skin cancer (melanoma), are associated with exposure to ultraviolet (UV)  light. Sunscreen is one of the most common methods of protection  against UV exposure used by Americans. To lower the risk of skin cancer,  the Centers for Disease Control and Prevention and FDA recommend  that consumers use broad spectrum sunscreens with a sun protection  factor (SPF) of 15 or more as directed and in conjunction with other sun- protective measures, such as seeking shade and wearing protective  clothing, hats, and sunglasses. Current recommendations also state that  sunscreen should be reapplied every 2 hours and after swimming,  sweating, and toweling off. When used incorrectly, sunscreen may  provide a false sense of protection, which can ultimately lead to increased  UV exposure.

FDA Regulation of Sunscreens and Other OTC Drugs

Because sunscreens are intended to help prevent sunburn and, in some  cases, decrease the risks of skin cancer and early skin aging caused by  the sun, these products are considered drugs under the Federal Food,  Drug, and Cosmetic Act. Sunscreens are regulated as OTC (i.e.,  nonprescription) drugs, which are drugs considered to be safe for use by  consumers without the intervention of a health care professional, such as  a physician.

Broad Spectrum Sunscreen and Sun  Protection Factor (SPF)  There are two types of ultraviolet (UV)  radiation from which one needs protection— UVA and UVB. UVA radiation penetrates the  skin more deeply and can cause skin cancer  and other skin damage. UVB radiation can  cause sunburn and result in skin damage.  Broad spectrum sunscreens provide  protection against both UVA and UVB rays.  Products labeled as “broad spectrum” have  been tested for both UVA and UVB protection.  Sunscreens are made in a wide range of  SPFs. The SPF value indicates the level of  sunburn protection provided by the sunscreen  product. Higher SPF values (up to 50) provide  greater sunburn protection. Because SPF  values are determined from a test that  measures protection against sunburn, SPF  values primarily indicate a sunscreen’s UVB  protection.

Most OTC drugs, including nearly all sunscreen products, are marketed in  the United States by following the OTC monograph process. An OTC  monograph is a regulation that specifies the active ingredients that may  be used to treat certain diseases or conditions without a prescription, and  the appropriate dose and labeling for use, among other things. OTC  drugs that meet a monograph’s requirements may be marketed without  FDA’s prior approval, assuming compliance with all other applicable  regulations.

FDA regulations designate categories of OTC drugs, including antacids,  cough and cold products, and sunscreens, to be covered by OTC  monographs. OTC drug products that do not fit under an existing  monograph must be approved under an NDA to be marketed, which is an  application also used for new prescription drugs. See table 1 for a  summary of the differences between marketing an OTC drug product,  such as a sunscreen product, under the OTC monograph process  compared to under an NDA. According to FDA officials, more than  100,000 OTC drugs are marketed under the OTC monograph process,  and about 400 are approved to be marketed under NDAs.

The sunscreen monograph currently includes 16 active ingredients. The  last active ingredients (avobenzone and zinc oxide) were added to the  sunscreen monograph in the late 1990s. FDA issued a final sunscreen  OTC monograph in 1999; before it could go into effect, however, FDA  stayed its effective date indefinitely, because the agency had not yet  established UVA/broad spectrum testing and labeling requirements for  sunscreen products. To date, the sunscreen monograph is not in effect.

While the sunscreen monograph’s effective date is stayed, FDA has  indicated that it will not take enforcement action against the marketing of  sunscreens using the 16 active ingredients included in the stayed final  monograph or some combination thereof, provided the products are  marketed in compliance with other applicable regulations and consistent  with FDA’s 2011 draft guidance.

In 2002, FDA created a two-part process, referred to as the TEA process,  by which an active ingredient that was not included in OTC drugs  marketed in the United States prior to the beginning of the monograph  process in the 1970s can be considered for marketing under the OTC  monograph process by receiving a GRASE determination.

Part 1: Eligibility determination. To be eligible for review under the TEA  process, the sponsor must submit an application showing that the active  ingredient has been marketed in OTC drugs for a material time and to a  material extent, as shown by, for example a minimum of 5 continuous years in the same country, or multiple  countries outside the United States, or in an OTC product with an  approved NDA in the United States; and a sufficient quantity as measured by the total number of dosage units  or weight of active ingredient sold, and in a population reasonably  extrapolated to the population of the United States.

