Those of us working in drug development for several years have likely, at one time or another, focused on the requirements for the development of a combination product. They are listed in 21CFR300.50 Fixed-combination prescription drugs for human use; a regulation dated March 27, 1975 and amended on January 5, 1999. FDA also issued a guideline in 2013, Codevelopment of Two or More New Investigational Drugs for Use in Combination (the 2013 Codevelopment Guidance) that further expands on the information in the regulation.
In developing a combination product, it is necessary to show the contribution of each of the individual components. If both products are marketed, this becomes relatively simple as one must show that the combination is better than either of the individual components. When one or both components are not marketed products or marketed for a different indication and thus have not been proven to be safe and efficacious in the intended indication, the task becomes more complicated. Additional complexity is added when one or more of the components are not expected to have activity as a single agent.
Focusing on oncology products only, the draft guidance issued in July 2025 entitled, Development of Cancer Drugs for Use in Novel Combination – Determining the Contribution of the Individual Drugs’ Effects, provides insights on approaches to demonstrate the effects of each component of the combination in this setting.
Unlike many of the recently issued guidances, this one does not address dose or safety – only efficacy. There are a number of recently issued guidances that discuss the need for dose ranging and dose selection. The assumption is that there will be more side effects with the combination and, as a result, safety fits into the benefit/risk assessment, which is part of the development and approval process. (I discussed this in the February 29, 2024 blog written on benefit-risk assessments for new drug and biological products.)
The reason FDA believes that it is of vital importance to address the individual contribution of each component from an efficacy standpoint is that the benefit/risk decision must weigh the benefit against the additional toxicity when administering two therapeutics rather than one.
From the beginning of the development of a combination product, there must be a strong biological rationale for a novel combination, with nonclinical and clinical data to support this.
This guideline outlines two types of study designs that may be used to demonstration this “contribution of effect.” The first is Factorial Designs and the second is External Data.
Not surprisingly, the expectation from FDA is that adequate and well-controlled studies will be used to demonstrate the contribution of each agent as well as to document substantial evidence of efficacy. FDA makes clear their preference for Factorial Design with a randomized concurrent control by which the contribution of each component can be measured in the same trial. Recognizing that this is not always possible or feasible, considerable information on the use of external data sources is also provided in the guidance.
Factorial Designs
When each component of the combination is active, a factorial trial design including monotherapy, the combination, and the standard of care (if different from one of the monotherapies) is suggested. Adaptive designs are also useful in this situation to allow ineffective therapies to be dropped early. As always, it is suggested that trial design and choice of endpoints be discussed and agreed with FDA in advance.
The take-home message from this section of the guidance is that a traditional factorial randomized controlled trial with multiple arms to assess the effect of each component in a combination treatment provides the greatest strength of evidence for establishing contribution of effect of each component.
External Data
FDA also recognizes that there are situations where the use of external data may be useful. For this, the appropriateness of the external data needs to be considered. Current FDA expectations are complete, high-quality, patient level data. Summary-level data from published clinical studies are generally not sufficient. This is one of the major obstacles in using these types of data sources A recent guideline issued by Center for Devices and Radiological Health entitled, Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices, recognizes that the Sponsor may not always be able to access patient level data. The hope is that acknowledging this challenge may be followed by regulatory support for overcoming it.
External data must be fit for purpose and the suitability of the data source investigated prior to embarking on this approach. The guidance provides information on the various items to be considered in evaluating external data sources.
If a randomized study is not feasible and the use of external data can be justified, the following external sources were listed for possible consideration, keeping in mind that they provide different levels of evidence depending on the relevance and reliability of the data:
- External data from clinical trials (same setting, same indication)
- Prospectively collected patient-level data (e.g., registry data) that includes demographics, disease characteristics, and treatment and outcomes of interest
- Other patient-level Real-World Data (RWD) sources
Much of this section of the guidance provides valuable information on how to determine whether the proposed external data is fit for purpose. Information to consider includes the following:
- Selection of the most appropriate endpoint
- Differences in endpoints between control and trial
- Pros and cons of each endpoint type
Conclusion
When the combination product consists of two investigational products, evaluating the contribution of each individual drug as early as possible in development is recommended.
The take home message here, for me, is that a randomized controlled trial is the gold standard and should be conducted if possible. If one is looking to external controls to determine the contribution of one or more of the components of a combination product, the choice of this control should be explored carefully and the approach discussed with FDA.
We at PROMETRIKA have experience designing clinical trials including using novel and adaptive study designs, evaluating and using external control arms in pivotal analyses for FDA submission, and guiding our clients through the FDA review process.
