The document summarizes the history of dermal absorption assessment at the FDA. It discusses how prior to the 1990s, topical dermal drugs had little direct assessment of in vivo bioavailability and clinical efficacy trials were used instead. In the mid-1990s, the FDA began requiring "maximal use trials" (MUsT) to better understand absorption under conditions maximizing exposure. MUsTs became standard for new drug applications. The document then focuses on sunscreen absorption studies showing circulating levels and the FDA's own studies evaluating absorption of 7 ingredients under MUsT conditions. It concludes MUsTs provide important safety data but the FDA has not said sunscreens are unsafe.

1. A History of Dermal Absorption
Assessment at the FDA-
Sunscreen
E. Dennis Bashaw, PharmD.
Senior Science Adviser
Office of Clinical Pharmacology
Office of Translational Sciences
US Food and Drug Administration

2. 2
Disclaimer
• The presentation today should not be considered, in whole or in
part, as statements of policy or recommendation by the US Food
and Drug Administration.
• Throughout the talk or the discussion/Q&A portion of the
program representative examples of commercial products may
be given to clarify or illustrate a point. No commercial
endorsement is implied or intended.
• The focus on my presentation will be on the IND/NDA and OTC
workspace. Extrapolation to either policies of the Office of
Generic Drugs or the Center for Food Safety and Nutrition
policies is not intended and should not be inferred.

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A SHORT HISTORY OF DERMAL DRUG
EVALUATION AT THE FDA
https://commons.wikimedia.org/wiki/File:Janus1.JPG

4. 4
Dermal Drug Review
“Paleoregulatory”*
Prior to the early 1990s, most topical dermatologicals had
little or no direct assessment of in vivo bioavailability.
Clinical efficacy trials or surrogate markers of drug
absorption were used.
Waivers of in vivo bioavailability testing were the norm and
not the exception
“Maximal dosing” was an unexplored concept
Sunscreen absorption was not considered
*Jon Wilkin, MD

5. 5
Common Features of In Vivo Dermal
Bioavailability Studies
pre-1990
• Study done in subjects with healthy skin
• Study done on small surface areas
• Study done with inadequate analytical methods
• Study done with too few subjects
• Study done as a single dose study
The information gained from such studies was inadequate
for a relevant assessment of absorption following clinical
use per the proposed labeling

6. 6
Why Do We Need to Know?
It has been the lack of an ability to assess local
drug concentrations and a lack of correlation
between systemic levels and local therapeutic
effect that has required the use of clinical trials to
assess bioavailability.
http://www.nku.edu/~dempseyd/SKIN.htm

7. Delivery
System
Factors
Ingredient
Factors
Skin
Factors
Primary Factors
• Diseased vs Non-diseased
• Surface Area
• Site of Application
• Scalp
• Back, Chest, etc.
• Aged Skin
Primary Factors
• Molecular Weight
• Solubility
• Melting Point
• pKa
• Concentration
Primary Factors
• Dosage Form Technology
• Cream
• Lotion
• Gel, etc.
• Deployability
• Spreadability
• Dosing Pattern
• Amount Applied
Intersection of
Factors Controlling
In Vivo
Bioavailability
Factors* That Influence Dermal Bioavailability
*A non-exhaustive list of factors

8. 8
The Maximal Use Trial
In the mid 1990s the FDA developed and implemented the use of
the “maximal use” trial as part of an in vivo bioavailability
program.
Outgrowth of the dissatisfaction with previous bioavailability
assessments
Made possible by the refinement of analytical methodologies
“Maximal” being defined here as the highest dose in terms of
such factors as amount, concentration, and surface area that
were to be studied in clinical trials and placed into labeling.
Trial design has been presented and discussed at various national
meetings and workshops (AAPS, FIP-BioInternational, ASCPT,
etc.)

9. 9
Published in the Scientific
Literature

10. 10
Maximum Use Trial
“Standard Language”
It has been the Agency's policy to request that a maximal usage trial
be undertaken in a suitable number of subjects with the
dermatological disease of interest at the upper range of severity as
anticipated in both your clinical trials and proposed labeling. Such a
trial would attempt to maximize the potential for drug absorption to
occur by incorporation of the following design elements:
a) Frequency of dosing
b) Duration of dosing
c) Use of highest proposed strength
d) Total involved surface area to be treated at one time
e) Amount applied per square centimeter
f) Method of application/site preparation
The trial itself could be a stand alone trial in phase II or could be a
sub-group of subjects in a larger phase III trial. Either approach is
acceptable and has been used successfully by other sponsors

11. 11
MUsT Survey 1996-2016
Original NDAs Only
• A total of 66 MUsT trials have been conducted over 20yrs
– An additional 20-30 trials have also been submitted as part of supplements
• Of the 66 trials they enrolled 1,545 patients
– 887(58.6%) Male and 658(43.4%) Female

12. 12
WHY THE FDA IS REQUIRING FOR MORE SAFETY
DATA ON MOST CURRENT AND PENDING SUNSCREEN
INGREDIENTS.

