Michael Weitz was out of options. The Californian had endured chemotherapy, radiation and surgery but his lung cancer still spread to his bones and brain.
With time running out, the emergency room physician entered a Phase I study - the earliest stage of human testing for a new medicine - of crizotinib. The drug works for about 4 percent of advanced lung cancer patients with a mutated form of a protein called ALK.
"Once I knew that I had that mutation, I knew that I had an exciting new chance," said Weitz, now 55, who is cancer-free after three years of taking the drug now sold by Pfizer as Xalkori after an unusually swift development process.
It typically has taken a decade and $1 billion to bring a new treatment to market. But in the last two years a handful of cancer drugs - including Onyx Pharmaceutical Inc's Kyprolis for multiple myeloma, Roche's Zelboraf for melanoma, and Pfizer's Xalkori - were approved in about half that time because of improved genetic screening, more definitive Phase I trials and the dire need for new, effective treatments.
"We hope to be able to shave years off the time it takes to get final approval and save hundreds of millions of dollars per drug," said Robert Schneider, director of translational cancer research at New York University Cancer Institute. "We're going to see this as a sea change over the next five years."
Weitz's story is a dramatic example of how personalized medicine is advancing 10 years after researchers sequenced the human genome, enabling drugs to target specific genetic variations. The emerging trend is likely to bring more effective treatments to desperate patients faster, increase the number of annual drug approvals and cut research costs through earlier and more reliable data. It will also help drug makers identify ineffective therapies sooner, although it may not necessarily lead to lower priced medicines.
There are some concerns about the faster approval process but most agree that the benefits of a potentially life-saving drug outweigh the risks. "The accelerated development of new drugs can be a double-edged sword," said Mace Rothenberg, head of oncology for Pfizer. "As you move more quickly some questions may be unanswered."
He said those answers can come from trials conducted after drugs are approved, and the Food and Drug Administration often requires post-marketing studies following expedited approvals
Historically, Phase I trials did little more than reveal the dose of an experimental drug that could safely be tolerated before larger studies determined clinically meaningful benefit. But advances in genetic screening and an improved understanding of the biology of cancer are enabling researchers to identify patients most likely to benefit from specific cancer treatments.
"You can see positive signals much more quickly, and clinically you can spare patients for whom the drug is not likely to work," said Dr. Michael Davies, assistant professor in the department of melanoma medical oncology at MD Anderson Cancer Center in Houston.
Richard Scheller, head of research and early development for Roche's Genentech unit, which has produced most of the company's top-selling cancer medicines, said, "you can cut a couple of years out of the clinical trial process by basically doing your pivotal trial straight from Phase I."
Drug makers who have benefited from the expedited approval process declined to discuss how much money was saved from the industry average for drug development.
FDA's new 'breakthrough' designation
With impressive enough early results, health regulators are more willing than ever to accept early or midstage trials as adequate proof of safety and effectiveness, rather than insisting on larger, more expensive and time-consuming pivotal Phase III studies that have been a standard requirement.
"The drugs are simply better," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said of the new targeted cancer medicines.
With older highly toxic chemotherapy drugs, he said, "many of the discussions we had at the agency dealt with whether we should approve the drug or not. With some of these newer drugs, the issue is how fast we can approve them, not whether they should be approved," Pazdur said.
The FDA has come up with a new breakthrough designation for drugs it views as a substantial improvement over existing therapies. With the designation - five have been awarded so far with 12 more drugs currently under consideration - the agency works more closely with drug makers to identify approval requirements and work out commercial manufacturing issues.
Key to faster approval is that drugs are becoming more narrowly targeted as researchers better understand the pathways of cancer - a series of biochemical steps that fuel the growth of cancer cells. The aim of the treatments is to block the culprit proteins, or biomarkers, within a pathway.
"It's much easier for us to offer patients in Phase I studies the real possibility of a dramatic response," said Paul Sabbatini, an oncologist at Memorial Sloan-Kettering Cancer Center in New York.
Now far fewer patients need to be tested in order to get definitive results in early trials because they are selected only if their tumors contain proteins or gene mutations that the experimental drug is targeting. Patients typically learn about these studies from their doctors or websites such as ClinicalTrials.gov.
"What we're looking at many times is Phase I data where we're seeing levels of response that we haven't seen before in patients that have exhausted most of the therapies in a disease," said FDA's Pazdur.
Scheller estimated that cancer researchers are working on 50 different targets that could yield effective future therapies.
NYU's Schneider, a co-founder of the biotech company ImClone, said historically perhaps only 3 percent of oncology drugs that began Phase I trials went on to be approved. With new diagnostic tools and targeted drugs, he said, "one would hope that 10 or even 15 percent of drugs might be approved for the right patient populations in the next five years."
Roche's Zelboraf and Pfizer's Xalkori both were developed along with companion diagnostic tests to identify the specific gene mutations in patients that the drugs were designed to target. They proceeded relatively rapidly through clinical trials.
The company said development of Zelboraf, which costs $56,000 for a six-month course of treatment, was the fastest conducted by Genentech and Roche. The clinical trial process took less than five years.
Pfizer's Xalkori took just over four years to develop. Had it been tested in the traditional manner among the general lung cancer population rather than on those with the specific ALK mutation, it would likely have been dismissed as a failure or required further research to try to glean which subgroup of patients were helped by the drug that costs $115,000 a year.
Finding failures faster
In the past, large pharmaceutical companies were reluctant to develop drugs for limited patient groups, preferring to search for medicines to treat ailments such as high cholesterol and arthritis that could be taken by a large swath of the population and become huge money-makers.
Pfizer Chief Executive Ian Read has embraced the newer personalized approach. Noting recent advances in genetic understanding, Read said: "We can get clearer results earlier. That will clearly speed up our development, as you saw with Xalkori."
The recent advances may also grant a long-held wish of drug makers - identifying failed drugs faster.
"It's much better to find that out in Phase I than half a billion dollars later in Phase III," Genentech's Scheller said.
"If you have a targeted therapy and you don't see activity in your first 10 or 20 patients that have your particular diagnostic marker or particular biomarker that you're looking for, forget it, we're through, project ends," Scheller said.
Even with all the recent successes, many hurdles remain. Researchers have yet to figure out why drugs that work by spurring the immune system to fight cancer, such as Bristol-Myers Squibb's Yervoy, have long-lasting effects on some patients and not others. And they need to figure out why cancer often comes back even when targeted therapies worked.
"We need to know why these drugs stop working sometimes," said Sloan Kettering's Sabbatini. "If we understand the cause, we could preemptively combine drugs, or at the first sign of (disease) progression, understand what is the most logical next step as we learn more about the pathways."
But as long as the United States does not have price controls for medicines as Europe does, and the FDA does not consider economics in its approval decisions, quicker, less expensive development may not translate into lower prices.
"I would hope it would bring down the cost of drugs, but whatever the market bears is what the market will get," Schneider said.