Guidance for Industry

Photosafety Testing

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

May 2003

Pharmacology and Toxicology
Guidance for Industry

Photosafety Testing

Additional copies are available from:

Office of Training and Communication

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

 http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

May 2003

Pharmacology and Toxicology
Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. INTRODUCTION................................................................................................................. 1

II. BACKGROUND ................................................................................................................... 2

A. Photoirritation and Photococarcinogenicity ...........................................................................2

B. Historical Approach to Photosafety Testing...........................................................................3

III. TESTING CONSIDERATIONS.......................................................................................... 4

A. Considerations for Testing a Drug Product or Drug Substance...........................................4

B. Testing for Photochemical Irritation.......................................................................................5

IV. TESTING FOR ENHANCEMENT OF UV-ASSOCIATED SKIN CARCINOGENESIS

(DIRECT PHOTOCHEMICAL CARCINOGENICITY OR INDIRECT EFFECTS IN

SKIN)...................................................................................................................................... 7

A. Considerations and Decision Tree for Testing Photosensitizing Drugs for Long-Term

Photosafety.................................................................................................................................7

B. Decision Tree for Testing Nonphotoreactive Drugs for Long-Term Photosafety ...............9

C. Mechanistically Based and Other Assays .............................................................................11
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Guidance for Industry1

Guidance on Photosafety Testing

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It

does not create or confer any rights for or on any person and does not operate to bind FDA or the public.

An alternative approach may be used if such approach satisfies the requirements of the applicable statutes

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate

number listed on the title page of this guidance.

I. INTRODUCTION

This guidance is intended to help applicants decide whether they should test for photoirritation

and assess the potential of their drug product to enhance UV-associated skin carcinogenesis. The

guidance describes a consistent, science-based approach for photosafety evaluation of topically

and systemically administered drug products. Basic concepts of photobiology and phototesting

are described, along with a process that can be used to make testing decisions or communicate

risks.

Use of the principles expressed in this guidance should reduce unnecessary testing while

ensuring an appropriate assessment of photosafety. The document does not recommend specific

tests but refers to some available testing methods. Sponsors may choose to use some of these

tests to evaluate photoirritation, photochemical carcinogenicity potential, or potential to enhance

UV-associated skin carcinogenesis. Sponsors also can propose other assays that are

scientifically sound. Tests involving biomarkers in the skin of humans receiving the drug

product may clarify mechanisms of direct or indirect photoeffects seen in nonclinical studies (see

section IV.C., Mechanistically Based and Other Assays).

Photosafety testing (testing for adverse effects of drug products in the presence of light) is only

recommended when it is felt that the results of such testing would yield important safety

information or would be informative for the consumer and healthcare practitioner.

The glossary at the end of the document defines abbreviations and important terminology used to

describe photobiologic concepts. The clinical definition of photosensitivity includes both

phototoxicity (photoirritation) and photoallergy. This document uses the clinical definition but

addresses nonclinical testing for photochemical irritation (photoirritation) only. At this time,

 

1

 This guidance has been prepared by the Pharmacology Toxicology Coordinating Committee in the Center for Drug

Evaluation and Research (CDER) at the FDA.
Contains Nonbinding Recommendations

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nonclinical models of testing for photoallergy are not considered to be predictive of clinical

effects and are not recommended.

Flowcharts for evaluation of photoirritating drug products and nonphotoreactive drug products

are also provided at the end of the document. The flowcharts illustrate the decision-making

process but do not address all situations that could arise during drug development.

FDA's guidance documents, including this guidance, do not establish legally enforceable

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should

be viewed only as recommendations, unless specific regulatory or statutory requirements are

cited. The use of the word should in Agency guidances means that something is suggested or

recommended, but not required.

II. BACKGROUND

A. Photoirritation and Photococarcinogenicity

Photobiology is the study of the effect of UVA and/or UVB, visible, and IR radiation

upon living systems (Smith 1989; Kochevar et al., 1993). The first law of

photochemistry (Grotthaus-Draper Law) states that light must be absorbed for a

photochemical event to occur (Megaw and Drake 1986). Chromophores in drug products

and DNA in dermal tissue are targets for photochemical reactions. Photoirritation and/or

photoallergy occur when a photoactive chemical enters the skin by dermal penetration or

systemic circulation and becomes excited by appropriate UV or visible light photons.

