Guidance for Industry 
 
Codevelopment of Two or More 
New Investigational Drugs for 
Use in Combination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2013 
Clinical Medical   
   
Guidance for Industry 
 
Codevelopment of Two or More 
New Investigational Drugsfor 
 
Use in Combination 
 
 
 
 
 
Additional copies are available from: 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave. 
Silver Spring, MD 20993 
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2013 
Clinical Medical   
    Contains Nonbinding Recommendations 
 
 
 
Table of Contents 
         
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  DETERMINING WHETHER CODEVELOPMENT IS AN APPROPRIATE 
DEVELOPMENT OPTION........................................................................................................2 
IV.  NONCLINICAL CODEVELOPMENT.........................................................................4 
A.  Demonstrating the Biological Rationale for the Combination...................................................4 
B.  Nonclinical Safety Characterization.............................................................................................4 
V.  CLINICAL CODEVELOPMENT..................................................................................5 
A.  Early Human Studies (Phase 1)....................................................................................................5 
1. Safety of the Individual New Investigational Drugs........................................................................5 
2. Safety and Dosing of the Combination............................................................................................5 
B.  Clinical Pharmacology...................................................................................................................6 
C.  Proof of Concept Studies (Phase 2)..............................................................................................6 
D.    Confirmatory Studies (Phase 3)....................................................................................................9 
VI.  REGULATORY PROCESS ISSUES IN CODEVELOPMENT................................10 
A.    Early Interaction with FDA........................................................................................................10 
B.  Investigational New Drug Applications (INDs).........................................................................10 
1. INDs for the Combination and the Individual New Investigational Drugs...................................10 
2. IND Safety Reports........................................................................................................................11 
3. IND Annual Reports.......................................................................................................................11 
4. Other IND Submissions..................................................................................................................11 
C.  Marketing Applications...............................................................................................................12 
D.    Labeling........................................................................................................................................13 
E.  Postmarketing Safety Monitoring Considerations....................................................................13 
  i Contains Nonbinding Recommendations 
 
 
1
Guidance for Industry  
 
Codevelopment of Two or More New Investigational Drugs for Use 
in Combination 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 is intended to assist sponsors in the codevelopment2 of two or more new drugs 
that have not been previously developed for any indication to be used in combination to treat a 
disease or condition.  For purposes of this guidance, these not-previously-developed drugs are 
referred to as new investigational drugs.  The guidance provides recommendations and advice on 
how to address certain scientific and regulatory issues that may arise during codevelopment of 
two or more new investigational drugs.  It is not intended to apply to development of fixed 
combinations of previously approved drugs or to development of a single new investigational 
drug to be used in combination with a previously approved drug or drugs.  FDA believes the 
recommendations in this guidance relevant to demonstrating the contribution of the individual 
new investigational drugs to the effect(s) of the combination are consistent with the requirements 
of 21 CFR  300.50, fixed-combination prescription drugs for humans.  This guidance applies 
only to drugs and biological products regulated by the Center for Drug Evaluation and 
Research.3  The guidance is not intended to apply to biological products regulated by the Center 
for Biologics Evaluation and Research or medical devices.  
                                                 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
(CDER) at the Food and Drug Administration.  
 
2 The term codevelopment as used in this guidance refers to the concurrent development of two or more new 
investigational drug products that are intended to be used in combination to treat a disease or condition.  A sponsor 
may elect to codevelop two or more new investigational drug products to be marketed as individual agents intended 
to be used in combination as a fixed-combination or co-packaged drug.  
 
3 For purposes of this guidance, the term drug includes therapeutic biological products that are regulated by CDER.  
Consult the Therapeutic Biologics Web page for further information on the types of biological products to which 
this guidance applies, on the Internet at 
  1 Contains Nonbinding Recommendations 
 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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 
 
Combination therapy is an important treatment modality in many disease settings, including 
cancer, cardiovascular disease, and infectious diseases.  Recent scientific advances have 
increased our understanding of the pathophysiological processes that underlie these and other 
complex diseases.  This increased understanding has provided further impetus to develop new  
therapeutic approaches using combinations of drugs directed at multiple therapeutic targets to 
improve treatment response, minimize development of resistance, or minimize adverse events.  
In settings in which combination therapy provides significant therapeutic advantages, there is 
growing interest in the development of combinations of new investigational drugs.  
 