For ingredients found to meet the eligibility requirements, FDA publically  posts this determination in the Federal Register and requests safety and  effectiveness data to be submitted for the agency’s review.

Part 2: GRASE determination. FDA reviews the safety and  effectiveness data submitted by sponsors and other interested parties to  determine whether the ingredient is generally recognized as safe and  effective for OTC use. Standards for GRASE determinations are  established in FDA regulations.

General recognition is based upon published studies, which may be  corroborated by unpublished studies and other data.

Safety means a low incidence of adverse reactions or significant side  effects under adequate directions for use and warnings against  unsafe use, as well as low potential for harm, which may result from  abuse that can occur when the drug is widely available.

Effectiveness means a reasonable expectation that, in a significant  proportion of the target population, the pharmacological effect of the  drug, when used under adequate directions for use and warnings  against unsafe use, will provide clinically significant relief of the type  claimed.

Based on its review, FDA may initially determine that the active ingredient  is GRASE or not GRASE for OTC use; a not GRASE determination could  result from FDA’s determination that the safety and effectiveness data  submitted are insufficient. FDA issues its initial GRASE determination in  the Federal Register and provides a period of time for public comments.  The agency then reviews any comments received and issues its final  GRASE determination in the Federal Register.

SIA altered the process FDA is required to use for its review of sunscreen  active ingredients and established time frames for the agency’s review. It  also established a process for convening the agency’s Nonprescription  Drugs Advisory Committee to review and provide recommendations  regarding sunscreen applications at certain points in the process, and  created a mechanism for sponsors to request FDA’s Office of the  Commissioner to review sunscreen applications. At the time SIA was  enacted in November 2014, FDA had received TEAs for eight sunscreen  active ingredients. For all eight of these ingredients, FDA had deemed the  applications eligible for review under the TEA process (that is, the  sponsors demonstrated that the ingredients had been marketed for a  material time and to a material extent), and the agency had requested  data to demonstrate safety and effectiveness.

FDA Implemented SIA Requirements for Reviewing Applications for Sunscreen Active Ingredients within Mandated Time Frames

FDA implemented requirements for reviewing applications for sunscreen  active ingredients within the time frames required by SIA. For example, by  November 2016, FDA issued final guidance for applications for sunscreen  active ingredients, such as guidance on safety and effectiveness testing  standards and on convening the Nonprescription Drugs Advisory  Committee to discuss sunscreen active ingredients. In May 2016, FDA  also issued its first required report to Congress on specific performance  metrics, such as the number of sunscreen applications with pending  GRASE determinations. In addition to requiring FDA to issue two  additional reports to Congress in 2018 and 2020, SIA requires FDA to  finalize the sunscreen monograph by November 26, 2019. See table 2  for the status of FDA’s implementation of SIA requirements and  corresponding time frames.

FDA also implemented changes to the process for reviewing sunscreen  applications as required by SIA.

Administrative orders. SIA changed the process for issuing initial  and final GRASE determinations for sunscreen applications to  administrative orders. FDA officials stated that this approach is more  efficient than rulemaking. Agency officials noted that administrative  orders are not subject to multiple-stage rulemaking procedures, and  generally undergo fewer levels of review outside of FDA.

Time frames. SIA established time frames for each step in the review  process for sunscreen applications. For example, the agency is  required to determine whether a new application for a sunscreen  active ingredient is eligible for review and notify the sponsor within 60  days of receipt by the agency. These time frames only include FDA’s  review, and do not include the time for the sponsor or other interested  parties to prepare and submit safety and effectiveness data, or  respond to additional FDA requests.

Filing determination. SIA added a step, known as a filing  determination, in which FDA reviews the safety and effectiveness data  to determine whether it is sufficiently complete for the agency to begin  its more substantive review to determine whether an active ingredient  is GRASE. If FDA determines that the data are sufficiently complete to  determine whether the active ingredient is GRASE, the agency will file  the application and further analyze the data. If FDA determines that  the data are not sufficiently complete, the agency can refuse-to-file  the application, which involves notifying the sponsor and providing  reasons for the refusal. Sponsors can protest FDA’s decision to  refuse-to-file the application, known as “file over protest,” in which  case FDA will proceed with its more substantial review to determine if  the active ingredient is GRASE.