Fortunately, the skin is an optically heterogeneous medium that modifies the amount of

radiation that can reach deeper dermal structures and functions as a protective barrier that

minimizes damage from light exposure. Protective mechanisms include reflection,

refraction, scattering, and absorption (Kornhauser et al., 1996). Excision-repair and other

DNA repair mechanisms of UV-damaged DNA (Hessel et al., 1992; Kraemer et al.,

1994; Lindahl et al., 1997) provide further protection against gene mutation and skin

cancer.

Photoirritation is a light-induced, nonimmunologic, skin response to a photoreactive

chemical. The route of exposure to the photoreactive chemical can be by direct

application to the skin or by the circulatory system following systemic administration.

Photoirritation reactions resemble primary irritation reactions in that they can be elicited

following a single exposure, in contrast to photoallergic reactions, which have an

induction period before elicitation of the response. A photoactive chemical can be the

parent drug or an excipient in a drug product, or it can be a metabolite, impurity, or

degradant. Many diverse classes of drugs (including antimicrobials, NSAIDs,

antidepressants, anticonvulsants, diuretics, and antihypertensives) have been reported to

cause photoirritation in humans (Holzle et al., 1991; Johnson 1984; Physicians’ Desk

Reference 2000). Acute photoirritation reactions can resemble sunburn and may range

from a mild erythema to blistered skin with sloughing. Although a relatively small

percentage of the population may show clinical symptoms of photoirritation, a much
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larger percentage may have immediate subclinical effects. Nonclinical tests can identify

some photoirritating drug products before widespread clinical exposure occurs, allowing

appropriate precautions to be implemented.

Photoallergy is an acquired, immunologically mediated reaction to a chemical activated

by light. The occurrence of a photoallergic response to a chemical is idiosyncratic

(highly dependent upon the specific immune reactivity of the host). Compounds that

elicit a photoirritation response also may be capable of initiating a photoallergic reaction.

Examples of photoallergens in humans include promethazine, benzocaine, and

p-aminobenzoic acid (Holzle et al., 1991, Johnson 1984). Photoallergy is best assessed

clinically; several approaches for evaluation of clinical photoallergy potential are

available.

Data from animals and humans suggest that at least some photoirritants enhance UVassociated skin carcinogenesis. 8-Methoxypsoralen (8-MOP), used in PUVA therapy

(Stern and Lunder 1998), is considered to be a photococarcinogen in humans, while

several fluoroquinolones have been demonstrated to be photoirritants and photochemical

carcinogens in hairless mice (Physicians’ Desk Reference 2000). However, data for

many other classes of pharmaceuticals are unavailable.

Other drug products that are not photochemical irritants can enhance UV-induced skin

carcinogenesis. Epidemiologic data (Abel 1989; Frezza et al., 1997; Penn 1988) indicate

that persons on chronic immunosuppressive therapy (e.g., cyclosporin following organ

transplantation) are at greater risk for skin cancer than the general population. A

compound can also enhance UV carcinogenicity indirectly by altering biologic processes

or optical or structural features of the skin that function as protective mechanisms. Data

from animals exposed to vehicles that decrease protective properties of the skin support

this concept (Gibbs et al., 1985).

Changes in the optical properties of the skin, such as those caused by a drug vehicle, can

result in a greater UV dose to the viable layers of the skin. Data on correlation of

latitude, UV exposure, and cancer risk in humans suggest that an increase in UV

exposure as small as 20 percent could result in a 4-fold increase in basal-cell carcinoma

(Moan et al., 1999).

B. Historical Approach to Photosafety Testing

Historically, the majority of systemically administered drugs have not undergone

controlled testing for determining their potential for photoirritation. Yet a number were

later identified as phototoxic to humans. Topically applied dermatologic drugs routinely

have been tested for photoirritation in both animals and humans if they absorb light in the

UVA, UVB, or visible spectrum. In the absence of data from photoirriation or

photoallergy tests conducted in animals or humans, warnings about the potential for

photoirritation or photoallergy generally have been added to labels after reports of

adverse reactions resulting from widespread clinical use of the products.
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Relatively few drug products have been tested to elucidate their potential for enhancing

UV-mediated carcinogenic effects on the skin. By itself, UV light is a carcinogen in

humans (IARC, 1992). The regulatory issue is whether a drug enhances the carcinogenic

effect of UV light to such an extent that it significantly increases the potential human

carcinogenic risk, making it important that the patient and the physician be informed.