Because existing developmental and regulatory pathways focus primarily on assessment of the 
safety and effectiveness of a single new investigational drug acting alone, or in combination with 
a previously approved drug, FDA believes guidance is needed to assist sponsors in the 
codevelopment of two or more new investigational drugs.  Although interest in codevelopment 
has been most prominent in oncology and infectious disease settings, codevelopment also has 
potential application in other therapeutic settings.  Therefore, this guidance is intended to 
describe a high-level, generally applicable approach to codevelopment of two or more new 
investigational drugs.  It describes the criteria for determining when codevelopment is an 
appropriate option, makes recommendations about nonclinical and clinical development 
strategies, and addresses certain regulatory process issues.   
 
 
III.  DETERMINING WHETHER CODEVELOPMENT IS AN APPROPRIATE 
DEVELOPMENT OPTION  
 
Codevelopment generally will provide less information about the clinical safety and 
effectiveness and dose-response of the individual new investigational drugs intended to be used 
in combination than would be obtained if the individual drugs were developed alone.  How much 
less information will vary depending on a variety of factors, including the stage of development 
at which the individual new investigational drugs cease to be studied independently.  For 
example, in codevelopment scenarios in which rapid development of resistance to monotherapy 
is a major concern, it may not be possible or appropriate to obtain clinical data for each drug in 
the combination beyond phase 1 testing.  Because co-development generally will provide less 
information about the individual new investigational drugs, it may present greater risk compared 
                                                                                                                                                             
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati
ons/TherapeuticBiologicApplications/default.htm. 
  2 Contains Nonbinding Recommendations 
 
to clinical development of an individual drug.   Given this concern, FDA believes that 
codevelopment should ordinarily be reserved for situations that meet all of the following criteria:     
 
  The combination is intended to treat a serious disease or condition.4 
 
  There is a strong biological rationale for use of the combination (e.g., the agents inhibit 
distinct targets in the same molecular pathway or steps in disease pathogenesis, provide 
inhibition of both a primary and compensatory pathway, or inhibit the same target at 
different binding sites to decrease resistance or allow use of lower doses to minimize 
toxicity). 
 
  A full nonclinical characterization of the activity of both the combination and the 
individual new investigational drugs, or a short-term clinical study on an established 
biomarker, suggests that the combination may provide a significant therapeutic advance 
over available therapy and is superior to the individual agents5  A nonclinical model 
should demonstrate that the combination has substantial activity and provides greater 
activity, a more durable response (e.g., delayed resistance), or a better toxicity profile 
than the individual agents.   
 
  There is a compelling reason why the new investigational drugs cannot be developed 
independently (e.g., monotherapy for the disease of interest leads to resistance, one or 
both of the agents would be expected to have very limited activity when used as 
monotherapy). 
 
FDA recommends that sponsors consult with FDA on the appropriateness of codevelopment 
before initiation of clinical development of a combination. 
 
 
 
 
                                                 
4 For purposes of this guidance, the term serious disease or condition refers to a disease or condition associated with 
morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually 
not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease 
or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day 
functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more 
serious one.  This definition is consistent with various statutory and regulatory provisions concerning the use of 
FDA-regulated medical products to treat serious or life-threatening diseases and conditions.  See, e.g.  561 of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 USC  360bbb) and corresponding regulations (21 CFR 
part 312 subpart I) regarding expanded access to unapproved therapies and diagnostics;  505-1 of the FD&C Act 
(21 USC  355-1) regarding Risk Evaluation and Mitigation Strategies; FDA regulations at 21 CFR part 314 subpart 
H and 21 CFR part 601 subpart E regarding accelerated approval; and  506 of the FD&C Act (21 USC 356 
regarding fast track development and designation.   
5 For purposes of this guidance, the term available therapy is interpreted as it is described in the guidance for 
industry on Available Therapy.   This guidance is available on the CDER guidance page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
  3 Contains Nonbinding Recommendations 
 