Office of the Commissioner review. SIA established a mechanism  for sponsors to request the Office of the Commissioner to issue  GRASE determinations if FDA does not meet required time frames.  The mechanism has not been employed to date, because, as of  August 2017, FDA had met its required time frames for reviewing and  initially responding to sunscreen applications.

Figure 1 illustrates the post-SIA process for FDA’s review of pending and  new applications for sunscreen active ingredients, including time frames.

All Eight Sunscreen Active Ingredient Applications Pending After FDA Determined More Safety and Effectiveness Data Needed; Sponsors Questioned Need for Additional Data

FDA completed its review of the safety and effectiveness data for each of  the eight sunscreen active ingredient applications that it received prior to  the enactment of SIA. The agency concluded that the ingredients were  not GRASE because the data were insufficient and additional safety and  effectiveness data are needed to determine otherwise. Sponsors  questioned FDA’s request for additional data and no data have been  provided.

FDA’s Review of Sunscreen Active Ingredient Applications Determined Additional Safety and Effectiveness Data Needed, and Most Took More than 8 Years

As of February 2015, FDA completed its review of the safety and  effectiveness data—that is, the initial GRASE determination—for each of  the eight sunscreen applications submitted between the creation of the  TEA process in 2002 and SIA’s enactment in 2014. FDA’s review  concluded that the eight sunscreen active ingredients were not GRASE,  because the data were insufficient to make a determination, and that  additional data are needed to determine otherwise. (See fig. 2.)

For all eight pending sunscreen applications, FDA requested additional  safety and effectiveness data to support a GRASE determination. The  data FDA requested include

Human clinical safety studies including skin irritation, sensitization,  and photosafety studies, as well as human pharmacokinetic tests  (which measure the amount of absorption of a drug into the body).  Among other studies, FDA specifically recommends that sponsors  conduct a Maximal Usage Trial (MUsT), a type of human  pharmacokinetic study, to support an adequate assessment of  safety.

Human safety data from adverse event reports and other safety- related information from marketed products that contain the active  ingredient. This includes a summary of all available reported adverse  events potentially associated with the ingredient, all available  documented case reports of serious side effects, any available safety  information from studies of the safety and effectiveness of sunscreen  products containing the ingredient in humans, and relevant medical  literature describing adverse events.

Nonclinical animal studies that characterize the potential long-term  dermal and systemic effects of exposure to the active ingredient.  These tests include dermal and systemic carcinogenicity studies, as  well as toxicokinetic tests (to help determine the relationship between  exposure in toxicology studies in animals and the corresponding  exposure in humans). In most cases, FDA also recommended  developmental and reproductive toxicity studies to evaluate the  potential effects of the active ingredient on developing offspring.  FDA’s guidance states that if the ingredient is not absorbed into the  body past an identified threshold, some of these studies will not be  needed.

Effectiveness data from at least two SPF studies showing that the  active ingredient prevents sunburn. FDA stated these studies should  demonstrate protection at an SPF of 2 or higher.

FDA’s 2016 guidance on safety and effectiveness data for sunscreen  states that its approach for evaluating the safety of sunscreen active  ingredients is based on the agency’s current scientific understanding of  topical products for chronic use. According to FDA, the standard for  determining GRASE has remained the same over time. However, FDA  reports that the increase in the amount and frequency of sunscreen  usage, coupled with advances in scientific understanding and safety  evaluation methods, has changed the agency’s perspective on what it  needs to determine if sunscreen active ingredients are GRASE. As a  result, the agency stated that these additional tests, such as the MUsT,  are necessary to determine whether a sunscreen active ingredient is safe  for chronic use. FDA reported that the studies it is requesting are not  novel and are consistent with the requirements for chronically used  topical drug products approved through the NDA process.

For the eight sunscreen applications FDA received since 2002, FDA took  between approximately 6 and 13 years to issue initial GRASE  determinations starting from the date that the application was submitted.  For six of the eight sunscreen applications, it took FDA more than 8 years  to issue an initial GRASE determination. (See table 3.) Sponsors or other  parties may submit safety and effectiveness data after FDA determines  the application is eligible for review. From the most recent date that safety  and effectiveness data were submitted for each application, the range of  time for FDA to issue an initial GRASE determination was between about  4 and 11 years.

