Cancer revolution is possible with more flexible FDA 

Last week at a meeting of the American Society of Clinical Oncology, ASCO President George Sledge painted a hopeful, but also challenging, picture about new genomic technologies for fighting cancer.

These technologies can unravel the genetic mechanisms driving the disease and point the way to new strategies to overcome cancer-drug resistance.

Sledge’s enthusiasm was balanced by realism: Revolutionary progress against cancer will depend not so much on the technology we use, as on our ability to rethink old paradigms for drug development and FDA drug approval.

Cancer is a disease defined by uncontrolled cell growth that occurs when the body’s normal mechanisms for correcting or preventing genetic mutations fail.

Once a cell accumulates enough mutations for uncontrolled growth and metastasis, it spreads throughout the body like a virus. And like a virus, it can mutate to evade the very drugs that are designed to kill it.
New genetic-sequencing tools have helped researchers understand that many different genetic pathways can drive tumor growth. These pathways can even change over time, as tumors continue to mutate.

This means that finding a single “magic bullet” to kill many types of metastatic solid tumors is extraordinarily unlikely. Traditional chemotherapy can kill some vulnerable cells, but it leaves others to develop resistance or grow using different pathways altogether.

As Dr. Sledge put it, attacking cancer will require not a “magic bullet” but a “magic shotgun,” where multiple drugs attacking multiple cancer-causing pathways are given to patients at the same time.

The key challenge will be matching cocktails to the particular tumor mutations of particular patients.
The good news is that with the rapidly falling cost of genome sequencing, it may soon be possible for cancer patients to have their tumors tested to identify the key mutations driving their disease and then (hopefully) match them with drug cocktails designed to shut them down.

The problem is that regulators have traditionally insisted that companies test one drug at a time, and they won’t allow a drug to be sold unless it can prove it “works” on its own.

This flies in the face of what science is telling us about cancer biology: not only will it require cocktail treatments for maximum effect, but it’s even possible that a drug that’s useless on its own could turn out to be a critical component in a cocktail. The FDA has issued interim guidance for companies testing drugs in combination, but more work needs to be done.

Another problem: Companies have been hesitant to share information about drugs in development that might be used in a prospective cocktail with a competitor’s product.

Concerns about patent protection, lack of standardized biomarkers for measuring a drug’s effect on specific pathways, and the complexity of designing drug trials testing multiple potential cocktails simultaneously have all slowed progress.

Overcoming these obstacles will require a new paradigm for drug discovery and approval, and new diagnostics that empower individual patients and their physicians to learn about their cancers and quickly find drugs to treat them.

Regulators must shift from their traditional role of approving drugs to validating new diagnostic tools (like biomarkers) that allow physicians and patients to personalize new treatments “on the fly,” rather than after years of laborious research.

Companies will have to find innovative ways of sharing data that suggest which drugs work best in combination. And oncologists will have to embrace electronic health records that allow researchers to analyze genomic tumor data and drive new drug development.

Cancer research is revealing that “genomic chaos” — the rapid ability of tumors to mutate —  underlies the ability of cancer cells to evade traditional treatment approaches.

Reaching the full promise of personalized medicine to tame cancer will require a reinvention of drug development and drug approval that transforms this “chaos” into usable, life-saving information.

Paul Howard is senior fellow and director of the Manhattan Institute’s Center for Medical Progress, as well as the managing editor of Medical Progress Today, a Web magazine.

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