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Improving the Value Paradigm in Drug Development Will Require More Efficient Clinical Trials, New Biomarkers

September 2014, Vol 5, No 7

Los Angeles, CA—Much remains to be done to usher in the era of personalized healthcare, including better methods of drug development, said presenters at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

“We’re using an insurance paradigm to incubate developing technologies, and frankly I don’t think that makes an ounce of sense,” said Louis Jacques, MD, Senior Vice President and Chief Clinical Officer at ADVI, Washington, DC.

Drug development has focused on small effects for big populations, creating high numbers needed to treat to prevent an adverse outcome but also exposing many patients to potential harm. The best way to do research in this paradigm is unclear, but randomized controlled trials will not necessarily lead to the solution. Instead, the methodological rigor needs to match the risk of making an erroneous conclusion, Dr Jacques said.

Clinical Trials Are Inefficient

“We expose patients…to technologies that may have little, if any, chance of real benefit,” said Dr Jacques. “We’re spending a whole lot of money on really big, long trials with tiny effects, and then we argue about the meaning of the results.”

What payers want is straightforward and consistent across payer types, he claimed. Payers want persuasive evidence (usually peer-reviewed evidence) that a treatment strategy—a drug or a device—leads to clinically meaningful improvements in outcomes.

Too often drug development revolves around “me too” products, combinations of generics at a premium price point, and new molecular entities that do not improve quality of life, daily patient function, or morbidity and mortality. None of these approaches are of interest to payers, argued Dr Jacques.

Health outcomes of interest to payers include longer life and improved function, improvement of symptoms, and a reduction in the need for burdensome tests and treatments (Table). An outcome of lesser interest is an improvement in disease-specific survival without an improvement in overall survival.

Finding small effects requires large and long trials that are expensive to conduct, complex statistical analyses, and the use of composite end points, resulting in evidence that may not be clear and consistent.

Research and development (R&D) in the cancer arena need to move beyond the status quo, agreed Christiane Langer, MD, Group Medical Director in Oncology US Medical Affairs at Genentech, South San Francisco, CA. The knowledge of biology should be applied to tailor the design of early clinical studies to increase the success rate of R&D, which stands at ‹10%.

“We need to move from just pure luck and chance to enhanced predictability,” Dr Langer said.

The average per-patient cost of oncology clinical trials has jumped from $38,300 in 2007 to $65,300 in 2010 as a result of the increased complexity and longer timelines of the trials. An improved understanding of disease mechanisms through the human genome should improve the efficiency of clinical trials, but simply identifying targets does not mean that the right drugs will be developed or will be applied to optimize outcomes.

Companion Diagnostics Key to Improved Outcomes

The development and regulation of companion diagnostics are also of interest to payers, because linking a drug to a specific test may narrow the potential market for the drug but improve outcomes. The lack of FDA oversight of companion diagnostics, however, may “scare” payers, said Dr Jacques. “Imagine something that doesn’t even have fundamental analytic or clinical validity data, except what the company is giving us,” he said.

The coverage and payment of companion diagnostics are challenges at the moment, because the test and the treatment may cross Medicare program benefit boundaries. For example, Medicare Part B administrative contractors may deal with the test, whereas Part D plans deal with the drug.

An increase in the number of molecularly targeted therapies in the oncology R&D pipeline is a driver for the need to develop companion diagnostics, and, in the future, targeted ther­apies will be codeveloped with a companion diagnostic, Dr Langer predicted. Overall, 36% of cancer therapies in phase 3 clinical trials currently in the pipeline involve targeted therapies compared with 45% that are in phase 1 trials, reflecting a growing focus on targeted agents.

For a biomarker to be useful as part of a companion diagnostic, its predictive value would need to be differentiated from its prognostic implications, she said. One example of a biomarker of response that predicts benefit from a drug is the KRAS mutation status of colorectal cancer, which improves the cost-effectiveness of EGFR monoclonal antibody–based therapy. Patients with KRAS wild-type have a doubling of median overall survival with cetuximab (Erbitux).

Another example is vemurafenib (Zelboraf), which shrinks target lesions in patients with BRAF V600E–mutated metastatic melanoma. The codevelopment of vemurafenib and the BRAF V600E mutation test took only 5 years from the New Drug Application to the FDA approval and launch.

“This is a really accelerated timeline for getting a very valuable drug in a targeted population on the market and to the patients,” Dr Langer noted. Barriers to Personalized Medicine

Identifying an “actionable” target is one of the barriers to personalized medicine. Tumor heterogeneity is a challenge to identifying dominant mutations. The relevance of circulating tumor cells in relation to circulating tumor DNA is also not known, because they appear to be distinct entities. Changes in the molecular characteristics of the tumor after primary treatment may have consequences for second- and third-line therapies.

“There’s so much we don’t know and we need to know before we can really move effectively and make personalized medicine a real success,” Dr Langer said.

Economic barriers include the lengthy duration of drug development and the high cost of R&D. Several “supertargeted” drugs may be needed for subsets of cancers, adding further cost.

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