FDA Guidance: Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination

Combination therapy is an important treatment modality in many disease settings, including cancer, cardio-vascular 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 for new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets to improve treatment response or minimize development of resistance. In settings in which combination therapy provides significant therapeutic advantages, there is growing interest in the development of combinations of investigational drugs not previously developed for any purpose. 

Because the existing developmental and regulatory paradigm focuses primarily on assessment of the effectiveness and safety of a single new investigational drug acting alone, or in combination with an approved drug, the Food and Drug Administration (FDA) recently published a guidance to industry to assist sponsors in the codevelopment of two or more unmarketed drugs. 

The guidance, entitled “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination,” is intended to describe a high-level, generally applicable approach to codevelopment of two or more unmarketed 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.  

This guidance is intended to assist sponsors in the codevelopment2 of two or more novel (not previously marketed) drugs to be used in combination to treat a disease or condition. The guidance provides recommendations and advice on how to address certain scientific and regulatory issues that will arise during codevelopment.

It is not intended to apply to development of fixed-dose combinations of already marketed drugs or to development of a single new investigational drug to be used in combination with an approved drug or drugs. The guidance is also not intended to apply to vaccines, gene or cellular therapies, blood products, or medical devices.

Therefore, FDA believes that codevelopment should ordinarily  be reserved for situations that meet the following criteria:    

• The combination is intended to treat a serious disease or condition.
• There is a compelling biological rationale for use of the combination (e.g., the agents inhibit distinct targets in the same molecular pathway, 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 preclinical model (in vivo or in vitro) or short-term clinical study on an established biomarker suggests that the combination has substantial activity and provides greater than

FDA recommends that sponsors consult with FDA on the appropriateness of codevelopment before initiation of clinical development of the combination. Additionally, the guidance discusses codevelopment issues in:

–       Phase 1 Trials: Early Human Studies

–       Phase 2 Trials: Proof of Concept Studies

–       Phase 3 Trials: Confirmatory Studies

Early Interaction with FDA

Sponsors are encouraged to communicate as early as possible (e.g., pre-IND meeting) with the appropriate FDA review division when considering codevelopment of innovative combination therapy. Sponsors also are encouraged to consult FDA frequently throughout the development process. We believe such communication will help facilitate development of the combination therapy.  

With respect to Investigation New Drug (IND) submissions and Marketing Applications for codevelopment of drugs, FDA recommended that these decisions be made on a case-by-case basis in consultation with the appropriate review division until the agency has more experience with codevelopment.

Labeling Issues: FDA also anticipates that the content of labeling for the combination and/or the components will be case specific, depending on the nature of the combination, the intended uses of the individual components, the marketing strategy, and other factors. Therefore, FDA does not believe it can

provide generally applicable labeling guidance at this time. Again, we recommend consultation with the appropriate review division.  

Regulatory Process of Codevelopment

Early Interaction with FDA Sponsors are encouraged to communicate as early as possible (e.g., pre-IND meeting) with the appropriate FDA review division when considering codevelopment of innovative combination therapy.  Sponsors also are encouraged to consult FDA frequently throughout the development process.  We believe such communication will help facilitate development of the combination therapy. 

Pharmacovigilance  

Applicants should develop a pharmacovigilance plan that takes into account the additional postmarket risks presented by initial marketing of two or more previously unapproved drugs for use in combination (compared to risks associated with marketing of a single drug).  Risk will vary, depending on the nature of the combination and how the combination is marketed.  The risk assessment should consider, among other things:

• Potential for use of each drug individually;

• Potential for use of any of the components of the combination in combinations with other drugs; and

• Drugs likely to be co-administered with the combination.

Applicants should discuss their pharmacovigilance plans with the appropriate review division and the Office of Surveillance and Epidemiology.