According to FDA officials, the delays in reviewing sunscreen applications  can be attributed to inadequate resources to carry out the agency’s OTC  drug responsibilities and a lengthy multi-step rulemaking process, which  the applications were subject to prior to SIA. The officials added that the  delays in FDA’s review of sunscreen applications are indicative of the  larger issues affecting the OTC monograph process more generally. For  example, though the OTC monograph process began over 40 years ago,  FDA officials said that the agency has still not been able to complete  many monographs, or make timely changes based on emerging safety  issues and evolving science, because of the burdensome regulatory  process and inadequate resources. FDA officials estimate that as of  October 2017 approximately one third of the monographs are not yet  final, and several hundred active ingredients, including those used in  sunscreen products, do not have a final GRASE determination.

Some stakeholders and sponsor representatives said that one effect  associated with SIA was that FDA took action on the sunscreen  applications that had been pending for many years. Without the act, some  of them questioned whether FDA would have reviewed the sunscreen  applications or provided feedback to the sponsors. Though the agency  has made an initial GRASE determination, the timing of FDA’s final  GRASE determination for each of the eight sunscreen active ingredients  will be determined, in part, by when each ingredient’s sponsor provides  FDA with the additional safety and effectiveness data the agency  requested.

Sponsors Questioned FDA’s Request for Additional Safety and Effectiveness Data; No Additional Data Have Been Provided

Sponsor representatives and some stakeholders questioned the  additional safety and effectiveness data requested by FDA citing the  following reasons

Requested test not previously conducted on sunscreen. Some of  the sponsor representatives and stakeholders we interviewed stated  that they were not aware of one of the tests FDA requested, the  MUsT, ever being conducted on sunscreen active ingredients. Some  of these sponsor representatives and stakeholders said there is a lack  of knowledge by sponsors and testing laboratories on how to conduct  this test, as well as a lack of testing protocols. Further,  representatives from some of the sponsors said that the thresholds  set by FDA for these test results, which affects whether FDA will  recommend additional testing, were unreasonably low or unrealistic.  FDA officials stated that a MUsT is a fairly recent term for a  pharmacokinetic test under maximum use, which is a test that has  been used for dermal products since the 1990s. They added that the  threshold FDA established for this test is considered by the agency to  minimize risk, and that at or above this threshold, the risk for cancer  may increase. According to agency officials, FDA’s draft guidance on  conducting a MUsT is expected to be issued in 2018.

Equal to or more rigorous than NDA testing requirements. Some  of the sponsor representatives and stakeholders said that the  additional safety and effectiveness data FDA requested are equal to  or more rigorous than what are submitted for an NDA. In particular, a  stakeholder noted that FDA requested additional safety and  effectiveness testing for an application to market the ingredient under  the OTC monograph process from a company that already had an  approved NDA for a product containing the same active ingredient  (ecamsule). FDA officials indicated that active ingredients under  consideration for inclusion in an OTC monograph may require some  studies to demonstrate that the ingredient is GRASE for OTC use that  would not be required for approval of an individual drug product  through an NDA. Specifically, FDA officials said such studies may  be needed because once an ingredient is found to be GRASE it can  be formulated in many ways (in accordance with the monograph) and  marketed in multiple sunscreen products without further agency  review. Additionally, the combination of sunscreen active ingredients  with other inactive ingredients in a sunscreen spray, for example, may  affect the absorption of the sunscreen active ingredient, according to  FDA officials. In contrast, NDAs are product-specific and once  approved, further changes to the products require FDA approval.

Raising the bar. Some of the sponsor representatives and  stakeholders said that FDA’s requests for additional safety and  effectiveness data equate to FDA raising the bar or otherwise  changing what is required to demonstrate GRASE for additional active  ingredients in sunscreen. Some stakeholders noted that sunscreen  active ingredients that are currently marketed are not subject to this  level of scrutiny. According to FDA officials, given the increased  usage of sunscreen, coupled with increased knowledge of how drugs  are absorbed into the skin, the agency has changed its perspective on  what it needs to determine if sunscreen active ingredients are  GRASE. FDA officials said that when the OTC monographs first  started in the 1970s, it was thought that topical products would remain  on the skin rather than be absorbed, but science has shown that  some topical drugs, including some active ingredients used in  sunscreens, are absorbed through the skin. Because of this  knowledge, FDA officials said that the agency now considers potential  dermal absorption for every topically applied drug.

