Guidance for Industry 

Nonclinical Safety Evaluation 

of Drug or Biologic 

Combinations 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2006 

Pharmacology and Toxicology 
Guidance for Industry 

Nonclinical Safety Evaluation 

of Drug or Biologic 

Combinations

Additional copies are available from: 

Office of Training and Communications 

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) 

March 2006 

Pharmacology and Toxicology 
TABLE OF CONTENTS 

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

II. NONCLINICAL STUDIES FOR A COMBINATION OF TWO OR MORE 

PREVIOUSLY MARKETED DRUGS OR BIOLOGICS (FIGURE A)..................... 2

A. Safety Considerations ....................................................................................................................3

B. Nonclinical Study Recommendations/General Procedure .........................................................4

III. NONCLINICAL STUDIES FOR A COMBINATION OF DRUGS OR BIOLOGICS 

WHEN ONE OR MORE IS PREVIOUSLY MARKETED AND ONE IS A NEW 

MOLECULAR ENTITY (FIGURE B)........................................................................... 6

A. General Toxicology Studies...........................................................................................................6

B. Reproductive and Developmental Toxicology.............................................................................6

C. Animal Models of Efficacy ............................................................................................................7

D. Further Studies ..............................................................................................................................7

IV. NONCLINICAL STUDIES FOR A COMBINATION OF TWO OR MORE 

DRUGS OR BIOLOGICS WHEN ALL ARE NEW MOLECULAR ENTITIES 

(FIGURE C) ...................................................................................................................... 7

A. General Toxicology Studies...........................................................................................................7

B. Animal Models of Efficacy ............................................................................................................8

C. Safety Pharmacology .....................................................................................................................8

D. PK/ADME and Toxicokinetics......................................................................................................8

E. Genetic Toxicology.........................................................................................................................9

F. Special Toxicology..........................................................................................................................9

G. Reproductive and Developmental Toxicology.............................................................................9

H. Further Studies ..............................................................................................................................9

I. Carcinogenicity ............................................................................................................................10

APPENDIX: RECOMMENDED GENERAL PROCEDURES ............................................ 11

Figure A: Combinations of Previously Marketed Drugs or Biologics ............................................11

Figure B: Combinations of Previously Marketed Drugs or Biologics with NMEs........................12

Figure C: Combinations of NMEs with NMEs .................................................................................13
Contains Nonbinding Recommendations

Guidance for Industry1

Nonclinical Safety Evaluation of 

Drug or Biologic Combinations

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. 

You can use an alternative approach if the 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 provides recommendations on nonclinical approaches to support the clinical study 

and approval of fixed-dose combination products (FDCs), co-packaged products, and some 

adjunctive therapies.2 The intent of this guidance is to delineate general guiding principles. To 

receive more detailed advice regarding a particular drug or biologic combination development 

program, sponsors should contact the appropriate review division before submitting an 

investigational new drug application (IND). In addition, the Food and Drug Administration 

(FDA) is in the process of publishing more specific guidance for certain categories of drug 

combinations.3 

 

1

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

Evaluation and Research (CDER) at the Food and Drug Administration. 

2

 For the purposes of this guidance, a fixed-dose combination product (FDC) is one in which two or more separate 

drug components (active pharmaceutical ingredients) are combined in a single dosage form. A co-packaged product

consists of two or more separate drug products in their final dosage forms, packaged together with appropriate 

labeling to support the combination use. An adjunctive therapy refers to the situation in which a patient is 

maintained on a second drug product that is used together with (i.e., in adjunct to) the primary treatment, although 

the relative doses are not fixed, and the drugs or biologics are not necessarily given at the same time. Adjunctive 

therapy products may be co-packaged, and may or may not be labeled for concomitant use. However, adjunctive 

therapies are only covered in this guidance when the adjunctive therapy products are already labeled for concomitant 

use, a sponsor intends to seek labeling to address concomitant use, or when, in light of the factors described in 

section II.A, there is an identified cause for concern about a potential serious interaction. For the purposes of this 

guidance, the terms co-packaged product, FDC, and adjunctive therapy are collectively referred to as combinations. 

