Published on BioPharma Dive
Author: Malorye A. Branca
Creating a breakthrough drug is one of the highest risk ventures in healthcare: Success can mean billions of dollars in revenue for years to come, but failure can mean as much as a $1 billion wasted and a huge gap in a company’s product pipeline.
“Clinical trials are very expensive, and the cost is only going up,” says Laurie Halloran, president of the Halloran Consulting Group. So shouldn’t drug makers be thrilled by President Trump’s recent call to relax regulations to help speed drugs to market? Actually, not so much.
In his recent first address to congress, Trump repeated his claim that the Food and Drug Administration’s approval process is “slow and burdensome.” He promised to “slash the restraints, not just at the FDA but across our government.”
But some companies are pushing back on that idea and saying, “we like the FDA’s risk-benefit assessment,” said John LaMattina, former president of Pfizer Global R&D and now a member of the board of directors at Puretech Health. “The last thing the pharmaceutical industry needs is more claims that things don’t work or aren’t safe.”
Halloran concurs. She points out that there has been a longstanding argument that FDA should concentrate on safety and let the market determine which drugs are deemed efficacious. “But picture grandma getting a drug, and she doesn’t die from a side effect, but it doesn’t work,” she says.
So, FDA regulations can be seen as both an obstacle (especially when a company is denied an approval), but also a valuable imprimatur (when they receive one). “It’s not just patients and doctors who need to be convinced,” LaMattina explained. “FDA approval also helps secure insurance coverage … and insurance companies are more and more reluctant to pay for questionable treatments.”
That doesn’t mean people don’t want change. Drug makers and regulators have been struggling for decades to find better ways of getting drugs to market more safely and quickly. But with patients’ lives at stake, it’s not surprising that this is one of the most highly regulated industries in the world. That’s one of the key reasons bringing a drug to market is such a big gamble.
The early stages of drug development, in the laboratory and testing drugs on just small groups of patients, are certainly fraught with risk. But it’s in the last dash to the finish line – the much larger Phase 2 and Phase 3 trials, that things get the costliest and most time-consuming. Such trials typically require a massive investment and only occur after as much as a decade — and sometimes more — of prior work has gone into a treatment.
New ways to accelerate trials
Most of the challenges of late-stage clinical trials are well-known. These trials require lots of patients and planning; they take a long time and are very expensive and complex, often involving sites in multiple countries.
Many drug developers have turned to two key solutions for many of those problems: contract research organizations (CROs) and technology.
Outsourcing clinical trial management to CROs is a longstanding trend, but it is reaching a milestone, according to John Lewis, head of policy and public affairs at the Association of Clinical Research Organizations (ACRO).
“Employment in the CRO industry has more than doubled in the last 10 years, while comparable jobs in pharma are decreasing,” he said.
There has also been a shift in expertise focus at CROs.
“Ten to fifteen years go, the CRO industry was focused on providing staff and expertise to run the basics of the clinical trials – clinical monitoring, site selection, patient recruitment, data management and data analysis,” Lewis said. “Now they have expanded to include new services such as collecting real world evidence, detecting biomarkers and more.”
Real world evidence is a particularly important issue, because too often drugs succeed in clinical trials but disappoint when they reach the market. That’s because “real world” patients are usually much more heterogeneous than those in clinical trials.
“With real world evidence, you can detect things like unanticipated side effects or whether a drug works in other indications than what it was initially approved for,” Lewis added.
Halloran sees steady progress in the use of technology, including the cloud, electronic data capture (EDC), big data and social media, as opposed to paper-based processes in clinical trials. Companies have also increasingly used tools such as Skype to conduct trials via remote monitoring.
Research suggests that EDC alone can reap huge cost savings, while the cloud allows companies of any size to handle all their clinical trial data much more efficiently and at a lower price.
“The biggest change has been the power of being able to aggregate lots of data in the cloud,” she said. Social media, meanwhile, has “panned out [as a recruitment tool], especially when patients are being advocates for themselves in the face of poor options.”
The use of social media for recruiting is also growing, a trend that is “still in its infancy,” Lewis noted.
Tackling patient variation
Another key problem is that it can be very difficult to get the right number of patients with the required characteristics. The larger and more homogeneous the patient pool is, the more robust the statistics will be and thus the more likely the trial sponsors will get a useful result. But many diseases just don’t present that way; different patients have different symptoms at different times.
That problem has led some researchers to explore new ways of designing trials.
The Collaborative Trajectory Analysis Project (cTAP), for example, was born from the recognition that there are large differences in the rate at which Duchenne muscular dystrophy (DMD) progresses. This disease affects motor function, and a key way to track its progress is to measure motor decline. But that varies widely among patients, and researchers became convinced this extreme variation caused a string of clinical trial failures that hobbled progress against the disease.
“We realized that unless we could learn how to predict, much more accurately, the functional changes each patient was likely to undergo in the next year or two of their lives, clinical trials in Duchenne would continue to be at high risk of failing,” Susan Ward, cTAP’s Executive Director, said.
In response to that issue, Ward helped spearhead cTAP – a partnership enabling clinical experts and drug developers to use novel methods to design trials that provide clear evidence of a drug’s potential. “Our vision is there will be no more clinical trials generating results that are equivocal,” said Ward. After all, pursuing a dud is just as bad as letting a good drug get away because the trial was flawed.
The project includes patient advocacy groups, major pharmaceutical companies and biotechs, leading academic research groups and experts in complex data analysis. At its core is a registry of data about the health history of more than 1,300 patients, representing more than 10,000 clinic visits. The initiative was launched in winter 2015, and the group has already published two papers that will help drug developers design better clinical trials of drugs for Duchenne.
Ward sees even wider applications for their methods, though.
“Duchenne is far from the only disease that suffers from longitudinal heterogeneity,” she said. “There are many rare diseases like that, but also common ones such as Alzheimer’s and depression.
“If we can solve the challenges in Duchenne, the potential to adapt those solutions for other diseases is real,” she added. If this new process does work, it will be welcome news to other conditions where companies have also seen large numbers of failures.
Despite such progress, the specter of a catastrophic failure still haunts drug R&D professionals.
In a recent post on Forbes’ contributor blog, LaMattina reminisced about a high-profile Phase 3 failure his Pfizer team experienced in 2006. The company had reportedly spent more than $800 million to develop a compound called torcetrapib, which they hoped would become a breakthrough treatment for high cholesterol. But the drug’s Phase 3 trial, which involved over 15,000 patients, failed, and Pfizer pulled the plug on it.
When he got that news, early in the morning at home, LaMattina was devastated. “With this phone call, 17 years of work on the part of hundreds of scientists evaporated,” he wrote.
It’s not surprising, therefore, that some are skeptical of President Trump’s call to speed the drug approval process. So far, change has been agonizingly slow, but also steady. The innovations already made are having an effect, and more are surely on the horizon.