Lack of access to some requested data. In some cases, the  sponsor or another interested party submitted a study’s summary  results or summary information on adverse events associated with an  active ingredient, but FDA requested more detailed data behind the  study or detailed data on adverse events. However, some sponsor  representatives and stakeholders said that the sponsor may not have  access to this level of detail if it had not conducted the study itself or  received the associated adverse event reports. For example, if the  sponsor is the company that manufactures the active ingredient, it  would not necessarily have access to adverse event reports for  specific sunscreen products, because these reports would instead be  submitted to the company that manufactures the actual sunscreen  product used by consumers. One stakeholder also questioned why  FDA has not attempted to obtain relevant adverse event data directly  from regulatory agencies in other countries. FDA officials said that the  agency does not generally have access to adverse event reports from  foreign regulatory agencies, and that the agency relies on sponsors to  provide adequate information to support a GRASE determination.

Some stakeholders supported FDA’s request that sponsors provide  additional safety and effectiveness data to determine if an active  ingredient is GRASE for use in sunscreens. In particular, some of the  stakeholders we interviewed stated that FDA is justified in requesting  additional safety and effectiveness data from the sponsors given that  science has evolved and the recommended use of sunscreen has  changed over time.

As of October 2017, FDA officials said that the agency has not received  any of the additional safety and effectiveness data requested for the eight  sunscreen active ingredients seeking a GRASE determination. According  to sponsor representatives we spoke with, the sponsors are either still  considering whether to conduct the additional tests FDA requested or  they do not plan to do so. The reasons cited by the sponsor  representatives and stakeholders included

Return on investment. Sponsor representatives said the testing FDA  requested is extensive, would cost millions of dollars, or take several  years to conduct. Some of the stakeholders said the profit margins for  these types of products can be low, and other stakeholders and  sponsors said that once an active ingredient is determined to be  GRASE and added to the OTC monograph, then anyone can market  products using that active ingredient, as there is no period of market  exclusivity granted to sponsors. Additionally, some stakeholders and  sponsors added that the sponsors are reluctant to spend money on  additional testing, because many of these sunscreen active  ingredients have been on the market in other countries for many  years. Instead, according to one sponsor representative, sponsors  may choose to devote their resources into developing a newer  generation of sunscreen active ingredients.

Alternatives not accepted. Some sponsor representatives and  stakeholders said that when alternative testing methods were  proposed to FDA in place of the MUsT and other tests recommended  by the agency, FDA rejected the alternatives. Further, when a sponsor  asked the agency if the ingredient’s experience being marketed in  other countries could be used to waive some of the carcinogenicity  studies requested by FDA, the agency said that marketing experience  can guide the design of studies, but it is not sufficient to appropriately  assess carcinogenicity. The main purpose of carcinogenicity studies,  according to FDA, is to detect the potential for cancer risks associated  with lifelong exposure to the active ingredient, which are difficult to  detect through the adverse event data associated with marketing  experience.

Animal testing. Some sponsor representatives and one stakeholder  mentioned concerns about conducting tests on animals, because of  the effect it may have on a company’s ability to market products  worldwide. For example, European regulations prohibit cosmetics,  including sunscreens, from being tested on animals, though they  would not prohibit such testing as required by other countries.  Additionally, one sponsor and one stakeholder expressed concern  that sunscreen manufacturers may face backlash from animal rights  groups and shareholders if animal testing is conducted.

Uncertainty if more tests will be requested by FDA in the future.

One sponsor representative said that there is uncertainty whether  FDA may request additional studies in the future based on the  outcomes of the FDA-recommended tests. According to one  stakeholder, there is concern that sponsors may spend additional time  and money on conducting the tests requested by FDA and the  sunscreen active ingredient may still not be determined to be GRASE.