3

 For example, the Agency is developing a draft guidance specifically addressing oncologic drug combinations. In 

addition, in May 2004 (69 FR 28931), the Agency made available the draft guidance for industry Fixed Dose 

Combination and Co-Packaged Drug Products for Treatment of HIV (draft HIV guidance). When finalized, this 

guidance will provide recommendations on FDCs and co-packaged versions of previously approved antiretroviral 

therapies for the treatment of human immunodeficiency virus (HIV). Sponsors should consult these additional 

guidances when preparing an application for one of these types of products. 

1
Contains Nonbinding Recommendations

Drug and biologic combinations may involve: (1) two or more previously marketed drugs or 

biologics4 (MD/Bs); (2) one or more new molecular entities (NMEs) and one or more previously 

marketed drugs or biologics; or (3) more than one NME. The nonclinical studies considered 

important for each type of combination may differ, depending upon the information available on 

each drug substance. The nonclinical studies that the FDA recommends sponsors use to 

characterize the combination will depend on the toxicologic and pharmacokinetic profiles of the 

individual drugs or biologics, the treatment indication or indications, and the intended 

population. The number and type of studies will depend on the stage of clinical development. 

In this guidance, each of the three general types of combinations (i.e., MD/B-MD/B, MD/BNME, and NME-NME) will be discussed separately. This guidance covers combinations of 

drugs and biologics regulated by the Center for Drug Evaluation and Research (CDER). The 

ICH guidance for industry S6 Preclinical Safety Evaluation of Biotechnology-Derived 

Pharmaceuticals should also be consulted for nonclinical development of biologic products.5 

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. NONCLINICAL STUDIES FOR A COMBINATION OF TWO OR MORE 

PREVIOUSLY MARKETED DRUGS OR BIOLOGICS (FIGURE A) 

This section addresses the situation in which a sponsor submits an application to develop a 

combination of two or more previously marketed drugs or biologics or a combination of drugs 

and biologics. Generally the FDA believes that, in such a situation, sufficient clinical and 

nonclinical data will exist for each drug product separately. However, the indications for which 

each drug is marketed should be compared to those for which the combination is being proposed. 

For example, drug products marketed for acute use may not have nonclinical data to support 

chronic use. To the extent that there are gaps in the data, the FDA may recommend that 

additional nonclinical studies be conducted.6

 

4

 For purposes of this guidance, the phrase previously marketed drugs or biologics includes both drug/biologic 

products and active pharmaceutical ingredients. 

5

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

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

6

 In certain cases, adequate clinical data may exist not only for the individual components of a drug or biologic 

combination, but also for their concomitant use. In such cases, additional nonclinical studies may not be necessary. 

For example, the draft HIV guidance referenced in Footnote 3 discusses the FDA’s belief that certain antiretroviral 

therapies previously approved for the treatment of HIV may be approved for use in combination without additional 

in vitro studies, because the clinical safety and efficacy of concomitant use have been evaluated and described in 

product labels or peer-reviewed literature. Where adequate clinical data exists for the concomitant use of two 

previously approved drugs or biologics, a sponsor seeking approval for the drug and biologic combination should 

contact the appropriate review division to discuss whether any additional nonclinical data are warranted. 

2
Contains Nonbinding Recommendations

A. Safety Considerations

If existing clinical and nonclinical safety data for each separate drug or biologic are sufficient to 

support the safety of the proposed new indication, then the FDA recommends that the following 

factors relevant to the safety of the combination be considered to determine whether further 

nonclinical studies are warranted. 

1. Information available on prior human experience with the combination. The FDA 

recommends that the sponsor provide a summary of the available data in humans (if any) 

on the use of the combination. The FDA also encourages the sponsor to provide copies 

of any relevant published studies in humans (or animals). Such reports may not provide 

definitive safety data, but they may provide some measure either of assurance or reasons 

for concern. 

2. Information known about the individual drugs or biologics in animals and humans and 

concordance of pharmacokinetics (PK), pharmacodynamics (PD), and toxicologic effects 

in animals with the analogous data for humans. 

