The Pink Sheet - FDA Draft Co-Development Guidance Emphasizes Phase II Studies | Friends of Cancer Research

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The Pink Sheet - FDA Draft Co-Development Guidance Emphasizes Phase II Studies


Clinical trial strategies proposed in FDA's draft guidance for co-development

of drugs designed for use in combination in most cases whittle the design down to standard of care versus the combination before Phase III, offering the prospect of cutting not only development time but also clinical trial costs.

In fact, the draft guidance in most cases eschews the gold standard factorial design – a minimum four-arm study comparing the combination to individual components and standard of care/placebo – for its "limited utility" in testing the new combination therapies.

If findings from preclinical, Phase I and Phase II studies "adequately demonstrate the contribution of each component to the combination, Phase III trials comparing the combination to SOC or placebo generally will be sufficient to establish effectiveness," the guidance says.

FDA Commissioner Margaret Hamburg and Center for Drug Evaluation and Research Director Janet Woodcock announced the draft guidance Dec. 14 at the Faster Cures Partnering For Cures meeting in New York.

The draft guidance's top criterion is that the combination be intended to treat a serious disease or condition. Co-development will be permitted only when there is a compelling biologic rationale for doing so, Woodcock said ("FDA Issues Co-Development Guidance, But Only For Products Treating 'Serious' Diseases," "The Pink Sheet" DAILY, Dec. 14, 2010).

Making A Case For Co-Development

FDA is setting a high bar for entry into the co-development ring. Combination therapeutics are riskier than monotherapies because obtaining individual clinical data on both safety and efficacy may not be possible or appropriate beyond Phase I. Yet, a combination that produces synergistic efficacy might also produce synergistic toxicities.

In addition to the "serious disease or condition" stipulation and the "compelling biological rationale," the draft guidance poses two other tests.

There must be evidence from preclinical studies or a short-term clinical study using an established biomarker suggesting that the combination has "substantial activity and provides greater than additive activity or a more durable response" than the individual agents in monotherapy. And, there must be a "compelling reason" for not developing the agents separately.

Still, for drug makers and disease communities, who have lobbied the agency to create an approval pathway for drugs designed to be used in combination, the guidance is a breakthrough.

During her remarks at the Faster Cures meeting, Woodcock acknowledged the cancer think tank Friends of Cancer Research, which submitted a draft guidance to the agency in March based on a September 2009 stakeholder conference the group convened along with the Brookings Institution ("FDA Developing Guidance On Rational Development Of Combined Novel Drugs," "The Pink Sheet," June 14, 2010).

The FDA draft's scenarios for narrowing study designs before Phase III look a lot like the proposal in the report of that meeting (see chart).

FDA's draft is reflective of the agency's willingness to engage scientific experts from stakeholder communities, Jeff Allen, Friends executive director, said in an interview. "We took up the subject because it is completely biologically plausible that this is the way forward in cancer research, as well as in other areas" specified in the guidance. But raising the issue isn't as important as defining the path forward, "and I think the guidance does a very good job of adding some additional advice on tough questions," Allen said.

Historically, "cancer research has in many ways been a serial experimentation of adding standard of care plus new, and we're moving to much more of a biologically driven model where we'll be able to examine which pathways are malfunctioning and design the targeted therapies" for types of cancer, he said. "FDA certainly recognizes that this is the future of targeted medicine."

Guidance Could Spur Partnering Activity

In June, the same month FDA put out the Federal Register notice soliciting input for the draft guidance, two Big Pharmas announced they would join forces in a first-of-its-kind early-stage combination candidate deal ("In A First, Merck And AstraZeneca Team Up For Oncology Study," "The Pink Sheet" DAILY, June 1, 2009).

Under the agreement Merck adds its Phase I AKT inhibitor MK-2206 to AstraZeneca's Phase II AZD-6244, a mitogens-activated protein kinase 1 (Mek) inhibitor, with costs split equally and a joint steering committee to guide the research in consultation with FDA.

In a Dec. 15 note, Barclays Capital analysts called the draft guidance "an incremental positive" for oncology and anti-infectives, hepatitis C therapies in particular. In a first pass assessment, the analysts said the high-level implications of the draft guidance likely include increased partnering activity, greater interest in small-cap oncology and HCV assets, increases in multi-drug trials, and "to the extent that there has been significant progress in biomarker development and understanding of complementary drug activity … likelihood of success in oncology and HCV will increase."

Expedited co-development may also bear fruit for tuberculosis products ("TB Study Lights Pathway Toward Combination Drug Trial Guidance," "The Pink Sheet," Dec. 20, 2010).

Demonstating A "Biologic Rationale"

The draft guidance emphasizes the importance of in vitro and in vivo data for demonstrating the biological rationale for a combination. In development of an anti-infective, for example, the rationale might be to target different metabolic pathways or different steps in a pathogen's replication cycle to reduce the chance it can develop resistance.

In Phase I, the emphasis is on establishing the safety profile of each drug, including the maximum tolerated dose, dose-limiting toxicities and pharmacokinetics. In cases where toxicity prevents use of healthy volunteers and monotherapy would be unethical in patients, non-clinical studies of the combination can be used to support initial dosing in humans. In some cases a sequential Phase I safety study of the combination could be conducted in which subjects are given drug A, then drug B, then the combination to support dosing in subsequent studies.

Dose response has to be evaluated for each drug in the combination; if a drug can't be administered alone, "various doses of each drug administered as the combination" should be assessed. To increase exposure ranges in Phase III and to further assess dose-response, more than one dose of each of the drugs used in the Phase III trial should be considered.

Proof-Of-Concept Phase II Studies

Depending on the amount of data collected in Phase I, the Phase II program might have to continue the task of demonstrating the contribution of each component. In addition, it must show evidence of efficacy and it must optimize the dose or doses for Phase III studies.

In cases where the components cannot be administered individually – because one or all are ineffective as monotherapy or when resistance is likely to develop quickly – the guidance suggests a study directly comparing the combination to standard of care. An add-on design also could be used comparing the combination plus standard of care to standard of care alone, but only when SOC is an effective therapy.

In cases where each drug has some activity but the combination appears to have greater than additive efficacy and rapid development of resistance is not a concern, a classic four-arm trial comparing the individual components, the combination and placebo/standard of care or the combination and the individual drugs added to standard of care is recommended. In an adaptive trial design, the single-drug arms could be terminated early if it became clear that they had much less activity than the combination.

These designs could demonstrate the activity of each component without exposing the large number of patients typically required for Phase III trials to therapies with "inadequate activity," according to the draft guidance. Also, a clinical endpoint might not be necessary as a primary efficacy measurement; rather, a credible pharmacodynamic or other biomarker such as tumor response might be adequate.

Finally, in cases where early data suggest that one of the drugs is inactive or minimally active, but the combination has "substantial activity," the more active drug should be evaluated alone in a Phase II study. Phase I data likely will be enough to support the minimally active drug, particularly if it is a pharmacokinetic or metabolic enhancer.

In this scenario, proof of concept and the contribution of each component could be demonstrated using a three-arm comparison of the active drug alone, standard of care, and the combination, or the combination and the active drug added to standard of care, where SOC is an active therapy.

Confirmatory Phase III Studies

If the Phase I and Phase II studies adequately demonstrate the contribution of each component, a simple two-arm Phase III study should be enough to confirm those results. If, however, the contribution of the individual components is still not clear, and monotherapy studies are ethically feasible, a full-blown factorial study may be required. Other scenarios include the possibility of comparing the combination to the more active of two components to demonstrate that the combination is superior; hence, the less active component does make an efficacy contribution.