by Seth A. Mailhot, Special Counsel, Sheppard Mullin Richter & Hampton LLP
On June 14, 2013, FDA issued the Guidance “Codevelopment of Two or More New Investigational Drugs for Use in Combination.” The guidance discusses FDA’s recommendations for developing an entirely new combination therapy where none of the drugs to be used in combination have been previously developed. FDA notes in the guidance that the recommendations do not apply to combination therapies involving previously developed drugs, or the combination of a new drug with a previously developed drug. While codevelopment has generally been centered in oncology and infectious disease, FDA’s guidance is intended to address codevelopment from a high-level, making it applicable to other diseases.
The complexity of certain diseases, such as cancer, cardiovascular disease, and infectious diseases, presents unique challenges to medicine. As scientific understanding of pathophysiological processes has increased, development of combination therapies has become increasingly possible. The potential benefits of combination therapies include improving treatment response by directing treatments at multiple therapeutic targets, minimizing development of drug resistance, and countering drug side effects and adverse events.
FDA’s guidance is broken out into four sections. The first section addresses whether codevelopment is an appropriate development option. The second section discusses issues that should be addressed during nonclinical testing. The third section provides a roadmap for clinical testing, and the fourth section outlines regulatory guidance in interacting with FDA during codevelopment.
Determining Whether Codevelopment Is Appropriate
The complexity of the codevelopment process generally means that less information will be obtained about the individual drugs to be used in combination. The point at which each drug is tested separately will vary depending on a number of factors, such as the indication to be developed. Given these problems, FDA recommends that sponsors consult with FDA prior to initiating clinical development of a combination.
FDA also suggests that codevelopment should be reserved to combinations that meet the following four conditions:
1) Codevelopment should be limited to combinations intended to treat a “serious disease or condition.” In the context of the guidance, FDA defines a serious disease or condition as a disease or condition associated with morbidities that have a substantial impact on day-to-day functioning. This would include reversible morbidities, provided they are persistent or recurrent. FDA considers this definition to be consistent with statutory and regulatory provisions concerning serious or life-threatening diseases and conditions.
2) There must be a strong biological rationale for use of the combination. This could be shown through the compounds inhibiting different targets in the same molecular pathway, or the same target at different binding sites.
3) The combination needs to demonstrate the potential to provide a significant therapeutic advance over available therapies, and be superior to the drugs taken individually. This would either be shown through 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.
4) Finally, there is a compelling reason why the new investigational drugs cannot be developed independently, such as monotherapy leading to drug resistance.
Considerations for the Research of Combination Therapies
FDA outlines two considerations that should be addressed during nonclinical codevelopment. First, nonclinical codevelopment should demonstrate the biological rationale for the combination. Second, nonclinical safety should be established according to the recommendations in Section XVII of the International Conference on Harmonisation (ICH) guidance M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization.
Early Human Studies
During initial human testing, FDA outlines three goals for combination therapies: characterize the safety and pharmacokinetics of each new drug, characterize the safety and pharmacokinetics of the combination, and develop data supporting the dosage to be studied in phase 2 testing. Unless testing a monotherapy would be unethical (such as where the monotherapy would be too toxic alone without its companion drug), early monotherapy drug testing should evaluate the same parameters as would be evaluated for standard therapies: determination of the maximum tolerated dose, the nature of the dose limiting toxicity, and pharmacokinetic parameters. 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 drugs.
As with initial human testing, clinical pharmacology studies of each monotherapy should follow a similar path as with standard drug development. Therefore, assessment of bioavailability, characterization of pharmacokinetics, and mass balance would be conducted for each therapy separately, along with the dose-response, if feasible. FDA suggests that studies to evaluate the effects of intrinsic and extrinsic factors on pharmacokinetics and pharmacodynamics, and exposure-response may be conducted either with the individual drugs or the combination therapy.
Proof of Concept Studies
FDA recommends that phase 2 testing accomplish three goals:
- Demonstrate the contribution of each individual drug in the combination
- Provide evidence of the effectiveness of the combination; and
- Optimize the combination dose(s) for phase 3 trials.
