FDA to alter rules for cancer drug cocktails

[gdpawel]

A diagnosis of AIDS was a death sentence until the advent of drug cocktails in the 1990s, which helped patients suppress the disease indefinitely. Now researchers say a similar combination strategy may change the course of cancer.

That's the thinking at Roche Holding AG, Novartis AG and Sanofi-Aventis SA, whose latest efforts to conjure a new generation of combination medicines are spurring regulators to rewrite the rules for drug research. The guidelines may shave five years off development timelines and lead to better treatments, said Ira Mellman, head of cancer research at Roche's Genentech unit in South San Francisco.

For a decade, researchers have crafted drugs to disrupt the precise cellular processes that fuel cancer. So far, survival benefits are measured in months, not years. That's because cancer, like HIV, evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, scientists are now developing combinations designed to work in tandem to block cancer.

Cocktails that mix drugs still in development wouldn't have been possible just five years ago. FDA rules required that the merit of each active ingredient be proven before it could be added to another. Regulators were concerned about approving a combination where one of the ingredients didn't help, or worse, caused harm.

Twenty years of work on the human genome has helped illuminate the intertwined mechanisms of cancer. Scientists have a new understanding of the cellular and genetic links among different disease pathways. As a result, the Food and Drug Administration is ready to allow innovative testing of drug cocktails, said Richard Pazdur, the agency's top cancer regulator.

The new research guidelines describe three basic principles for early combinations.

First, there should be a scientific rationale for how the drugs will work together in the body.

Second, there should be evidence from mouse tests or small human trials that the benefit of combining the drugs is more than additive (think 1+1=3).

Finally, there should be a compelling reason why each drug can't be successful independently.

If conditions are met, companies may develop components simultaneously and forgo differentiating the drugs on the last and most expensive trials needed for regulatory approval. Those studies, pivotal Phase III trials, can cost hundreds of millions of dollars and take years to complete.

The promise of targeted cocktails is already changing how companies do business. There are several approaches being pursued. Pfizer Inc.and Roche are developing the needed parts in their own labs. Roche, based in Basel, Switzerland, has a combination that began safety tests in patients last year, and New York's Pfizer has four combinations in human trials.

A second group of companies is looking outside their labs to acquire components. Novartis, of Basel, and London's GlaxoSmithKline Plc started two studies this year combining an experimental drug from each company. AstraZeneca Plc, of London, and Merck & Co. of New Jersey also began a collaborative trial.

When Sanofi's scientists had an idea for a combination, they decided that instead of developing components, they would buy them. The company licensed a molecule from South San Francisco's Exelixis Inc. that inhibits a cancer-related enzyme and an antibody from closely held Merrimack Pharmaceuticals against a separate protein target.

Collaborations and acquisitions are likely to increase as FDA regulations are clarified. In some cases, individual components may not work at all without being combined.

About 800 targeted drugs are in various stages of development in cancer, aimed at about 300 genes relevant to the disease. For each type of malignancy, six or eight genes may be active, and the trick will be identifying and aiming drugs at the two or three most vital targets to each cancer type.

Source: FDA.gov