However, testing for photococarcinogenicity in humans is unethical; animal testing has

been used as a surrogate. The method that has commonly been used for testing the

potential photococarcinogenicity of a compound has been the Skh1-hr hairless mouse

model. A positive response in this photococarcinogenicity assay is a decreased time to

skin neoplasm development in animals exposed to the test material plus UV radiation

(i.e., sunlight simulation), compared with exposure to the same dose of UV radiation

alone. Information from this assay has been included in labels and may furnish a frame

of reference for comparisons between drugs. Numerous researchers have conducted

variants of this assay in several strains of haired mice that had been shaved. However,

because of the uncertainties involved in extrapolation from such animal testing to humans

and the apparent insensitivity of this assay to some topical immunosuppressants and

topical photogenotoxicants, other scientifically valid methods providing relevant

information for assessing the long-term adverse photoeffects of drug products on

biomarkers in human skin are desirable.

III. TESTING CONSIDERATIONS

 A. General Considerations for Testing a Drug Product or Drug Substance

For most drugs, it is generally adequate to test only the drug substance without the

excipients for adverse photoeffects. For topical products that will be applied to sunexposed skin, FDA recommends that the drug product, not just the active ingredient, be

evaluated under conditions of simulated sunlight. This is because many excipients in

these types of products modify the skin, and dermal applications usually deliver relatively

large amounts of both parent drug and vehicle to the skin. Many researchers have

reported the effects of topically applied vehicles on the skin, some of which alter the

optical properties of human skin. Some examples of these effects are as follows:

• Pharmaceutical vehicles (e.g., creams, gels, lotions, or solutions) can decrease the

amount of light reflected, scattered, or absorbed in the skin (Anderson and Parrish

1981; Serup et al., 1989) or increase the percutaneous absorption of drugs in the skin

of humans and mice (Marzulli and Maibach 1991; Baynes et al., 1996).

• Vehicles can increase or decrease adverse photoproperties (Kaidbey and Kligman

1974; Dearman et al., 1996) or photostability of drug products (Asker and Harris

1988; Islam and Asker 1995; Marti-Mestres et al., 1997). Vehicles can enhance the

effects of other components in the formulation and (1) increase epidermal thickening

in rodent skin (Wrench 1980), (2) change collagen gene expression in hairless mice

(Chaquor et al., 1997), or (3) influence the solubility and general stability of the drugs

(Chellquist and Gorman 1992).
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• Some cream-based vehicles have been found to be photosensitizers themselves

(proprietary), while some oil-based emollients can increase UVB transmission and

UV carcinogenicity in mice (Gibbs et al., 1985).

B. Testing for Photochemical Irritation

1. Background

Nonclinical tests for photochemical irritation are considered predictive of human effects.

The intent of the procedures discussed below is to ascertain the potential of

pharmaceuticals to elicit a photochemical irritation reaction before widespread human

use. The process attempts to address these safety concerns adequately while optimizing

the use of resources. To accomplish this goal, a decision tree approach is recommended

to assess whether testing should be conducted and what type of testing may be

appropriate. Other approaches may also accomplish this goal. It is recognized that even

short-term exposure to some nonphotoreactive drugs in the presence of ultraviolet light

could result in adverse effects in the skin (e.g., those that can immediately change the

optical properties of the skin).

2. Proposed Approaches to Identifying Photochemical Irritants (Flowchart

A1)

Short-term photoirritation testing in animals, perhaps followed by photoirritation and

photoallergy studies in humans, should be considered for all drug substances and

formulation components that absorb UVB, UVA, or visible radiation (290-700 nm) and

(1) are directly applied to the skin or eyes, or significantly partition to one of these areas

when administered systemically, or (2) are known to affect the condition of the skin or

eyes (see Flowchart A1). A drug product would not be considered for testing for

photoirritation potential if the person receiving the drug would not be exposed to light in

the sunlight spectrum while the drug or photoactive metabolites were in the body.

Additionally, it would not be appropriate to conduct photochemical irritation testing on a

drug product that was applied only to skin not exposed to the sun if the drug did not

undergo significant distribution to sun-exposed areas.

A description of the flowchart testing paradigm follows. Information regarding the

ultraviolet/visible radiation absorption spectrum for the drug substance or drug

formulation, as appropriate, is important in making a testing decision. A spectroscopic

scan will determine if a drug absorbs between 290 and 700 nm of the electromagnetic

spectrum. The scan is an important component of the safety assessment. Presentation of

only absorption maxima will not adequately address safety concerns. Drug products that

do not absorb between 290 and 700 nm will not be photoactivated (Box 1). Therefore,

they cannot be direct photochemical photosensitizers (Box 2). Some drugs elicit a

photosensitivity reaction that is unrelated to the UV absorbance of the administered drug.