In the guidance, FDA outlines phase 2 study designs for three different scenarios: where each drug alone has activity and can be administered separately , where the drugs cannot be administered separately, and where one drug administered alone is active and one is inactive. Notably, the scenario where each drug alone has activity and can be administered separately, FDA suggests a four-arm study design. FDA also emphasizes the importance of dose-finding studies to refine the combination dose(s) for phase 3 trials, and suggests evaluating different doses in terms of their risk/benefit profile.
FDA provides little guidance as to the design of phase 3 trials, noting that such designs would generally be a case-by-case determination. FDA does note that unexpected toxicity in phase 2 may be a complicating factor in progressing into phase 3 trials.
Codevelopment Regulatory Process
The theme throughout the guidance is the need to obtain early and regular input from the agency when embarking upon drug codevelopment. Interaction with FDA should start as early as possible.
FDA suggests that if a combination therapy is to be developed, there should be one IND for the combination that covers all of the drugs in the combination. This would not apply if the sponsor is undecided about development of a combination at the time the IND is submitted, or if individual drugs in the combination will also be developed as a monotherapy. Where individual drugs in a combination would be reviewed by different review divisions, the combination IND would be submitted to the division that has jurisdiction over the combination’s indication. IND safety reports for adverse events involving the combination would be submitted to IND for the combination and all INDs for the individual drugs in the combination. IND safety reports for adverse events involving an individual drug would be submitted to IND for the combination and the individual drug’s IND. Separate IND annual reports would be required, but those reports should cross-reference each other.
FDA notes that marketing applications and labeling 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. As for user fees, FDA references its policy on user fee bundling (Guidance for Industry, Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees). Postmarket safety monitoring of a combination therapy should consider the potential for use of each drug individually, the potential for use of any of the individual drugs in the combination with other marketed drugs, and other drugs likely to be co-administered with the combination.
FDA’s guidance sets out a careful path for drug codevelopment. Most importantly, the guidance specifically limits use of combination therapies to what FDA calls a “serious disease or condition.” Given the complexities that are presented with the development of biological products and botanical drugs, limiting drug codevelopment to such serious indications would appear to underestimate the current state of science in drug development.
Another limitation is on the requirement to demonstrate the potential benefit of the combination. A number of comments were received on the 2010 draft guidance. It is notable that the Cystic Fibrosis Foundation recommended that the draft guidance be revised to allow for codevelopment where there is no more than additive activity, provided there are other compelling justifications. The revised guidance requires the combination be “superior” to the drugs taken individually, but also requires that the combination provide a significant therapeutic advance over available therapies. FDA did not specifically address the Cystic Fibrosis Foundation’s comments in the recent Federal Register notice (or those of any of the other commenters), so it is difficult to know how this change specifically addresses the concern raised. Further, while this criteria is ostensibly proposed as a judgment for proceeding with codevelopment at an early stage, it is relevant to ask whether this criteria would also influence FDA’s risk/benefit analysis during marketing approval.
Another concern is that FDA does not define what it would consider drug codevelopment. For example, it is left unstated whether FDA would consider a racemic mixture to be a combination therapy, particularly if the racemic mixture could be separated into enantiomers. There are examples of many racemic mixtures which have been approved as drugs, which were later separated into one or more enantiomers which were marketed as separate drugs.
Finally, the guidance suggests that codevelopment will be inordinately expensive and time consuming, particularly where the therapy combines two (or more) drugs with activity that can be administered as a monotherapy. In that situation, FDA recommends four-arm phase 2 testing (or more arms, if more than two drugs with separate activity are combined).
As science continues to advance in drug development, FDA’s guidance, with its limitations on drug codevelopment, may become quickly outpaced by these technological advances.
Seth A. Mailhot is a special counsel in the Washington D.C. office, and is a member of Sheppard Mullin's Food and Drug Law Group, as well as the firm's Life Sciences group. His 14 years working in the U.S. Food and Drug Administration (FDA) provides a unique perspective in his counseling of clients on a broad range of matters involving the FDA.
Mailhot's practice includes representation of the medical device, pharmaceutical, dietary supplement, tobacco and food industries, and covers both premarket and postmarket issues. His practice is focused on development of premarket submission strategies and FDA enforcement of good manufacturing practices, both domestically and abroad. He may be reached at firstname.lastname@example.org.
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