“New and improved.” These words have been yoked together in so many marketing campaigns that we tend to accept them as inexorably linked. But when it comes to new medications, don't swallow them without a healthy dose of skepticism. Many or most new drugs are not—or at least not provably—an improvement over the best existing drug for a given condition, and the fast-track drug-approval processes that have prevailed in recent years have added to the uncertainty about their advantages.
A recent report in the British Medical Journal, entitled “New Drugs: Where Did We Go Wrong and What Can We Do Better?,” offers an analysis of the issue. The authors looked at 216 drugs approved by German regulators between 2011 and 2017; 152 were newly developed, and 64 were existing medications approved for new uses. Only 25 percent of the medications were deemed as offering a “considerable” or “major” advantage over the established treatment (termed the “standard of care”), and 16 percent had a minor or nonquantifiable advantage. Fully 58 percent had no proven added benefit in terms of lowering mortality, reducing symptoms or side effects, or improving health-related quality of life.
“This doesn't mean we are sure there's no added benefit,” lead author Beate Wieseler said in an interview. “It just means we have no positive proof. Either we have no studies at all [comparing the new medicine with the standard of care] or we have studies, but they aren't good enough.” The record was “particularly egregious,” she and her colleagues wrote, for drugs that treat psychiatric and neurological disorders and those for diabetes, with only 6 and 17 percent, respectively, offering a confirmed added benefit.
Wieseler and her co-authors work for Germany's Institute for Quality and Efficiency in Health Care, which evaluates new treatments and advises on whether the country's health care system should pay a premium for them. Such organizations, known as health technology assessment (HTA) agencies, have become “enormously more powerful” in many countries' efforts to manage the spiraling cost of new drugs, says Sean Tunis of the not-for-profit Center for Medical Technology Policy in Baltimore. HTA works a little differently in the U.S., he explains: “If payers think a new drug is not any better than a drug that we already have, they will do things like requiring you try the cheaper drug first.” Insurers and Medicaid will often insist on this kind of “step therapy.”
Germany's HTA is probably the most persnickety about demanding head-to-head trials to prove that a new treatment beats the existing standard. This is not always practical. For one thing, such studies can be hugely expensive and time-consuming, with no guarantee of success. “What the authors are focused on is getting new, differentiated medicines at a low cost, and what they are missing is a sense of the complex economic underpinning of developing new medicines,” says Ken Moch, president and CEO of Cognition Therapeutics, a biotech firm in Pittsburgh. Requiring trials that prove superiority, he says, can discourage companies from even attempting to develop new alternatives. This is already happening. Drug developers are increasingly focused on niches where there are no good treatments to compete with, such as rare diseases and advanced cancers. The sky's the limit on prices for these first-to-market drugs, which are often rushed through FDA approval with limited data on efficacy. Many new cancer drugs are approved when it is shown they can shrink tumors by 30 percent, even if there is no proof that they boost survival.
This lack of meaningful data to guide patients is a major point of Wieseler's paper. Tunis shares her concern: with accelerated approval, “there are more products approved, with a greater amount of uncertainty about risks and benefits.” But there are other solutions besides head-to-head drug trials. One idea is for regulators and payers to require postmarket studies to track the effectiveness of newly approved drugs—a step too often neglected.
Tunis's center is taking another approach. Last year it helped to convene the makers of seven experimental gene therapies for hemophilia with patient groups, regulators, HTA agencies and others to agree on a set of meaningful end points for the companies' final studies before they seek approval. Patients, for example, asked that improvements in chronic pain and mental health be measured along with the frequency of bleeding episodes. The center is now looking at sickle cell therapies. If developers all use the same outcome metrics, it will be possible to compare the various products. Patients and their doctors won't be left in the dark.