Sponsor representatives for the pending sunscreen applications and most  stakeholders said that the sponsors and FDA are essentially at a  standstill about adding more sunscreen active ingredients to the U.S.  market through the OTC monograph process. Sponsor representatives  acknowledged that they could have submitted an NDA to market a new  sunscreen product instead of seeking a GRASE determination for a  sunscreen active ingredient. However, some sponsor representatives and  a stakeholder said that NDAs are impractical for sunscreen products,  because the formulations are continually changing; for example,  sunscreen products may have a new fragrance based on the season.  Additionally, many of the sponsors that submitted sunscreen applications  manufacture the active ingredient, but not the finished sunscreen  products; yet, it is the finished products that receive approval through the  NDA process.

Though FDA stated that it needs additional resources to complete its  work related to the OTC monograph process—and most stakeholders  agree—additional resources alone will not lead to additional sunscreen  active ingredients on the U.S. market. Movement on sunscreen active  ingredients will also depend on sponsors and other interested parties  submitting data that FDA determines are sufficient for a GRASE  determination. Some stakeholders said that they agree with FDA on the  need for testing to ensure the safety and effectiveness of sunscreen  ingredients, but some of them said the agency should also consider the  potential benefit of preventing skin cancer if new ingredients—which  could offer better protection against UVA rays—become available for the  U.S. market.

We provided a draft of this report to the Department of Health and Human  Services for review and comment. The department provided technical  comments, which we incorporated as appropriate.

We are sending copies of this report to the Secretary of the Department  of Health and Human Services, appropriate congressional committees, as  well as other interested parties. In addition, the report is available at no  charge on the GAO website at http://www.gao.gov.

If your staff have any questions about this report, please contact me at  (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of  Congressional Relations and Public Affairs may be found on the last page  of this report. GAO staff who made key contributions to this report are  listed in appendix II.

Appendix I: Steps the FDA Has Taken To Review Applications for Non-Sunscreen Active Ingredients

To examine the steps the Food and Drug Administration (FDA) has taken  to review time and extent (TEA) applications for non-sunscreen active  ingredients, we reviewed the Sunscreen Innovation Act (SIA), applicable  FDA regulations and guidance, and other relevant documentation  associated with the non-sunscreen TEAs. We also interviewed FDA  officials and representatives of the sponsors associated with the six non- sunscreen TEAs submitted prior to the enactment of SIA in 2014.

SIA included requirements related to FDA’s review of non-sunscreen  TEAs. Specifically, SIA required FDA to provide sponsors of certain non-sunscreen TEAs submitted prior to  the enactment of SIA, upon request, with the opportunity to select  from among different options for FDA’s review (called a review  framework), including corresponding time frames;  issue regulations establishing time frames for reviewing non- sunscreen TEAs submitted after SIA was enacted, as well as metrics  for tracking the extent to which the time frames are met; and  submit a letter to Congress that includes a report on the status of  FDA’s review of non-sunscreen TEAs that were pending before SIA’s  enactment.

FDA implemented these requirements associated with non-sunscreen  TEAs by November 2016. For example, FDA provided each sponsor that  requested review framework options with the ability to select the process  and corresponding time frames to be applied to its pending TEA. The  review framework options included FDA using an administrative order or  rulemaking process, with or without a filing determination. The time  frames FDA established to initially respond to the pending non-sunscreen  TEAs ranged from 90 days (when an option with a filing determination is  selected) to 3.5 years (when an option without a filing determination is  selected) from the date the sponsor selected a review framework. For  example, when a sponsor chooses to receive a filing determination with  the administrative order process, FDA is to determine within 90 days  whether the safety and effectiveness data provided by the sponsor or  other interested party are sufficiently complete for the agency to begin its  substantive review and issue a filing determination. If FDA determines  that the application can be filed, the agency then has 2 years after the  filing date to issue a proposed order determining whether the ingredient is  generally recognized as safe and effective (GRASE). When a sponsor  chooses to not receive a filing determination with the rulemaking process,  FDA has 3.5 years to issue a proposed rule with the GRASE  determination.