3. Possibility of a PD interaction. Drugs/biologics may exhibit affinity for the same 

receptors or biologic targets or may produce similar effects on physiologic function, 

related or not to their mechanism of action. 

4. Possibility of a PK interaction. A PK interaction can manifest in several ways, some of 

which can be monitored in vivo and some of which cannot. One drug/biologic product 

may alter the absorption or excretion of another product, change its distribution into one 

or more tissues, or change its pattern or rate of metabolism. Drugs may compete for 

serum protein binding, resulting in an increase in circulating free levels and tissue uptake 

of one drug. 

5. Possibility of a toxicologic interaction (i.e., that the target organs for toxicity are similar 

for each drug/biologic). This situation may result in a lowering of the previously 

determined no-effect doses for one or both drug/biologic products and more severe 

toxicities in the affected organs. The FDA will consider all known toxicology on the 

product (e.g., general toxicity, reproductive toxicity, carcinogenicity, and safety 

pharmacology studies (cardiovascular, central nervous system (CNS), respiratory)). 

6. Margin of safety for each drug/biologic product. If one or more of the drugs/biologics 

has a narrow margin of safety (i.e., causes serious toxicity at exposures close to the 

predicted clinical exposure), then the possibility of drug interaction is of particular 

concern, especially if the toxicity is not reversible or cannot be monitored clinically. 

7. Possibility that the drugs/biologics compete for or alter the activity or endogenous levels 

of the same enzymes or other intracellular molecules (e.g., co-administration of two prooxidants could deplete endogenous levels of glutathione). 

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Contains Nonbinding Recommendations

8. Possibility of a chemical interaction. One drug may chemically modify another drug or 

biologic (e.g., one drug may oxidize, methylate, or ethylate the other drug or biologic). 

This could result in NMEs with new toxicities. 

9. Possibility that one drug/biologic may compromise the effectiveness of another 

drug/biologic for a lifesaving therapy. 

B. Nonclinical Study Recommendations/General Procedure 

If existing clinical and nonclinical safety data for each separate drug or biologic are sufficient to 

support the safety of the proposed new indication, including the dose, dosing schedule, duration, 

and new patient population, then additional nonclinical studies may not be needed. 

The general approach to addressing the safety concerns posed by the testing or marketing of 

combinations of previously marketed drugs or biologics is illustrated in Figure A. The safety of 

the combination should be assessed according to the factors listed in section II.A (see Figure A, 

Boxes 1 to 2). If neither individual drug or biologic product has serious toxicity at exposures 

well above the proposed clinical exposure or if there is substantial clinical experience with the 

combination, the FDA may recommend that additional nonclinical studies do not need to be 

conducted before testing in humans, during initial studies in humans, or at all (Boxes 2 to 3). 

The Agency’s recommendation to conduct nonclinical studies for further development of the 

combination will depend on what is learned from initial studies in humans or what is known 

from prior human use of the combination.7

If after evaluating the available data on the individual drug/biologic products and the potential 

for drug/biologic interaction there is no evidence to suggest a possible interaction, direct 

assessment of the combination by testing in animals may not be needed before the first small 

clinical studies with the combination. Even if an interaction is expected, nonclinical studies may 

not be necessary if the expected interaction is likely to result in predictable, nonserious, 

monitorable effects in humans. For example, if a metabolic interaction is predicted, the starting 

dose could be significantly lowered in humans. Metabolic interactions have been seen for 

combinations of two biologics. There is a possibility of drugs/biologics affecting the same tissue 

or biologic target or having a PD interaction. 

Generally, the FDA recommends that sponsors conduct nonclinical toxicity studies before 

clinical studies are initiated if: (1) the drug products have similar target organ toxicity or PD 

activity; and (2) either drug product causes serious or nonmonitorable toxicity in animals or 

humans at exposures near the clinical exposure; or (3) any other reason exists for serious clinical 

concern (see section II.A). The particular nonclinical studies recommended by the FDA will 

depend on a number of factors, including the nature of the toxicity and on the concerns identified 

in section II.A. For assessment of general toxicity, a bridging study may be appropriate, 

provided the duration is sufficient to elicit the toxicity of concern. For example, a general 

 

7

 For example, as previously mentioned, the draft HIV guidance discusses the FDA’s belief that certain antiretroviral 

therapies previously approved for the treatment of HIV may be approved for concomitant use without additional 

nonclinical (or clinical) studies, because the clinical safety and efficacy of concomitant use have been evaluated and 

described in product labels or peer-reviewed literature. 