IV.  NONCLINICAL CODEVELOPMENT 
 
A.  Demonstrating the Biological Rationale for the Combination 
 
The biology of the disease, pathogen, or tumor type should be sufficiently understood to provide 
a plausible biological rationale for the use of combination therapy to treat the disease or 
condition.  For example, in an oncology setting, the biological rationale may be to intervene at 
different steps in the cell proliferation pathway.  The biological rationale for a combination anti-
infective therapy may be to target different metabolic pathways or different steps in the 
replication cycle of the pathogen to reduce the chance of developing resistance to the therapy or 
increase efficacy in treating disease caused by resistant organisms (e.g., multidrug-resistant 
tuberculosis).   
 
Sponsors should develop evidence to support the biological rationale for the combination in an in 
vivo (preferable) or in vitro model relevant to the human disease or condition the product is 
intended to treat.  The model should compare the activity of the combination to the activity of the 
individual drugs.  The model should demonstrate that the combination has substantial activity 
and provides greater activity, a more durable response (e.g., delayed resistance), and/or a better 
toxicity profile than the individual new investigational drugs.  In addition to valuable activity 
data, a relevant model may provide information about the relative doses of the individual new 
investigational drugs.  
 
B.  Nonclinical Safety Characterization  
 
For detailed recommendations regarding nonclinical safety characterization for two or more new 
investigational drugs to be used in combination, sponsors should consult the International 
Conference on Harmonisation (ICH) guidance on nonclinical safety studies (ICH M3(R2)).6  
Section XVII of ICH M3(R2) (Combination Drug Toxicity Testing) includes a discussion of 
nonclinical safety studies appropriate in a combination drug development setting involving two 
early stage entities.  ICH M3(R2) defines early stage entities as compounds with limited clinical 
experience (i.e., phase 2 studies or less), so the discussion is specifically applicable to the type of 
development described in this guidance.  In situations in which it is possible to obtain only 
limited clinical data for the individual new investigational drugs, additional nonclinical data for 
the individual drugs or combination may be needed before beginning human studies with the 
combination (e.g., see section V.A.1 below).  For codevelopment of anticancer combinations, 
sponsors should consult the guidance for industry ICH S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals.7     
 
                                                 
6 See the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. ICH M3(R2) is a 
revision of the 1997 ICH guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for 
Pharmaceuticals.   
 
7 See the ICH guidance for industry ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals at 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm085389.pdf 
  4 Contains Nonbinding Recommendations 
 
V.  CLINICAL CODEVELOPMENT  
 
This section provides a general roadmap and guiding principles for concurrent clinical 
development of two or more new investigational drugs to be used in combination.  It includes 
recommendations for characterizing the clinical safety and effectiveness of the combination and, 
to the extent needed or possible, the individual drugs in the combination.   
 
Note: The appropriate review division should be consulted on the specifics of a given clinical 
development program. 
 
A.  Early Human Studies (Phase 1) 
 
The main objectives of early studies in humans are to characterize the safety and 
pharmacokinetics of both the individual new investigational drugs and the combination and to 
provide data to support appropriate dosing for the combination in phase 2 testing. 
 
1.  Safety of the Individual New Investigational Drugs 
 
Whenever possible, the safety profile of each individual new investigational drug should be 
characterized in phase 1 studies in the same manner as would be done for the development of a 
single drug, including determination of the maximum tolerated dose (MTD), the nature of the 
dose limiting toxicity (DLT), and pharmacokinetic parameters.  If there is a useful measure (e.g., 
biomarker) of pharmacologic activity, it will also be important to determine dose-response for 
that measure.  If testing in healthy volunteers is not possible (e.g., if nonclinical data suggest a 
drug may be genotoxic or otherwise unacceptable for studies in healthy volunteers), the safety 
profile of the individual drugs should be evaluated in patients with the disease of interest.  These 
safety data will guide decisions in later studies about starting doses, dose escalation increments, 
and final dose selection.     
  
