Washington Editor

WASHINGTON – When two or more drugmakers are gathered in development's name, will there be love? The FDA thinks it's possible.

And while the agency is not serving as the matchmaker for manufacturers, it has provided another tool as part of the FDA's effort to close the gap between advances in science and making "smart therapies" available to patients.

The FDA this week released a new draft guidance document encouraging drugmakers to develop and test two or more investigational medicines in combination when doing so may offer a significant advantage to patients.

FDA Commissioner Margaret Hamburg said the combination development scenario has unique relevance to targeted therapies, which she noted may need to be combined to enhance effectiveness or prevent resistance.

While developing drugs in combination is "obviously more challenging scientifically," it is "what patients need and what public health demands," Hamburg said Tuesday at the Partnering for Cures conference in New York, hosted by the nonprofit think tank FasterCures.

By identifying better ways to develop and evaluate potential treatments, "together, we can more quickly find new treatments that work, efficiently and effectively, and make them available to the people who so badly need them," Hamburg said.

With the growing interest by drugmakers in pursuing combinations of experimental treatments – especially for cancer, cardiovascular conditions and infectious diseases – and the fact that the existing development models and regulatory approval processes focus primarily on the effectiveness and safety of a single new drug, the FDA determined that new guidelines were needed.

The draft guidance describes approaches for co-development of two or more unmarketed drugs and the criteria for determining when developing them together as one therapy is appropriate. It also makes recommendations about nonclinical and clinical strategies and addresses certain issues about regulatory processes.

The FDA emphasized that its new guidelines are not aimed at fixed-dose combination products of already marketed drugs, like Orexigen Therapeutics Inc.'s experimental obesity drug Contrave (naltrexone/bupropion), which earlier this month won the backing of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee – the only one of three investigational weight-loss drugs recently under review at the agency to get the panel's blessing. (See BioWorld Today, July 16, 2010, Sept. 17, 2010, Oct. 26, 2010, Nov. 1, 2010, Dec. 8, 2010, and Dec. 9, 2010.)

The guidance also is not intended for single new investigational drugs to be used in combination with FDA-approved medicines. It also does not apply to vaccines, gene or cellular therapies, blood products or medical devices.

Since there likely will be less information about the safety and efficacy of two or more new agents concurrently developed for use as a combination drug, those new combined products pose a greater risk to patients, regulators said.

Therefore, co-development of never-before marketed agents should be reserved for medicines to treat serious conditions, said Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, who also spoke at the Partnering for Cures conference.

The FDA also wants co-development of new drugs to be used only when there is a compelling biological rationale for use of the combination, such as the agents inhibit distinct targets in the same molecular pathway or inhibit the same target at different binding sites to decrease resistance, Woodcock said.

Co-development also should be used in situations when a preclinical model or short-term clinical study on an established biomarker suggests that the combination has substantial activity and provides greater than additive activity or a more durable response vs. individual agents alone, she said.

There also should be valid reasons why the agents cannot be developed individually, for example, if a monotherapy would lead to resistance or both agents alone would have low activity, Woodcock said.

Companies in co-development projects must ensure that the biology of the disease, pathogen or tumor type was well understood to provide a plausible biological rationale for pursuing a combination product, regulators said.

Manufacturers engaging in co-development also must ensure that evidence is developed in an in vivo or in vitro model to support the biological rationale for the combination, the FDA said. The model should compare the activity of the combination to the activity of the individual components, with the combination having greater activity or a more durable response than the single components, the agency added.

Whenever possible, the safety profile of each individual drug should be characterized in Phase I studies in healthy volunteers in the same manner used for a single drug, regulators said.

Dose finding should be carried out in Phase II for each drug in the combination, based on the individual case, Woodcock said.

For Phase III confirmatory studies, if mechanistic or early clinical studies show contribution of each investigational drug to the overall effect, then a trial should examine the combination vs. standard of care, she explained.

Even if excessive toxicity with the combination has been observed in the Phase II studies, it may be possible to conduct the Phase III trials with the combination using a lower dose of the more toxic component, Woodcock said.

If the toxicity cannot be attributed to an individual component of the combination, additional studies may be needed to identify the more toxic component and appropriate dosing for the combination before initiating Phase III trials, she said.

"Together, we can rethink the development and review process and take leaps forward in the service of public health and better health care," Hamburg said.