4
Contains Nonbinding Recommendations

toxicity bridging study of 3 months’ duration could be considered for a chronic indication. The 

FDA suggests that combination studies include an assessment of several dose levels of the 

combination and a high dose of each drug alone. Other possible designs can be discussed with 

the review division. Sponsors are urged to select the doses of each drug used in combination to 

allow for additive or synergistic effects without unacceptable toxicity in the high-dose groups. 

Usually, assessment of the drug combination may be conducted in only one species if one of the 

following conditions exists: (1) toxicity in a particular species has high concordance with human 

toxicity or the toxicities are similar among species; or (2) one species is a more relevant model 

for human risk based on other factors such as PK/ADME (absorption, distribution, metabolism, 

and excretion) or expression of the pharmacologic activity. If a sponsor will be conducting only 

one general toxicity study, the FDA recommends that the sponsor provide justification for the 

species selected for testing the combination. There may be cases, however, in which the Agency 

may recommend conducting studies in two species despite one or both of these conditions being 

met. For example, depending on the results in the first species, a new cause for concern might 

warrant follow-up studies in a second species, if there is an appropriate second species. 

Sometimes one of the drugs proposed for the combination will be much more toxic in animals 

than in humans, such that animals cannot tolerate the combination at doses that produce exposure 

relevant to the anticipated clinical exposure (e.g., some nonsteroidal anti-inflammatory drugs 

(NSAIDs) and antibiotics). In those cases, general toxicity studies of the combination could be 

conducted at a dose giving less exposure than that achieved with the recommended clinical dose 

of the more toxic drug product, provided that a serious dose-limiting toxicity is achieved in the 

animals. The timing of the studies should be as described in the ICH guidance for industry M3 

Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. 

Combination genotoxicity studies generally will not be necessary if the individual agents have 

been tested consistent with current standards. Embryo-fetal development studies of the 

combination should be conducted per the timing described in ICH M3, unless the marketed 

products are already known to have significant risk for developmental toxicity (e.g., one of the 

marketed drugs has been assigned a pregnancy category “D” or “X”). If combination studies are 

needed, a single study could be conducted in the most appropriate species, based on what is 

known about the individual drugs or biologics. If a significant risk is only identified for a 

particular trimester of pregnancy, such as ACE inhibitors during the third trimester, studies to 

evaluate the effects of exposure to the NME or the combination during other trimesters may be 

needed. 

For chronic indications, a carcinogenicity study on the drug combination generally will only be 

recommended if statistically significant incidences of preneoplastic lesions were observed at a 

new organ or tissue site in nonclinical studies of the combination. Results of the nonclinical 

studies may be used to recommend modification of the clinical protocol (e.g., starting clinical 

doses, parameters to monitor) (Box 8). 

5
Contains Nonbinding Recommendations

III. NONCLINICAL STUDIES FOR A COMBINATION OF DRUGS OR BIOLOGICS 

WHEN ONE OR MORE IS PREVIOUSLY MARKETED AND ONE IS A NEW 

MOLECULAR ENTITY (FIGURE B) 

This section addresses the situation in which a sponsor submits an application to develop a 

combination of two or more drugs or biologics — one or more previously marketed and one an 

NME or a combination of drugs and biologics. 

A. General Toxicology Studies 

The Agency generally suggests that nonclinical studies be conducted on the NME for a product 

that is a combination of an NME and a previously marketed drug or biologic. The FDA believes 

that the standard battery of nonclinical studies (i.e., genetic toxicology, pharmacology, safety 

pharmacology, PK/ADME, general toxicity, reproductive and developmental toxicity, 

carcinogenicity) generally will be appropriate for the NME, as described in ICH M3. ICH S6 

should be consulted for nonclinical development of biologic products. If genotoxicity studies on 

the previously marketed product are consistent with current standards, it may be appropriate to 

conduct genotoxicity studies on only the drug NME portion of the combination. 

