People look at Big Pharma and they think we’re not going to do disruptive, innovative things,” Stein says. “I’m proud that Novartis was willing to do it. It’s patient-driven.” Across the medical establishment, researchers, clinicians, regulators, and patients are beginning to recognize that the era of personalized medicine must mean not only changes in treatment, but also changes in how medical research moves forward. Signature is just one of dozens, if not hundreds, of experiments aimed at adapting research methods to the new world created by next-generation genomic sequencing. With the growing number of molecular markers for various diseases and the realization that there are many subsets of diseases and many subsets of patients, experts are scrambling to adapt how we answer increasingly specific medical questions. Many of the new trial designs are even forcing researchers to change the kind of statistical logic they use to test their theories. To understand how revolutionary this is, it helps to remember that actually trying to prove that medical treatments work is a relatively new innovation. For most of human history, doctors relied mostly on observation. They tried something; if it worked, great. If not, the patient probably died. Progress crawled. In the 18th century, James Lind, a British naval surgeon investigating scurvy, came up with the idea of giving different treatments to different groups of patients and comparing how the patients fared. Yet a hundred years later, medicine continued to exist in a Wild West environment, with thousands of untested “patent medicines” marketed without any proof that they worked. Throughout the first half of the 20th century, the American government tried to bring some sort of order to drug development, with varying success. Clinical trials were developed, but their form was neither mandatory nor regulated. Drug disasters and scandals occurred regularly. Finally, in 1961, after the worldwide thalidomide scandal, in which a drug given to pregnant women to control nausea caused grievous birth defects in their babies, governments decided to standardize how drug investigations proceeded. In short, for the last half-century, regulators like the U.S. Food and Drug Administration have basically set this gold standard for randomized clinical trials (RCT): The trials need to be randomized, meaning patients are assigned to a particular treatment randomly. The hope is that this will help to eliminate bias from the results. The trials need to be double blind, meaning that neither the doctor nor the patient knows which drug a patient receives. Again, the goal is to avoid bias. The trials need to have a control group that does not receive whatever is being investigated. That way, researchers can compare whether the outcomes for patients who receive the drug are better than those for patients who don’t. This system has required huge numbers of test subjects, usually hundreds and often thousands. It demands that patients travel to wherever the research is being done. It can take decades, and it often costs more than $1 billion to bring a single new drug to market. The system emphasizes drug approval rather than discovery. Progress is incremental. “They test drug combination X against combo Y. They find a 5 percent difference and everybody cheers. But that’s just modest progress. Thousands of patients’ lives are lost in the meantime,” says Matthew Ellis, a professor of medicine at Washington University in St. Louis and author of several papers on innovative clinical trial designs. “My call to action is that we need to sit down and design clinical trials where genomics is the objective, where we get the right kinds of clinical specimens and right kinds of clinical data so you can do proper discovery science.”