If it is not possible to characterize the safety of the individual new investigational drugs in 
humans (e.g., where drug toxicity prevents use of healthy volunteers and even short duration 
monotherapy would be unethical in patients with the disease of interest), the sponsor should 
conduct nonclinical studies of the combination to support initial dosing of the combination in 
humans.  The nonclinical data for the combination should include pharmacokinetic (absorption, 
distribution, metabolism, and excretion) and toxicokinetic data and appropriate biomarker/target 
interaction data, if relevant.   
     
2.  Safety and Dosing of the Combination 
 
For initial human effectiveness studies of the combination, the combination starting dose, dosing 
escalation intervals, and doses to be used in dose-response studies should be determined 
primarily from the phase 1 safety data for the individual new investigational drugs, if available.  
If phase 1 safety data for the individual drugs are unavailable, nonclinical data for the 
combination may be needed to determine the initial combination dose in humans (see previous 
section).  Phase 1 safety studies of the combination may also be important in some cases because 
  5 Contains Nonbinding Recommendations 
 
of the potential for additive toxicity.  One study design that could be used is sequential testing in 
which subjects get drug A, then drug B, then A and B together.   
 
B.  Clinical Pharmacology 
 
The sponsor should conduct the same clinical pharmacology studies for each of the individual 
new investigational drugs in the combination as would be done if the drugs were being 
developed separately  including assessment of bioavailability, characterization of 
pharmacokinetics, and mass balance.  Studies to evaluate the effects of intrinsic (such as renal 
impairment and hepatic impairment) and extrinsic (such as food effect and drug interactions) 
factors on pharmacokinetics and pharmacodynamics, and exposure-response could be conducted 
either with the individual drugs or the combination.  The role of pharmacogenomics should be 
investigated and incorporated into the combination drug development plan to identify potential 
sources of pharmacokinetic or pharmacodynamic variability. 
 
The evaluation of drug interaction potential should follow the same sequence as is used in other 
development programs; results of in vitro drug metabolism and drug transporter studies would 
inform the need for in vivo drug interaction studies.     
 
If feasible, dose-response should be evaluated for each individual new investigational drug in the 
combination.  The results of such studies should be used to determine doses at which to further 
explore the combination.  If the individual new investigational drugs cannot be administered 
alone, various doses of each drug administered in combination should be assessed.  If one drug 
has no activity or minimal activity when used alone, dose-response should be assessed when the 
individual drugs are administered in combination using a number of different doses of both the 
active drug and the inactive drug.  A similar approach should be used to evaluate dose-response 
where each drug in the combination has minimal activity when used alone. 
 
Response should also be evaluated with respect to systemic drug concentration to provide insight 
into efficacy and safety as a function of drug exposure.  Concentration-response assessments 
should be done in phase 2 and phase 3 trials.  In phase 3 trials, use of more than one dose of each 
of the drugs in the combination should be considered to increase exposure ranges and further 
assess dose-response.     
 
C.  Proof of Concept Studies (Phase 2)  
   
In general, phase 2 testing should accomplish the following for a given combination: 
 
  Further demonstrate the contribution of each individual new investigational drug in the 
combination to the extent possible and needed (i.e., to the extent not sufficiently 
established by existing data); 
  Provide evidence of the effectiveness of the combination; and 
  Optimize the dose or doses of the combination for phase 3 trials. 
 
  6 Contains Nonbinding Recommendations 
 
The amount and types of clinical data needed and appropriate study designs will vary depending 
on the nature of the combination being developed, the disease or condition the combination is 
intended to treat, and other factors.  A factorial study designed to assess the effects attributable to 
each drug in the combination is generally the preferred design to support combination use.  
However, there may be circumstances in which it would be inappropriate to use one or more of 
the drugs in the combination as monotherapy in studies of the disease or condition of interest, or 
it would only be possible to administer the individual drugs in the combination as monotherapy 
for short durations.  In these circumstances, a factorial design will have limited utility.     
 