Depending on the duration of the proposed therapy, the FDA recommends that a sponsor conduct 

a bridging study of up to 90 days with the combination in the most appropriate species. Studies 

of shorter duration could be appropriate for shorter clinical studies or for nonchronic indications, 

per ICH M3. There may be cases, however, where studies in a second species may be 

appropriate. Because the drug ratio may change during drug development, it is important to 

design the toxicity studies to provide adequate margins of safety for future clinical studies. For 

combinations, the FDA recommends that the exposure to the drugs/biologics be at ratios that are 

relevant to the intended clinical use. 

Sometimes one of the drugs proposed for the combination will be much more toxic in animals 

than in humans, such that animals cannot tolerate the combination at doses that produce exposure 

relevant to the anticipated clinical exposure (e.g., some NSAIDs and antibiotics). In those cases, 

nonclinical studies of the combination could be conducted at a dose giving less exposure than 

that achieved with the recommended clinical dose of the more toxic drug product, provided that a 

serious dose-limiting toxicity is achieved in the animals. 

B. Reproductive and Developmental Toxicology 

Embryo-fetal development studies on the NME are recommended, as are fertility and other 

reproduction studies, by the ICH. Studies to evaluate the reproductive toxicity of the 

combination are not generally needed. Embryo-fetal development studies of the combination 

should be conducted unless the marketed drug substance or the NME is already known to have 

significant risk for developmental toxicity (e.g., the marketed drug has been assigned a 

pregnancy category “D” or “X”). If combination studies are needed, a single study could be 

conducted in the most appropriate species, based on what is known about the individual drugs or 

biologics. If a significant risk is only identified for a particular trimester of pregnancy, such as 

6
Contains Nonbinding Recommendations

ACE inhibitors during the third trimester, studies to evaluate the effects of exposure to the NME 

or the combination during other trimesters may be needed. 

C. Animal Models of Efficacy 

Animal models of efficacy are not generally needed. However, valuable data may be obtained 

from studying the combination in appropriate animal models of efficacy, if they are available and 

considered relevant. For example, there are situations in which one drug has been shown to alter 

the efficacy of the second drug. This information may be important if one or more of the drugs 

in the combination is for a serious or life-threatening indication. Identifying such an interaction 

permits an informed choice of dose of each product in the combination and an optimal schedule 

for the proposed clinical trial.

D. Further Studies 

The FDA recommends that a sponsor address any important data gaps for the marketed product 

or products that may be relevant for the proposed indication. After evaluating the available data 

on the individual drug products and the data on the bridging study of up to 90 days on the 

combination, a determination will be made on whether it is appropriate to conduct additional 

studies to address potential drug/biologic interactions. If a drug interaction is identified in the 

bridging study (synergistic effects) and the mechanism (e.g., PK, PD, or overlapping toxicity) is 

not apparent, then the FDA urges sponsors to consider studies to understand the nature of the 

interaction. The possible mechanisms of drug interaction listed in section II.A would also apply 

to combinations of one or more previously marketed drugs/biologics and an NME. Other than 

the general toxicology bridging study of up to 90 days and studies on embryo-fetal development, 

additional studies on the combination generally will not be needed. 

IV. NONCLINICAL STUDIES FOR A COMBINATION OF TWO OR MORE 

DRUGS OR BIOLOGICS WHEN ALL ARE NEW MOLECULAR ENTITIES 

(FIGURE C) 

A. General Toxicology Studies 

The FDA generally recommends that the sponsor conduct nonclinical studies on each NME to 

evaluate the safety of a combination of NMEs. Sponsors are encouraged to conduct the standard 

battery of nonclinical studies (i.e., genetic toxicology, pharmacology, safety pharmacology, 

PK/ADME, general toxicity, reproductive and developmental toxicity, carcinogenicity) on each 

NME, according to the timing as described in ICH M3, and according to ICH S6 for nonclinical 

development of biologic products. Depending on the duration of the proposed therapy, a 

bridging study of up to 90 days (for chronic indications) should be conducted with the 

combination in the most appropriate species if the NMEs were evaluated as separate entities 

(which is preferred) and not as a combination. There may be cases, however, where studies in a 

second species may be appropriate. If the two drugs or biologics are proposed to be marketed 

together only, then it is possible that it may be sufficient to conduct toxicology studies only on 

the combination. However, nonclinical studies conducted on each NME alone can be invaluable 

7
Contains Nonbinding Recommendations

should it become important to alter the clinical regimen from what is initially proposed or 

studied. 