These secondary mechanisms include perturbation of heme synthesis and increased

formation of other light-absorbing endogenous molecules resulting from administration
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of nonlight-absorbing drugs (e.g., aminolevulinic acid, Physicians’ Desk Reference

2000). These effects may be identified from standard toxicologic testing.

In addition to absorption of UV or visible radiation, the drug (or metabolites) should

reach the skin or eye at levels sufficient to cause photoirritation reactions (Boxes 3 and

4). Tissue distribution studies of systemically administered drug products, usually

included in IND submissions, can be used to assess the extent of partitioning into the skin

or eyes. In the absence of partitioning into light-exposed compartments, photoirritation

testing is unlikely to be informative and need not be conducted. However, agents used

for photodynamic therapy might be an exception, and valuable safety information (e.g.,

effects on internal organs after exposure to operating room lighting) can be generated

even if partitioning into the skin or eyes does not occur.

When drugs are identified as photoirritants, FDA recommends that the risk

communication include a warning to avoid sun exposure (Box 6). In the absence of

human data, a drug shown to be a photoirritant in nonclinical studies could be indicated

as potentially causing photosensitivity. When adequate human data addressing

photoirritation are available, they would be included in the description of the product and

would supplant animal data.

3. Testing of Reformulations (Flowchart A2)

In general, reformulations intended for administration by routes other than topical to the

skin do not have to be tested, provided that any new excipients undergo appropriate

evaluation. It is also not necessary to test most reformulations of a topical product for

nonclinical photoeffects. If the drug substance or excipients have previously been shown

to cause photoirritation, additional nonclinical photoirritation testing is generally not

needed (Box 3). However, FDA recommends that excipient changes that could modify

adverse photoeffects on the skin be tested (Boxes 4 and 5). For example, the Agency

recommends that a switch to a cream formulation from an ethanolic solution generally be

evaluated for photoeffects. Information on the photoirritant properties of excipients and

their effects on the penetration of the drug substance into the skin would be useful in

further defining whether new formulations should be studied. Studies of dermal

absorption of the drug substance for one formulation do not necessarily supply relevant

data on the absorption for all formulations. Inclusion of topical excipients not previously

studied for adverse photoeffects in a new formulation may also warrant testing of the new

formulation.

4. Tests for Evaluation of Photosensitivity

Testing should be conducted under conditions of simulated sunlight to be clinically

relevant. Even though a particular substance has ground state absorption in UVA or

UVB after it absorbs radiation, a transient or stable photoproduct may be produced that

absorbs in a different absorption range (Becker et al., 1996; Navaratnam and Claridge

2000). A number of methods and approaches are used that test for photoirritation.

Appropriate animal models (generally mice or guinea pigs, but also rabbits or swine)
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have been discussed by Marzulli and Maibach (1996, 1998) and Lambert et al. (1996).

Several in vitro screens for photoirritation, such as the 3T3 neutral red uptake

photocytotoxicity test, are available (Spielmann et al., 1998). The 3T3 assay may be

useful for products that absorb UVA, UVB, or visible radiation. This assay may not be

appropriate for the evaluation of some water-insoluble substances or complete drug

formulations. Data from in vitro studies may provide sufficient information when

conditions of the study are appropriate for the evaluation of the drug product of interest

and may be important in planning more efficient comprehensive in vivo assessments.

For in vivo nonclinical studies, acute drug exposure followed by simulated sunlight

exposure is generally considered adequate to identify potential risks. Assessments of

photoirritation may be incorporated into ongoing general toxicity studies in some

circumstances. Human studies are also often conducted to follow up on potential risks

identified based on animal or in vitro evaluations.

IV. TESTING FOR ENHANCEMENT OF UV-ASSOCIATED SKIN

CARCINOGENESIS (DIRECT PHOTOCHEMICAL CARCINOGENICITY OR

INDIRECT EFFECTS IN SKIN)

A. Considerations and Decision Tree for Testing Photosensitizing Drugs for

Long-Term Photosafety

Long-term photosafety testing is generally conducted only when it can provide useful

information. Long-term photosafety studies should be avoided when sufficient

information has already been collected for a drug or a class of drugs to appropriately

inform potential users regarding photoreactivity.

