The long awaited US FDA draft guidance on the co-development of novel unmarketed drugs was released for consultation in December, 2010. Although not legally enforceable, the report is an essential step forward in guiding future drug development, highlighting novel treatment combinations that should speed up drug development, reduce costs, and give patients faster access to new treatments. Importantly, the recommendations are very specific on what scenarios should be considered under this process and how patient safety should be protected. So what are the qualifying criteria? The disease must be considered “serious” and only drugs that have a robust biological rationale for use in combination, as opposed to use individually, should be assessed—ie, combined agents should have more than additive efficacy or provide a more durable response. Examples include agents that are inactive alone but potentiate the activity of another drug, drugs against which resistance occurs rapidly when used as a monotherapy but in combination remain effective for longer, and drugs that target different, but complementary, biological pathways. Of course the concept of combining drugs based on targeting different biological pathways is not new. Two or more marketed drugs have been used very successfully in combination in patients with cancer, and this guidance is the next logical step to prompt novel treatments for drugs that have not been tested and marketed individually, enabling fast-track marketing approval and earlier patient access. As the report suggests, co-development will generally provide less data on safety and efficacy, and when safety cannot be tested in phase 1 studies of individual drugs (eg, because of resistance), preclinical evidence, pharmacokinetic data, and biomarker evaluation should be sought. So is this strategy dangerous and unnecessarily risky? Not if patients are carefully and frequently monitored and the rationale is clear. Safety is considered prominently in the report, but deserves even more emphasis because drug combinations can have unexpected serious synergistic or additive toxicities. Indeed the guidance states that co-development could “present a greater risk” to the patient than if the drugs are developed initially as single agents. Co-development allows innovative adaptive trial designs in which patients treated with single agents that prove ineffective can crossover to the more active combination treatment. However, the biggest advance in the development of new treatment regimens could be made if the FDA now focused its attention wholeheartedly on facilitating head-to-head comparative effectiveness studies of drugs already on the market—as called for by the Obama administration. Comparative effectiveness studies—a current buzz phrase—refers to many types of study and is described by the FDA as “intended to help make decisions more consistent, transparent, and rational”, and “useful in identifying gaps and uncertainties”. However, these studies are often large randomised trials, and therefore expensive to complete, and can include a placebo control as well as the head-to-head comparison(s), adding further to the time and effort involved. Unsurprisingly, therefore, these are a difficult sell to drug manufacturers who are likely to have little interest in an expensive trial of their latest top-selling drug given their vested interests. Meta-analyses and cross-study comparisons have therefore traditionally filled this evidence gap. It is now time, however, for the FDA to use its considerable influence more effectively to incentivise manufacturers to complete such comparative research and provide specific guidance as to what it expects in terms of the optimum trial design. Particular emphasis on use of the appropriate control group for drugs before and after they are marketed will be vital. The rhetoric now needs to be translated into detailed specifics of how such collaborative and comparative research might be achieved so patients are best served. The US National Cancer Institute (NCI) has been at the forefront of cutting edge and practice-changing trial research and will be vital in complementing the FDA in its efforts. The NCI recently re-organised its clinical trials programme following recommendations from the Institute of Medicine report in April, 2010, and has consolidated its nine trial groups for adult cancer into four—with the aim of making the overall programme more cost effective and efficient. By collaborating with the FDA on combination drug trials for unmarketed agents, comparative effectiveness studies for marketed drugs, as well as drug and diagnostic co-development strategies, the NCI will ensure patients have access to more treatment options, better personalised treatment, and the latest magic bullets.
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Mar 19, 2024
Mazen Noureddin 
Open Access