Because the drug ratio may change during drug development, it is important to design the 

toxicity studies to provide adequate margins of safety for future clinical studies. The FDA 

recommends that the drugs or biologics be tested at doses that produce exposure ratios that are 

relevant (i.e., somewhat similar) to the intended clinical use, when feasible. 

Sometimes one of the drugs proposed for the combination will be much more toxic in animals 

than in humans, such that animals cannot tolerate the combination at doses that produce exposure 

relevant to the anticipated clinical exposure (e.g., some NSAIDs and antibiotics). In those cases, 

nonclinical studies of the combination might be conducted at a dose giving less exposure than 

that achieved with the recommended clinical dose of the more toxic drug, provided that a serious 

dose-limiting toxicity is achieved in the animals at the highest dose. 

B. Animal Models of Efficacy 

Animal models of efficacy are not generally needed. However, valuable data may be obtained 

from studying the combination in appropriate animal models of efficacy, if they are available and 

considered relevant. For example, there are situations in which one drug has been shown to alter 

the efficacy of the second drug. This information is especially important if one or more of the 

drugs or biologics in the combination is for a serious or life-threatening indication. Identifying 

such an interaction permits an informed choice of dose of each product in the combination and 

an optimal schedule for the proposed clinical trial. 

C. Safety Pharmacology

The FDA strongly recommends that sponsors assess the effects of drugs/biologics on a variety of 

organ systems before dosing in humans. Combination safety pharmacology studies of a 

particular organ system (e.g., cardiac, respiratory, CNS) may be valuable in many situations, 

such as when both drugs target the same organ system, a toxicity is associated with a class of 

compounds (e.g., QT prolongation), or the intended patient population is compromised (e.g., 

renal impairment). Sometimes when the molecular target is known, effects of the combination 

can be predicted. 

D. PK/ADME and Toxicokinetics 

The FDA recommends that sponsors conduct combination PK/ADME studies to assess the 

potential for a PK interaction between the drugs/biologics. These data are valuable for 

supporting the safety profile and guiding the drug/biologic development process. The FDA 

further recommends that PK/ADME combination studies (e.g., in vitro drug metabolism studies) 

be conducted early in drug development. The FDA encourages sponsors to evaluate serum 

protein binding and to monitor plasma concentrations of each drug in the toxicology studies. It 

may be possible to collect PK data as part of the toxicology studies instead of in a separate study. 

8
Contains Nonbinding Recommendations

E. Genetic Toxicology 

Genetic toxicology studies are not needed for biologic or drug/biologic combinations. Assessing 

the genotoxic potential of a drug/drug combination is generally not necessary, provided that 

adequate studies of the individual drug substances have been conducted. For the in vitro assays, 

genotoxic potential is routinely tested in the absence and presence of metabolic activation. 

Therefore, testing drugs in combination in these assays would not likely provide additional 

information to assays testing each drug alone, particularly if any potential interaction is expected 

to be from effects on hepatic metabolism. 

F. Special Toxicology 

The FDA may recommend that a sponsor conduct special toxicology studies, such as local 

tolerance studies, with the NME as well as with the combination in a particular therapeutic area 

relevant to the proposed use. The Agency may also recommend that targeted toxicity studies be 

conducted, depending upon the nature of toxicities seen in animals and humans with the drug 

products or drug class. 