Once a systemically or dermally administered drug has been identified as a photoirritant

in animal or human testing (see Flowchart A1), one should consider the drug’s potential

to increase UV-associated skin cancer risk (Flowchart B). Because patients are already

cautioned against excessive sunlight exposure during use of photoirritating drugs,

sponsors could choose to strengthen these warnings with regard to photocarcinogenic

potential, rather than conduct testing to determine the photochemical carcinogenicity

potential for photoirritating drugs. The option to strengthen the warning statements

without conducting additional testing would be appropriate primarily in those

circumstances where photochemical carcinogenic activity would not affect approvability

or significantly reduce the utility of a drug product. The warning statement should convey

the basis of the warning and the conditions under which the potential carcinogenic effect

is likely to be realized (see Box 5, Flowchart B).

Warnings alone may be sufficient because drug products that are photoirritants can cause

rapid erythema (sunburn) reactions in patients who expose themselves to sun without

adequate protection. Unlike many drug side effects, sunburn is immediately apparent to

affected patients, who become quickly aware of the reactions during use. However, not

all patients receiving a photoirritating drug may experience overt photoirrritation effects.
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Some drugs can cause subthreshold photoeffects (e.g., DNA damage) that are not

apparent to patients. Thus, these drugs can also pose a long-term risk for adverse skin

effects. It is important for product warnings to address this situation. Other

circumstances for which product warning statements, rather than long-term testing, may

be appropriate include the following:

• Drugs having structures significantly similar to known photochemical carcinogens

• Drugs that are in a known pharmacologic class of photochemical carcinogens

where the pharmacology of the product is believed to be directly related to the

carcinogenic potential

• Drugs for which several other tests for photoreactivity, such as in vitro

photogenotoxicity, adduct formation, human photoirritation, or short-term in vivo

nonclinical tests are positive

• Drugs that have been identified as carcinogens with potential human relevance in

other assays that do not include UV sunlight, such as traditional two-year

bioassays or transgenic assays

• Drugs for indications intended for populations in which the life expectancy is

short (i.e., less than 5 years)

The warning should be informative, advising patients to avoid sun exposure, or if

sunlight exposure cannot be avoided, to use protective clothing and broad-spectrum

(UVA/UVB) sunscreens (when the wavelengths eliciting photoirritation are in the range

covered by the sunscreen). However, it is important to recognize that subclinical

photoirritation responses with prolonged use could also result in increased skin cancer

risk. In general, for the above cases, warning statements are considered an adequate

option, and phototesting, although potentially scientifically informative, may not be

warranted. In those cases where additional testing may be of value, it can often be

conducted during phase 4 of the drug development process (i.e., postapproval).

For drugs where the approvability or utility would be an issue (e.g., sunscreens), testing

beyond that noted above may be appropriate. Testing should be conducted using a model

for which there is evidence that relevant end points are assessed and considered

scientifically valid (see Flowchart B, Box 6). In some circumstances, a drug sponsor may

want to demonstrate that, despite initial results suggesting a potential for

photocarcinogenicity, the drug does not pose a risk for UV-associated skin cancer. The

results of appropriately conducted assays would be included in any communication of the

overall risk (Boxes 4 and 5, Flowchart B).

Short-term assays that measure photoreactivity (such as photogenotoxicity) have been

developed in the hope that they would provide information about the potential to enhance

UV-induced skin carcinogenesis. However, the interpretation of such assays is not

always straightforward, and their role in the evaluation of human risk should be carefully
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assessed. Although the most widely performed test for the potential to enhance UVinduced skin cancer is the hairless albino mouse model with solar simulation, other

scientifically valid assays for evaluating the photochemical carcinogenicity potential can

also be considered for regulatory purposes. When considering testing strategy, we

encourage sponsors to discuss issues with the appropriate CDER review staff. One

potential strategy is the use of biomarkers in human skin to evaluate the consequences of

combined drug and UV exposure. Use of biomarkers should be considered and

supported, based on a thorough evaluation of the scientific data (see section IV.C.,

Mechanistically Based and Other Assays).

B. Decision Tree for Testing Nonphotoreactive Drugs for Long-Term

Photosafety

The decision-tree approach would apply to products used chronically or for chronic

conditions as defined in the International Conference on Harmonization (ICH) guidance

for industry S1B Testing for Carcinogenicity of Pharmaceuticals.

