A new final guidance document released by the US Food and Drug Administration (FDA) seeks to clarify the scientific and regulatory factors that must be taken into consideration when developing two or more new investigational products for use as a combination therapy in patients.
The guidance, Codevelopment of Two or More New Investigational Drugs for Use in Combination, is (as its name indicates) intended for drugs used in combination, but FDA is quick to note that it's not referring to drugs that have previously been approved by the agency. Rather, it's for two drugs that are both novel formulations - a development status that most often compounds the difficulties associated with regulatory clearance.
"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 co-development of two or more new investigational drugs," FDA wrote.
Regulators noted that the interest in co-development is most high in the field of oncology and infectious diseases, but observed that interest is increasing in the cardiovascular and other fields as well.
The first step in the development process should be to determine whether co-development is appropriate, FDA explains. Because co-development will be less adept at assessing the safety and efficacy of each respective drug in combination than would be independent development of each drug, companies will need to determine how much independent assessment of each drug will be necessary prior to the initiation of co-development.
"For example, in co-development 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," the agency said.
More generally, however, co-development will present additional risks to patients above and beyond single development testing because the risks of each drug are more difficult to assess, and the drugs may combine to present unique effects on the body as well.
Given those risks, FDA says four factors must be met before a company is permitted to start co-development:
- The combination must be intended to treat a serious or deadly disease or condition.
- The use of the combination must have a strong scientific rationale (e.g. the biology of the disease must be well-characterized) for the use of the combo therapy.
- The use of monotherapy must not be a feasible option.
- Nonclinical data must support a significant therapeutic improvement over previous treatments.
FDA said it should be consulted before companies start a co-development program for a drug product, and that any consultation would rely heavily on pre-clinical and scientific data generated by the company.
The guidance also contains what FDA calls a "general roadmap" for co-developed drugs once a company is cleared to begin clinical testing under an investigational new drug (IND) application.
Phase 1 clinical trials should not differ greatly from standard trials for individual drugs, regulators wrote. Sponsors should take care to determine the maximum tolerated dose, dose limiting toxicity, and pharmacokinetic parameters of each substance.
"One study design that could be used is sequential testing in which subjects get drug A, then drug B, then A and B together," FDA recommended.
Proof of concept studies (Phase 2) will represent the first major area where testing begins to differ from mono-development, with sponsors expected to demonstrate how each drug contributes to a therapeutic effect, provide evidence of effectiveness, and optimize dosing for Phase III studies. Regulators said a factorial study design was recommended in most cases.
Finally, for confirmatory (Phase 3) studies, FDA recommends a case-by-case approach depending upon the data obtained from the Phase 2 trial. For example, sponsors will need to determine whether a placebo or standard of care (SOC) should be used to confirm a relative effect, and whether the drug should be tested as a combo therapy or as a monotherapy arm, or both (e.g. drugs 'A&B' vs. 'A' vs. 'B').
The guidance concludes by noting a number of "regulatory process issues in co-development." Sponsors are advised to interact early in the development process with FDA, including through pre-IND meetings and throughout the IND process thereafter.
IND submissions may also differ depending on the intended use of the drug. If a sponsor only intends to co-develop the drugs, only one IND should be submitted and it should cover both drugs. If, however, a sponsor decided they wish to develop the new drugs both as a single entity and as separate entities, two separate INDs should be developed.
Safety reports should also be submitted to cover both drugs, FDA advised. Additional considerations covering user fees, applications, and postmarketing safety monitoring are also covered within the guidance.
The guidance is not intended to apply to biological drugs or products regulated by the Centers for Devices and Radiological Health (CDRH).
Codevelopment of Two or More New Investigational Drugs for Use in Combination