The following scenarios illustrate possible phase 2 study designs for combinations of two new 
investigational drugs in different situations. Scenario 1 includes a discussion of a standard factorial 
design as well as an adaptive factorial design that could be used if there is uncertainty about 
using the individual drugs as monotherapy.  Scenario 2 describes an alternative design that may 
be useful when the drugs in the combination cannot be administered as monotherapy.  Scenario 3 
describes a design that might be used when one drug in the combination has minimal or no 
activity and is intended primarily to enhance the activity of the other drug.      
 
Scenario 1: Each new investigational drug alone has activity and they can be 
administered separately 
 
If in vitro studies, in vivo animal models, or phase 1 or other early clinical studies 
indicate that each new investigational drug has some activity, but the combination 
appears to have greater activity, and rapid development of resistance is not a concern, a 
four-arm, phase 2 trial in the disease or condition of interest comparing the combination 
to each drug alone and to placebo or standard of care (SOC) (AB v. A v. B v. SOC or 
placebo8) should be used to demonstrate the contribution of the individual drugs to the 
combination and proof of concept.  If SOC is a known effective therapy (not solely 
palliative), a study design in which each of the arms is added to SOC could be used (AB 
+ SOC v. A + SOC v. B + SOC v. placebo + SOC).   
    
An adaptive trial design9 with the same four treatment arms might also be used where 
appropriate, initially using the treatment arms described above and terminating the single-
drug arms early if it becomes clear that the single agents have much less activity than the 
combination.  Such a design may demonstrate the contribution of each drug to the 
activity of the combination without exposing the large number of patients typically 
required for phase 3 trials to therapeutic products with inadequate activity.  When 
determining whether to terminate monotherapy treatment arms early, it may be necessary 
to use endpoints that provide evidence of treatment effect more readily than endpoints 
that would be used in confirmatory phase 3 trials to minimize the amount of time subjects 
may be exposed to a low activity drug.  For example, it may be preferable to use viral 
                                                 
8 Note that in this scenario the placebo arm is intended to show the effect size compared to no treatment, not to show 
the contribution of each drug.  
 
9 See the draft guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics.  This draft guidance 
is available at http://www.fda.gov/downloads/Drugs/.../Guidances/ucm201790.pdf. 
  
  7 Contains Nonbinding Recommendations 
 
load, response rate, or a persuasive pharmacodynamic or other biomarker rather than 
survival or cure rate.     
 
Scenario 2: The individual new investigational drugs in the combination cannot be 
administered separately 
 
If in vitro studies, in vivo animal models, or phase 1 or other early clinical studies 
indicate that the individual new investigational drugs in the combination cannot be 
administered separately in clinical trials in the disease of interest (e.g., because such 
testing would involve administering treatment known to be ineffective as monotherapy), 
or cannot be administered as monotherapy for the duration needed to evaluate 
effectiveness  (e.g., because of rapid development of resistance), proof-of-concept 
evidence for the combination ordinarily should come from a study directly comparing the 
combination (AB) to SOC.  Alternatively, if SOC is known effective therapy (not solely 
palliative), an add-on design could be used comparing the combination plus SOC to 
placebo plus SOC.    
 
In some resistance scenarios, it may be possible to administer the individual drugs in the 
combination as monotherapy for a short duration, but long enough to establish proof of 
concept in humans.  For example, direct-acting antivirals (DAAs) to treat chronic 
hepatitis C virus infection could be administered as monotherapy for 3 days to establish 
antiviral activity and for initial dose exploration.  For DAA studies of longer duration, the 
combination should be used or the individual drugs should be added to an active 
control.10   
 
Scenario 3: When administered separately, one new investigational drug in the 
combination is active and one is inactive 
 
If in vitro studies, in vivo animal models, or phase 1 or other early clinical studies suggest 
that one of the new investigational drugs in the combination is inactive or minimally 
active and one drug is modestly active, but the combination has substantial activity, the 
more active drug generally will require greater scrutiny and should ordinarily be studied 
as a single drug in a phase 2 study.  The minimally active drug generally would not 
require study as a single drug beyond initial phase 1 safety studies.  In this scenario, proof 
of concept and the contribution of each new investigational drug could be demonstrated 
using a three-arm comparison of the active drug alone, the combination, and SOC (A v. 
AB  v. SOC), or the combination and the individual drug added to SOC where SOC is a 
known effective therapy (AB + SOC v. A + SOC v. placebo + SOC).   
 