2

 As noted earlier, drug

products that do not cause photoirritation reactions can enhance UV carcinogenicity. The

decision tree used for nonphotoreactive products attempts to balance the risks associated

with these potentially silent enhancers of UV-induced skin carcinogenesis, while

attempting to identify areas where testing is unnecessary. Pharmacologic activity (see

subsection IV.B.3. below) could provide information on such risks. It is anticipated that,

even in the absence of information about such risks, most nonphotoreactive drugs would

not be tested for potential to enhance UV-induced skin carcinogenesis, even if they were

administered chronically. This assumes that when administered chronically, drugs

usually would be tested for carcinogenicity in traditional bioassays. Some secondary

mechanisms of enhancement of UV carcinogenicity, such as immunosuppression or

inhibition of DNA repair, would be detected by use of traditional carcinogenicity studies.

The approach for nonphotoreactive drugs is described as follows (see also Flowchart C):

1. Duration of use

Nonphotoreacting drugs that are not used long term or for chronic conditions do not

appear to present a significant risk of enhancing UV-induced skin carcinogenesis. Thus,

it is unlikely that these drugs would be tested in any assay for potential to enhance UVinduced skin cancer. In addition, drug products intended solely for use in populations

with a short life expectancy (less than 5 years) need not be tested. Chronic use may be

continuous or substantial, repeated use and may justify such testing.

2. Route of administration (Box 3)

In general, topically applied drugs for which the intended effect is localized only to the

area of application to non-sun-exposed skin and that do not reach pharmacologically

 

2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER

guidance page at http://www.fda.gov/cder/guidance/index.htm.
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measurable systemic levels will not need to be tested for potential to enhance UVinduced skin cancer. This principle also applies to other drugs that do not reach

measurable systemic levels (e.g., drugs with mainly local effects on the respiratory tract).

3. Reasons to suspect drug may enhance UV-induced skin carcinogenesis

(Box 5)

The majority of drug products that are investigated and marketed are not photoreactive

and are unlikely to be photococarcinogens. However, a major class of potent, known

human photococarcinogens (e.g., immunosuppressants such as cyclosporin (Abel, 1989;

Penn, 1988)) that cause skin neoplasms are nonphotoreactive. There are other examples

of drug vehicles or nonphotoreactive drugs that enhance UV-induced skin carcinogenesis

in mice (Jacobs et al., 1999; Learn et al., 2000). The mechanisms of enhancement by

these nonphotoreactive drugs or vehicles have not been studied and can only be surmised.

Some of the mechanisms by which nonphotoreactive vehicles or drugs can enhance UVinduced skin carcinogenesis include, but are not limited to, immunosuppression,

neoplastic promotion, inhibition of apoptosis or DNA repair, and irritation, altering the

protective layers of the epidermis and/or changing the optical properties of the skin. Such

mechanisms are applicable to both rodent and human skin and are biologically plausible

mechanisms of enhancement. Products, such as some emollients, which change the

optical properties of the skin or alter the protective layers of the epidermis, can greatly

change UV penetration of the skin or the effective UV dose that the skin receives. The

open literature contains ample references to the effects of vehicles on skin and on the

overall performance of a drug product. These and other indirect effects (discussed in

section IV.C., Mechanistically Based and Other Assays) can also occur in human skin

and may be as important as direct photoreactive effects. For example, studies sponsored

by the cosmetics industry suggested increased sensitivity to UVB by persons using alphahydroxy acid preparations. As a consequence, the Cosmetic Ingredient Review Expert

Panel (CIR 1998) recommended that persons using these products avoid unprotected

exposure to the sun. The alpha-hydroxy acids used in these studies do not absorb UV

between 280 and 400 nm. Thus, a thoughtful approach is called for when deciding if

additional testing for potential to enhance UV-induced skin carcinogenesis is justified.

4. Warning or test (Boxes 6, 7, 8)

If preliminary evaluations suggest that a drug or drug product may have the potential to

enhance UV-induced skin carcinogenesis, the sponsor should warn of this potential effect

or conduct studies to evaluate this potential. Such studies could be a panel of

appropriately selected and scientifically valid biomarkers in human skin, referred to in

section IV.C., Mechanistically Based and Other Assays. Although some drug products

that do not absorb light could lower the MED by changing the optical properties of the

skin, resulting in increased UV effects, drugs that do not absorb light are not tested for

photoirritation according to the current testing paradigm. If it were demonstrated that a

nonphotoreactive drug product increased transmission of UV radiation through the skin,

resulting in measurable increases in UV susceptibility, such as lowering the MED in

animals or humans, further photosafety studies in animals, such as a
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photococarcinogenesis study, may not be appropriate. A product that increases the dose

of UV penetrating the skin would likely shorten the time to skin neoplasms and could be

labeled appropriately.