Additionally, FDA issued a final rule in November 2016 outlining the  process and time frames by which the agency will review and take action  on new non-sunscreen TEAs submitted after the enactment of SIA,  including time frames for each step in the review process. (See fig. 3.) In  establishing these time frames, FDA noted that it considered the agency’s  public health priorities and available resources, as required by SIA, and  accounted for the anticipated variations in the content, complexity, and  format of submissions, as permitted by SIA. The overall time frames for  FDA’s review are estimated to be about 6 years from the date FDA  receives a TEA to the date a final GRASE determination is issued.  Specifically, the approximately 6 years consists of 180 days for an  eligibility determination, 90 days for a filing determination, 1,095 days for  an initial GRASE determination, and 912 days for a final GRASE  determination. These time frames only include FDA’s review, and do not  include time for the sponsor or other interested parties to submit safety  and effectiveness data, respond to additional FDA requests, or request  meetings with the agency before such filing.

FDA also established metrics for tracking the extent to which the agency  meets the time frames set forth in the regulations, and sent a letter to  Congress reporting on the status of the non-sunscreen TEAs submitted  prior to SIA. These metrics are included in FDA’s regulation for non- sunscreen TEAs. The metrics include the number of non-sunscreen TEAs  that have been submitted post SIA, and the number and percent of these  TEAs to which FDA has responded within its required time frames.  Agency officials said that FDA has not received any additional non- sunscreen TEAs as of August 2017 beyond the six that were submitted  prior to the enactment of SIA, and therefore has not publicly reported  metrics for non-sunscreen TEAs. Lastly, FDA submitted a letter to  Congress in May 2016 describing the status of the six non-sunscreen  TEAs submitted prior to SIA, including the review framework selected by  each sponsor, when applicable.

Non-Sunscreen Active Ingredient TEAs Submitted before SIA Was Enacted

As of August 2017, FDA had not issued a GRASE determination for any  of the six TEAs for non-sunscreen active ingredients that were submitted  before SIA was enacted. FDA has not made a GRASE determination  because

FDA refused to file the applications. Two non-sunscreen TEAs  were determined by FDA to contain insufficient information to be filed  for review in 2016. FDA requested that the sponsors for these  applications provide a detailed chemical description of the active  ingredients, assessments of carcinogenicity, and safety and efficacy  data, among other things. Representatives of sponsors for both  ingredients said they do not plan on conducting the additional tests  that FDA requested, because of concerns about return on investment.  According to FDA officials, the sponsors of these applications did not  elect to “file over protest.”

Sponsors withdrew their applications. Three non-sunscreen TEAs  were withdrawn in 2016. Representatives of the sponsors of these  three applications said the companies did so because of increased  regulatory scrutiny of the active ingredient, and the additional safety  and effectiveness data requested by FDA.

TEA is still pending FDA’s initial GRASE determination. One non- sunscreen TEA that was submitted in 2004 to add an anti-dandruff  ingredient to the over-the-counter monograph was pending FDA  review as of August 2017. The sponsor for this application did not  request to select a review framework from the agency and so the  application is subject to the regulations that FDA issued in November  2016. In accordance with the time frames established in the  regulations, FDA officials expect to issue a proposed rule with a  GRASE determination for this TEA in 2019—within 1,095 days (3  years) of when the regulation was finalized. This date is nearly 15  years after the application was originally submitted.

For those two non-sunscreen TEAs for which FDA refused to file the  applications, FDA’s determination came about 8 and 13 years after the  TEA was originally submitted. Sponsors that withdrew the three non- sunscreen TEAs did so 11 or more years after submitting the application.  (See table 4.)

Appendix II: GAO Contact and Staff Acknowledgments

In addition to the contact named above, Kim Yamane (Assistant Director),  Rebecca Hendrickson (Analyst-in-Charge), Kristin Ekelund, and Toni  Harrison made key contributions to this report. Also contributing were  George Bogart, Karen Howard, Drew Long, and Vikki Porter.

Some sunscreen active ingredients are not used in products marketed in the United States, although they have been available in other countries for more than a decade. Companies that manufacture some of these sunscreen ingredients have sought to bring them to the U.S. market by submitting applications to FDA between 2002 and 2009.

We looked at the status of the applications and found that, as of August 2017, all remain pending after FDA determined that more data are needed to determine that the ingredients are safe and effective. Some of the companies questioned FDA’s requests for more data, and no additional data have been provided.