If the inactive drug in a combination contributes to the activity of the combination only 
by increasing the systemic concentrations of the active drug, human pharmacokinetic data 
                                                 
10 See the draft guidance for industry Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral 
Agents for Treatment (section III.A.4.b  Phase 1b (proof-of-concept) trials)) or consult the Division of Antiviral 
Drug Products in CDER for more specific recommendations. This draft guidance is available on the CDER guidance 
page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
  8 Contains Nonbinding Recommendations 
 
may provide adequate evidence to support the contribution of the inactive drug.  A 
confirmatory study of the combination would usually be needed to provide evidence of 
effectiveness for the combination (see section V.D).   
 
Dose Finding  Dose-finding studies could be very important to refine the combination dose or 
doses and select doses for phase 3 trials.  Depending on the role of each new investigational 
drug, it may be useful to test multiple doses of both drugs to establish the optimal combination 
dose in terms of risks and benefits.  If one new investigational drug in a two-drug combination is 
more active than the other, it may be more important to study multiple doses of the more active 
drug (as part of the combination).  For the same reason, it may be more important to study 
multiple doses of a drug that is significantly more toxic than the other drug in the combination.  
Other study designs and types of studies also may be appropriate.      
 
D.    Confirmatory Studies (Phase 3)  
 
The appropriate phase 3 study design generally will be a case-by-case determination based on 
what has been previously demonstrated about the effects of the combination and the individual 
new investigational drugs, the feasibility of monotherapy and SOC alone treatment arms, and 
other factors.  For example: 
 
  If findings from in vivo or in vitro models and/or phase 2 trials adequately demonstrate 
the contribution of each new investigational drug to the combination, phase 3 trials 
comparing the combination to SOC or placebo generally will be sufficient to establish 
effectiveness.  
  
  If the contribution of the individual new investigational drugs is not clear and it is 
ethically feasible to use one or more of the individual drugs as monotherapy in a study 
arm, the contribution of the individual drugs could be demonstrated using a factorial 
design (see Scenario 1 in section V.C).  It may be possible to do a factorial study using 
only active drug treatment arms (AB v. A v. B).  This design would be adequate to 
demonstrate the contribution of each new investigational drug, but would not be able to 
directly measure the overall treatment effect.  However, if the effect of SOC is well-
established and known to be small, it may be possible to estimate the treatment effect of 
the combination without a concurrent SOC or placebo arm.   
 
  If phase 2 data do not provide sufficient evidence of the contribution of each new 
investigational drug in a two-drug combination, but do provide strong evidence that the 
combination is superior to one of the drugs alone, a two-arm design comparing the 
combination to the more active drug alone (AB v. A) may be needed to demonstrate that 
the less active drug (B) contributes to the activity of the combination.  In this situation, it 
may be useful to study more than one dose of the more active drug.   
 
Unexpected toxicity (e.g., serious adverse events observed at higher than expected rates) in phase 
2 trials is a potential complication for development of a combination and progressing to phase 3 
trials.  If the toxicity can be attributed to one drug in the combination, it may be possible to 
conduct phase 3 trials with the combination using a lower dose or doses of the more toxic drug.  
  9 Contains Nonbinding Recommendations 
 
If the toxicity cannot be attributed to an individual drug in the combination, additional studies 
may be needed to identify the more toxic drug and appropriate dosing for the combination before 
initiating phase 3 trials.  The specifics of any phase 3 design should be discussed with the 
appropriate FDA review division at an end-of-phase 2 meeting. 
 
 
VI.  REGULATORY PROCESS ISSUES IN CODEVELOPMENT  
 
Sponsors should consider a number of regulatory issues when planning the codevelopment of 
two or more new investigational drugs for use in combination.  Key issues are outlined below. 
 