C. Mechanistically Based and Other Assays

Mouse and human skin share many of the same responses to sunlight and drugs.

Exposure to sunlight clearly modifies DNA and causes nonmelanoma skin cancer in both

animals and humans (IARC, 1992). Although there are a number of differences, many of

the proposed mechanisms by which drug substances or drug products can enhance UVassociated skin carcinogenesis are shared by mice and humans. Pyrimidine dimer

formation and P53 protein induction have been demonstrated in human skin in situ after

suberythemal doses of solar-simulated light (Burren et al., 1998). Evaluation of the

potential to indirectly enhance UV carcinogenicity using biomarkers in skin may be

appropriate, provided that the biomarkers are scientifically supported. A testing strategy

can be discussed with the appropriate CDER review division. To improve testing

procedures, it would be helpful to identify appropriate surrogate markers in human skin

for increased UV exposure or UV damage.

Useful tests would be those that provide information on the relevance of, or sensitivity to,

adverse photoeffects in vitro or in animals relative to humans. Tests could include, but

would not be limited to, in vitro measures of photocytotoxicity, in vitro measures of

photogenotoxicity (e.g., in Salmonella, yeast, or V79 cells), transgenic models, and

biomarkers (molecular, biochemical, cellular, or structural) for enhancement of

UV-induced skin carcinogenesis in human skin. Changes in the MED, sunburn cell

number (Lavker and Kaidbey, 1997), p53 alterations, dimer formation in DNA (Katiyar

et al., 2000), and other end points have been proposed as markers of increased UVB

exposure or skin damage. Markers for increased UVA exposure, as well as for UVB

exposure, would be desirable. Although the preferred radiation exposure in these assays

would be sunlight simulation, at a minimum, the appropriate absorption spectrum for a

photoreactive drug product should be covered. Assays assessing immunosuppression or

inhibition of DNA repair, particularly in human skin, may be useful in testing some

products. It is important to define the strengths and limitations of the assays. Correlation

of the in vitro results for photoirritation with data from controlled clinical studies would

add to the potential utility of such tests. Correlation of the biomarker response in animal

skin with the biomarker response in human skin for the same UV dose could provide a

basis for evaluation of the size of a response in a clinical surrogate that would translate

into a clinically meaningful increase in skin cancer risk. Submission of a test or rationale

including relevant data should accompany any proposal to use novel methods.

The recommendations of this guidance recognize both the importance of adverse

photoeffects and the difficulty in appropriately assessing human risks. This guidance

allows a flexible approach to be used to address adverse photoeffects and does not require

that a specific assay be used. Most important, it encourages the development of methods

that can efficiently be used to evaluate human safety.
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REFERENCES

Abel, E. A., 1989, “Cutaneous Manifestations of Immunosuppression in Organ Transplant

Recipients,” J. Am. Acad. Dermatol. 21 (2 part 1): 167-179.

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Contains Nonbinding Recommendations

13

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Contains Nonbinding Recommendations

14

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Contains Nonbinding Recommendations

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GLOSSARY

ADR: Adverse drug reaction

IR: Infrared radiation 0.76 μm- 1000 μm

MED: Minimal erythema dose

8-MOP: 8-Methoxypsoralen

NSAID: Nonsteroidal anti-inflammatory drug

Excipients: Ingredients that are intentionally added to therapeutic products but that do not

directly exert pharmacologic effects at the intended dosage

Indirect photoeffects: Effects of an agent, vehicle, or product on the optical, structural,

molecular, or physiologic properties of the skin, such that the interaction of light and skin or

effects of drug in skin are altered.

Nonphotoreactive: Drugs or chemicals that do not react with another molecule in the

formulation or skin after exposure to UVA, UVB, or visible radiation

Photoallergy: An acquired, immunologically mediated reaction to a drug or chemical initiated

by the formation of photoproducts when that drug or chemical is exposed to light

Photochemical carcinogenesis: Carcinogenesis resulting from a reaction with a photoactivated

drug or chemical

Photococarcinogenicity: The direct (photochemical carcinogenesis) or indirect enhancement of

UV-associated skin carcinogenesis (e.g., sunlight-associated carcinogenesis) by a drug or

chemical

Photoirritation or Photochemical irritation: A light-induced, nonimmunologic, skin response

to a photoreactive drug or chemical

Photoproducts: Compounds resulting from absorption of radiation by a drug or chemical

