To patients grappling with incurable diseases, new therapies can't come quickly enough. A bill that hopes to address this need sailed through the House in the summer with the goal of getting more "21st Century Cures" through the drug approval pipeline. But a pair of new studies found that speeding up this process could put drugs that are ineffective or harmful on the market.
At least for complex neurological diseases, such as Alzheimer's, Parkinson's and depression, recent history suggests that approving drugs faster based on biomarkers — early signs that a drug could be working — might make drugs that ultimately don't work available to patients, two teams of researchers found.
These early biomarkers are one of several ways the House bill could speed up the drug approval process. A Senate version of the bill is expected to be presented soon, with many wondering how similar it will be to the House version. The Food and Drug Administration has said the House legislation wouldn't override its ability to approve safe and effective drugs.
Under a faster approval process, a cancer drug can be approved based on evidence that a tumor has stopped growing, or an osteoporosis drug could be authorized if it shows increases in bone density. But such surrogate endpoints, while encouraging, do not mean the drug affects the aspect of the disease that people most care about — only a rigorous trial can determine whether cancer patients live longer and osteoporosis patients experience fewer fractures.
In a study published in the journal Nature Reviews Drug Discovery last week, a group of Harvard Medical School researchers found that early trials of certain central nervous system drugs weren't very predictive of whether the drugs ultimately worked.
Traditionally, drug trials progress through three phases: The earliest phase 1 trials are used to ascertain the safety of a drug and the correct dose. Phase 2 trials are larger, but are mainly designed to look for side effects as well as signs the drug might be working. Phase 3 trials are the largest, longest and most expensive trials, used to vet a drug's safety and effectiveness.
The journal study found that, in late-stage trials, drugs for diseases like multiple sclerosis and depression had a far lower success rate than other kinds of drugs tested between 1990 and 2012. That suggests that approving drugs based on these exciting, but preliminary signs, could lead to medicines that don't work very well — or at all.
"It’s the science where we need to be focusing to address the backlog and not the regulation causing a backlog," said Aaron Kesselheim, an associate professor of medicine at Harvard Medical School who led the work.
A second study published in the British Medical Journal this week examined three Alzheimer's drugs that progressed to late-stage trials based on positive data in earlier stage trials that suggested the drugs were working. In each case, the team found that the phase two trials suggested the drugs would work — two showed encouraging decreases in measurements of beta amyloid, a protein that builds up in the brains of Alzheimer's patients. One drug, semagacestat, was then tested in 1,537 patients and was found to cause skin cancer and even worsen patients' ability to perform activities of daily life. The other two drugs looked promising in intermediate trials, but also failed once tested in large numbers of patients.
The researchers projected that if the semagacestat had been approved based on its encouraging results in intermediate trials, the treatment would likely have cost thousands of dollars a year, treated 234,000 patients, and caused 19,000 cases of skin cancer.
"This is just yet another example where, if you look at these very reasonable surrogate endpoints ... you can get results that are completely different when you look at things you really care about, which, in this case, is memory loss and the ability to function, day-to-day," said Diana Zuckerman, president of the National Center for Health Research.
The two new studies aren't the first to raise questions about a faster drug-approval process. Already, several studies have suggested that these surrogate endpoints may result in the approval of drugs that don't actually extend life in cancer. A study published in JAMA Internal Medicine in October found that two-thirds of cancer drug approvals between 2008 and 2012 were made based on an interim biomarker, such as tumors had stopped growing. Over half of those have still failed to show a gain in survival.