FDA’s final guidelines for co-development of investigational drugs for combination use retain the key principles laid out in a 2010 draft document but provide more extensive instruction to companies on how to submit INDs and marketing applications for such products.

Released June 14, the final guidance, “Co-development of Two or More New Investigational Drugs for Use in Combination,” discusses general considerations for deciding whether to submit a single or multiple INDs and the types of marketing applications that should be submitted for combination products comprising two or more investigational drugs and their individual components.

The guidance is aimed at streamlining the development of two or more investigational drugs intended for combination use.

Although there are no major changes to the heart of the guidance on novel-novel combos, the final document appears to allow for more flexibility on Phase III trial design than was suggested in the draft document.

Scope Of Products

The guidelines for co-development of multiple investigational drugs are expected to help streamline the development of novel combination treatments in areas such as oncology and antivirals. FDA officials have pointed to the draft guidance, released in December 2010, as an example of the agency’s regulatory flexibility and its interest in spurring therapeutic innovation for serious diseases Also see "FDA Issues Co-Development Guidance, But Only For Products Treating "Serious" Diseases" - Pink Sheet, 14 December, 2010..

The final guidance has undergone a name change from its predecessor, which was entitled “Co-development of Two or More Unmarketed Investigational Drugs for Use in Combination.” This name change and other revisions in the text appear aimed at answering industry’s request for clarity on the scope of the drugs to which it applies.

In comments on the draft guidance, pharmaceutical companies suggested marketed drugs should be encompassed under the guidance if they are being investigated for an entirely different indication than the one approved. Industry commenters also objected to the guidance’s exclusion of combinations that include vaccines, gene or cellular therapies, blood products or medical devices Also see "Drug Developers Ask For Flexible Combinations In Co-Development Regulation" - Pink Sheet, 21 February, 2011..

Although FDA apparently agreed there was a need to clarify the guidance’s scope, it did not give ground on these issues.

“This guidance is intended to assist sponsors in the co-development 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,” the final guidance states. “For purposes of this guidance, these not-previously-developed drugs are referred to as new investigational drugs.

Furthermore, the guidelines apply only to drugs and biologics regulated by the Center for Drug Evaluation and Research. “The guidance is not intended to apply to biological products regulated by the Center for Biologics Evaluation and Research or medical devices.”

INDs And NDAs

The 2010 draft gave short shrift to regulatory considerations for INDs and marketing applications.

Addressing the issue in a single paragraph, FDA said decisions about the types of IND submissions and marketing applications needed would depend upon the sponsor’s overall co-development and marketing strategy. “Until FDA has more experience with co-development, FDA recommends that these decisions be made on a case-by-case basis in consultation with the appropriate review division,” the draft guidance said.

In contrast, the final guidance spends almost three pages on the topic of INDs and marketing applications, and the agency lays out several general principles for IND submissions.

For example, if a sponsor intends to co-develop two or more investigational drugs for combination use, “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 plans to develop one or more of the individual drugs for monotherapy use, as well as in combination, separate INDs for the combination and each of the individual drugs being developed would be required.

“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.”

The guidance also provides five examples of the types of marketing applications FDA expects will be submitted for different types of combinations (see chart).

Examples Of Marketing Application Submissions For Combination Products
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

Threshold Criteria

The final guidance generally retains the draft document’s four threshold criteria for co-development Also see "FDA Draft Co-Development Guidance Emphasizes Phase II Studies" - Pink Sheet, 20 December, 2010..

The combination must be intended to treat a serious disease or condition, and there must be a “strong biological rationale” for use of the combination, the guidance states.

A full nonclinical characterization or a short-term clinical study must suggest the combination “may provide a significant therapeutic advance over available therapy and is superior to the individual agents.” Notably, FDA excised the draft’s language requiring a showing that the combination “provides greater than additive activity” compared to the individual agents alone. Industry commenters had questioned what the agency meant by “greater than additive” and suggested this created a higher standard than exists for marketed drugs.

The fourth criterion requires a compelling reason why the new investigational drugs cannot be developed separately, such as the risk of resistance with monotherapy.

The guidance also retains a focus on narrowing study designs before Phase III, at which point a full factorial design study that compares each of the active ingredients against the combination and standard of care or placebo may not be necessary Also see "FDA Draft Co-Development Guidance Emphasizes Phase II Studies" - Pink Sheet, 20 December, 2010..

In a change from the draft guidance, the final document emphasizes that the appropriate Phase III study design generally will be determined on a case-by-case basis according to what has previously been demonstrated about the effects of the combination and the individual agents, the feasibility of monotherapy and standard-of-care treatment arms, and other factors.

The guidance also suggests that it may be possible to conduct a factorial study design using only active drug treatment arms (AB v. A v. B) if the contribution of the individual new investigational drugs is not clear and use of one or more of the individual drugs as monotherapy is ethically feasible.

As with the other suggested trial designs, such an approach could help sponsors reduce the size and cost of clinical trials, although the agency acknowledges limitations.

“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,” the guidance states. “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.”

Co-Development Guidance Gives More Attention To IND, NDA/BLA Submissions

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