Photoreactive: Drugs or chemicals that react with another molecule in the formulation or skin

after exposure to UVA, UVB, or visible radiation

Photosafety testing: Testing for the potential of a drug product to cause photoirritation or

photoallergy or to enhance UV-induced skin carcinogenesis

Photosensitivity: A photoirritation- or photoallergy-induced reaction
Contains Nonbinding Recommendations

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Photosensitizer: A drug or chemical that causes an adverse effect in the presence of UVA/UVB

or visible light

Phototoxicity: A light-induced, nonimmunologic response to a photoreactive drug or chemical

PUVA: Psoralen plus UVA treatment

UV: Ultraviolet radiation (wavelengths between 10 and 400 nm)

UVA: Ultraviolet radiation A (wavelengths between 320 and 400 nm)

UVB: Ultraviolet radiation B (wavelengths between 290 and 320 nm)

UVC: Ultraviolet radiation C (wavelengths between 200 and 290 nm)
Contains Nonbinding Recommendations

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ATTACHMENT

A1. DECISION TREE TO IDENTIFY WHEN IT IS RECOMMENDED THAT

TESTING BE CONDUCTED FOR SHORT-TERM PHOTOCHEMICAL IRRITATION

2. Further

 testing for

adverse

photoeffects

generally not

needed.

(See text for

discussion of

photodynamic

therapy)

3. Significantly partitions to eye or skin or

affects eye or sun-exposed skin? (See text for

discussion)

4. Positive in photoirritation clinical or

nonclinical testing?

6. Recommend indicating in risk communication

that drug may cause photoirritation, and users of

drug should avoid sun exposure while drug is in

the body.

Yes

No

No

Yes

Yes

1. Absorbs UVA, UVB, or

visible (290 -700 nm)

light?

No 5. Indicate in risk

communication that

no effect observed.
Contains Nonbinding Recommendations

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A2. DECISION TREE TO IDENTIFY WHEN IT IS RECOMMENDED THAT

TESTING BE CONDUCTED FOR PHOTOCHEMICAL IRRITATION AFTER

REFORMULATION OF A TOPICAL PREPARATION

2. No further

testing for adverse

 photoeffects

 needed.

3. UV-absorbing drug substance or excipients

previously found to cause photoirritation?

4. New formulation has significantly different effects on

skin that could result in photoirritation (e.g., allows

much greater penetration of UV-absorbing drug

substance or excipient into the skin)?

5. Recommend testing new formulation for

photoirritation.

YES

NO

YES

NO

YES

1. Topically applied formulation

absorbs UVA, UVB, or visible

(290 -700 nm) light?

NO
Contains Nonbinding Recommendations

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B. TESTING FOR THE PHOTOCHEMICAL CARCINOGENICITY POTENTIAL* OF

PHOTOREACTIVE IRRITATING DRUG PRODUCTS AND LABELING

OUTCOMES

2. Has additional testing been conducted?

* Testing should be in an appropriate model. Assays of

appropriate in vivo biomarkers can be used; consultation

with CDER staff is recommended.

6. Testing may

be needed. *

1. Drug product is a human or animal photoirritant.

4. If drug is to be marketed,

communicate risk.

NO YES

3. Is approvability or utility

an issue?

YES NO

5. Communicate

risk for

photoirritants.

YES
Contains Nonbinding Recommendations

21

C. TESTING OF NONPHOTOREACTIVE DRUG PRODUCTS FOR POTENTIAL* TO

ENHANCE UV-INDUCED SKIN CARCINOGENESIS

4. No need

for testing for

potential to

enhance UVinduced skin

carcinogenesis.*

2. Is administration

systemic?

5. Any reason to expect that drug product could

enhance UV carcinogenicity? In structural or

pharmacologic class of UV carcinogenicity

enhancers? Adversely changes protective layers of

epidermis, such as changing optical properties?

Persistence in skin?

*Products specifically intended for use in sunlight should be tested for potential to enhance UV

carcinogenicity. Testing should be in an appropriate model. Assays of appropriate in vivo biomarkers

of increased UV exposure may be used; consultation with CDER is recommended.

 1. Chronic use in population with life expectancy > 5-years?

3. If topical administration,

is skin exposed to sun?

No No

No

Yes Yes

Yes

6. Sponsor and CDER review Division agree about

potential to enhance UV-induced skin

carcinogenesis?

7. Communicate risk.

Yes

8. Recommend sponsor conduct study for

potential to enhance UV carcinogenicity

and results are described in risk

communication.

No

Yes No