G. Reproductive and Developmental Toxicology

Embryo-fetal development studies on each NME are generally recommended by the ICH, as are 

fertility and other reproduction studies. Studies to evaluate the reproductive toxicity of the 

combination are not generally needed, if this has been evaluated for the individual NME. If 

developmental toxicity has been assessed only on each NME separately, then the FDA 

recommends that developmental toxicity studies be conducted on the combination as well, in the 

most appropriate species, before treatment of women of childbearing potential. Embryo-fetal 

developmental studies of the combination may not be needed if one of the NMEs is known from 

the nonclinical studies to have significant risk for developmental toxicity, such as results 

indicating potential labeling as a “D” or “X.” If a significant risk is only indicated for a 

particular trimester of pregnancy, studies to evaluate the effects of exposure to the combination 

during other trimesters may be needed. 

H. Further Studies 

After evaluating the available data on the individual drug/biologic products and the data on the 

bridging study of up to 90 days on the combination, a determination will be made as to whether 

it is appropriate to conduct additional studies to address potential drug/biologic interactions. If a 

drug/biologic interaction is identified in a study and the mechanism (e.g., PK, PD, or overlapping 

toxicity) is not apparent, then the FDA urges the sponsor to consider studies to evaluate the 

nature of the interaction. The possible mechanisms of drug/biologic interaction listed in section 

II.A would also apply to combinations of more than one NME. Generally, studies of the 

combination other than the general toxicology bridging study of up to 90 days (depending on the 

chronicity of the indication) and studies on embryo-fetal development will not be needed. 

9
Contains Nonbinding Recommendations

I. Carcinogenicity

Depending on the duration and intended use of the combination, the Agency may suggest that the 

sponsor conduct carcinogenicity studies on the combination, if each individual NME has not 

been tested for carcinogenicity. 

10
Contains Nonbinding Recommendations

APPENDIX: RECOMMENDED GENERAL PROCEDURES 

Figure A: Combinations of Previously Marketed Drugs or Biologics 

1.* Evaluate each individual drug/biologic (section II.A).

2. Concern about combination based on factors in 

section II.A (e.g., PK, PD, 

or toxicologic interaction; 

toxicity that cannot be 

 monitored)? 

3. Proceed with 

clinical study. 

No 

5. Evaluate in No 

vitro metabolism data; if 

not available, 

conduct in 

vitro metabolism studies 

(in vitro may 

not be 

appropriate for 

biologics). 

*

Box numbers correspond to references in the text 

document and do not depict the order in which one 

proceeds. 

4. Concern limited to 

metabolic interaction? 

Yes 

6. Metabolic 

interaction? Yes

8. Adjust clinical study 

design as appropriate. 

Yes 

No 

7. Conduct toxicology studies on 

combination to address concerns. 

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Contains Nonbinding Recommendations

Figure B: Combinations of Previously Marketed Drugs or Biologics with NMEs 

Evaluate each individual drug or biologic (ICH); address data gaps 

(i.e., generally all studies recommended for NME). 

Usually conduct toxicology study of up to 90 days (shorter durations for shorter 

clinical use and nonchronic indications) and embryo-fetal developmental study on 

combination; see the text for details on determining whether other studies are 

appropriate. 

Do toxicology 

studies suggest an 

interaction? 

Yes If nature of interaction is 

not apparent, consider 

studies to understand the 

interaction. 

Proceed with clinical study at doses 

derived from toxicology studies. 

 No 

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Contains Nonbinding Recommendations

Figure C: Combinations of NMEs with NMEs 

Preferably, evaluate each NME (ICH) before evaluating the combination. Usually conduct 

toxicology study of up to 90 days and embryo-fetal developmental study on combination (see the 

text for details). If only individual NMEs are studied, use the following approach to address safety 

concerns. 

Proceed with clinical 

study at doses derived 

from toxicology studies. 

Concern about a 

metabolic 

interaction? 

Evaluate in 

vitro metabolism data; if 

not available, 

conduct in 

vitro metabolism studies 

(in vitro may 

not be 

appropriate for 

biologics). 

Metabolic 

interaction? 

No 

Yes

Conduct toxicology studies to 

address concerns other than PK? 

Adjust clinical 

study design as 

appropriate. 

Conduct PK 

clinical study. 

Concern about 

combination based on 

factors in section II.A? 

No

Yes

Yes 

No 

13