A.    Early Interaction with FDA 
 
Sponsors are encouraged to communicate as early as possible (e.g., pre-IND meeting) with the 
appropriate CDER review division when considering codevelopment.  Sponsors also are 
encouraged to consult FDA as needed throughout the development process.  We expect that such 
communication will help facilitate development of the combination therapy. 
 
B.  Investigational New Drug Applications (INDs) 
 
1.  INDs for the Combination and the Individual New Investigational Drugs 
 
Decisions about IND submissions required under 21 CFR part 312 for the combination and 
individual new investigational drugs in the combination will depend on the development 
objectives and the timing of the decision to pursue codevelopment.  The following general 
principles apply: 
 
  If a sponsor intends to undertake codevelopment as described in this guidance, there 
should be one IND for the combination that covers all of the drugs in the combination 
at the point in time at which the sponsor initiates clinical studies of the combination.       
 
  If a sponsor is undecided about development of a combination, it may be appropriate 
to conduct preliminary proof-of-concept clinical studies for the combination under an 
IND for one of the drugs in the combination, provided that there is a single agent IND 
in effect for each drug in the combination (i.e., provided FDA has the information 
required under the IND regulations for each of the drugs).  If the sponsor then decides 
to pursue development of the combination, it could do so under the single agent IND 
(which will become the combination IND) or submit a new IND for the combination.   
 
  If a sponsor intends to develop a combination and develop one or more of the drugs in 
the combination for use as a single agent, there should be a separate IND for the 
combination and each of the individual drugs being developed. 
 
  If the individual drugs in a combination would be reviewed by different review 
divisions within FDA, the combination IND should be submitted to the division that 
has jurisdiction over the indication for the combination. 
  10 Contains Nonbinding Recommendations 
 
 
Decisions about IND submissions for codevelopment scenarios that are not covered by these 
general principles will be determined on a case-by-case basis in consultation with the appropriate 
review division(s). 
 
When submitting an IND for a combination, sponsors may cross-reference existing INDs for the 
individual drugs in the combination.  If the sponsor of the combination IND is not the sponsor of 
the IND for one of the drugs used in the combination, the sponsor of the combination IND must 
obtain written authorization to cross-reference any content in the other sponsors IND that is 
used to support the combination IND ( 312.23(b)). 
   
2.  IND Safety Reports 
 
In cases in which there is an active IND for the combination and active INDs for one or more of 
the individual drugs in the combination, IND safety reports required under  312.32(c) for 
adverse events that occur in studies of the combination should be submitted to the IND for the 
combination and all INDs for the individual drugs in the combination.  If a reportable adverse 
event occurs in a study of one of the individual drugs in the combination, the report should be 
submitted to the IND for that individual drug and to the IND for the combination.   
 
The IND safety report submitted to the IND for the study in which the adverse event occurred is 
considered the original report.  Reports submitted to other INDs should be clearly identified as 
duplicates to ensure that the same adverse event is not counted more than once.  If a report is 
submitted to multiple INDs, each IND safety report should identify all INDs to which the report 
is submitted.      
 
3.  IND Annual Reports   
 
There must be separate IND annual reports (21 CFR 312.33) for the combination IND and any 
individual drug INDs.  The reports should cross-reference each other.  Each annual report should 
identify all INDs to which the report is cross-referenced.11   
 
4.  Other IND Submissions 
 
Where there is a combination IND and INDs for one or more individual drugs, sponsors should 
consider whether the information in a planned IND submission is relevant to only one IND or to 
multiple INDs.  Consider the following examples: 
 
  A protocol submission for a study of the combination should be submitted only to the 
combination IND. 
 
  Chemistry, manufacturing, and controls for the combination should be submitted only 
to the combination IND. 
                                                 
11 Also see the ICH guidance for industry E2F Development Safety Update Report, section II.E, available at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  11 Contains Nonbinding Recommendations 
 
 
  A nonclinical information amendment describing carcinogenicity studies with the 
combination should be submitted to the combination IND and any INDs for the 
individual drugs in the combination. 
 