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Sunscreens
With one exception, all of the current OTC
sunscreens came to the US market as part
of proposals in the OTC Monograph, which
has not been finalized. Also since the
process started in the 1970s, attitudes
regarding sun exposure in societal and
clinical settings have changed.
http://cdn.loc.gov/service/ll/fedreg/fr043/fr043166/fr043166.pdf#page=204
Federal Register vol 43, #166
(ANPR) Aug 25,1978

14. 14
Contrasting SPF Thought 2019
2019 Proposed Rule
Published 2/26/2019
Suffice to say the proposed rule has many
elements in it that a full discussion of would
exceed the time we have today. The FDA
opened a docket for comments and nearly
15,000 comments were received.
https://www.govinfo.gov/content/pkg/FR-2019-02-26/pdf/2019-03019.pdf

15. 15
Is There Really a Concern?
• Conventional wisdom was that
topical products were not
absorbed.
• Any absorption was considered
insignificant
• However, analytical technology
finally caught up with the
question in the 1990s.
• Experience with modern
analytical methods have shown
that topically applied products
do reach the systemic circulation
and can have biologic effects
(safety related)

16. 16
Sunscreen Absorption
Data was collected from 54 women who gave birth at the University
Women’s Hospital Basel between 2004 and 2006 during the
corresponding summer-late fall. The majority women self-reported
some use of sunscreen containing cosmetics during the time periods
before and after delivery.
Other studies have also demonstrated circulating levels
of sunscreen in the population at large

17. 17
The FDA Sunscreen Absorption Studies

18. 18
FDA Sunscreen Studies
Evaluated 7 Ingredients Under MUsT Conditions
May 2019 Jan 2020

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Summary Results
JAMA. 2019;321(21):2082-2091. doi:10.1001/jama.2019.5586
JAMA. 2020 Jan 21;323(3):256-267. doi: 10.1001/jama.2019.20747

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Consistent Conclusions
JAMA. 2019;321(21):2082-2091. doi:10.1001/jama.2019.5586
JAMA. 2020 Jan 21;323(3):256-267. doi: 10.1001/jama.2019.20747

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Complexity of Topical Formulations
Topical Dosage Forms
Solid
Powder
Aerosol
Plaster
Liquid
Lotion Liniment Solution Emulsion
O/W W/O
Suspension Aerosol
Semi-Solid
Ointment
Paste
Cream
Gel
Why Didn’t the FDA Identify the formulations used???
The FDA Did!

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Supplemental Content
If you download the article from any site EXCEPT the JAMA website
you will not have access to both the underlying design, data, and
formulation identification. This is in the “Supplemental Content”

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• Supplement 1, pages 65 of 138, and
pages 110-111 of 138 reveals the
products used
• Table 1 in Supplement 2, page 9 of 20,
provides the qualitative list of
ingredients.
Supplemental Content
(2019 Study)*
*Similar information is located in the 2020 supplemental materials
The placement of the formulation information here,
rather than in the main body of the text, was done to
abide by the policy of JAMA and at their direction.

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CONCLUSIONS

25. 25
Conclusions
Since the mid-1990s, all topically applied products, for local use,
approved under an NDA have had an assessment of in vivo
bioavailability testing under “maximal use” conditions
The design elements were chosen to MAXIMIZE the ability of the
study to detect in vivo blood levels independent of it being for an
NDA product or an OTC active ingredient.
For OTC topical products the same MUsT paradigm provides
Important data to identify the need for additional pre-clinical
studies and to link human exposure to pre-clinical safety studies.

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Conclusions
• The use of the MUsT in the evaluation of sunscreen safety has
been a topic of discussion with both the medical community,
industry, and academia for many years including outreach at AAD
Annual Meetings, the Photomedicine Society Annual Meeting,
AAPS, DIA, FDA Advisory Committee meetings and others.
• The FDA sponsored sunscreen studies were done to both
demonstrate how such a study could be done with sunscreens
and to get an initial estimate as to the degree of absorption
• The FDA has NOT said that Sunscreens are unsafe

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Contact Info
E. Dennis Bashaw, PharmD.
Senior Science Advisor
Office of Clinical Pharmacology
Office of Translational Sciences
US Food and Drug Administration
Edward.bashaw@fda.hhs.gov
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