Where information is relevant to more than one IND, the information can be submitted in its 
entirety to each IND or can be submitted to one IND and cross-referenced in the other INDs. 
 
C.  Marketing Applications 
 
In general, decisions about the type or types of marketing application(s) to be submitted for a 
drug-drug combination (e.g., combination application, individual drug applications) will depend 
on how the applicant intends to market the combination and the individual drugs, as well as the 
data submitted in support of the application.  We anticipate that applications will be submitted 
and user fees assessed consistent with FDAs user fee bundling policy (see Guidance for 
Industry, Submitting Separate Marketing Applications and Clinical Data for Purposes of 
Assessing User Fees).  The following examples illustrate how we anticipate applications may be 
submitted for different types of combinations, but FDA should be consulted prior to making any 
of the submissions discussed in this section: 
 
Example 1:  If the individual drugs in the combination will be marketed as distinct 
products (separate packaging), a separate marketing application for each drug in the 
combination should be submitted. 
 
Example 2:  In Example 1, if the applicant also intends to market one or more of the 
drugs in the combination for use as monotherapy, the same marketing application can 
be used for the combination and monotherapy uses. 
 
Example 3:  If the drugs in the combination will be marketed as a combination drug 
product (i.e., either a co-packaged or a fixed-combination drug), a single marketing 
application for the combination should be submitted. 
 
Example 4:  In Example 3, if the applicant also intends to market one or more of the 
drugs in the combination for use as monotherapy, a separate marketing application 
should be submitted for the individual drug(s) for monotherapy use.  
 
Example 5:  If the individual drugs in a combination drug product are marketed first as 
a co-packaged drug, an application for a corresponding fixed-combination drug may 
be submitted as a supplement to the co-packaged drug application.  
 
 Other examples not listed here should be discussed with FDA.  
 
If an application cross-references any information in an IND or marketing application not owned 
by the applicant that is needed to support approval of the marketing application, the application 
must contain a written authorization to cross-reference such information (21 CFR 314.50(g)(1)). 
 
  12 Contains Nonbinding Recommendations 
 
D.    Labeling 
 
Decisions about how to meet the labeling requirements in 21 CFR 201.57 will also depend on 
how the applicant intends to market the combination. 
 
  If the individual drugs in the combination will be marketed together as a combination 
drug product (either a fixed-combination or co-packaged drug), the prescribing 
information for the combination should be a single document describing use of the 
combination. 
 
  If the individual drugs in the combination will be marketed as distinct products intended 
for use in combination, there should be separate prescribing information for each distinct 
product.  The prescribing information for each drug should include pertinent information 
concerning the safe and effective use of the combination, reference the labeling of the 
other product(s), and state that the drug was developed and studied for use in 
combination with the other drug(s).   
 
There are a range of other potential scenarios in which one or more of the drugs in a combination 
may be limited to combination use only, or may be indicated for combination use, monotherapy, 
and/or in combination with drugs other than those with which the drug was codeveloped.  It is 
advisable for applicants to consult FDA concerning their specific circumstances.   
 
Decisions about how to provide patient-directed information such as a Medication Guide or 
administration instructions should be made on a case-by-case basis in consultation with FDA.  
 
E.  Postmarketing Safety Monitoring Considerations   
 
Postmarketing safety monitoring should consider additional postmarketing risks that may be 
presented by initial marketing of two or more new investigational drugs for use in combination 
as compared to the risks associated with marketing a single new investigational drug.   Risks 
will vary depending on the nature of the combination and how the combination is marketed.  
Applicants should consider potential postmarketing risks from, among other things: 
 
  Potential for use of each drug individually; 
  Potential for use of any of the drugs in the combination with marketed drugs other than 
those with which the drugs were codeveloped; and 
  Other drugs likely to be co-administered with the combination. 
 
FDA encourages sponsors to consult with the appropriate FDA divisions to discuss their 
proposed approach to postmarketing safety monitoring.    
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