The obstacles to developing and getting a new drug to market are daunting. The process can take upwards of a decade, and in 2014 was estimated on average to cost $2.55 billion. It’s likely to be significantly more now.
Because those time and cost barriers can spell the difference between life and death for patients suffering from diseases without good therapeutic options, the FDA’s “accelerated approval” regulatory pathway is critically important. This “quick-on, quick-off the market” mechanism for medicines to reach the marketplace can work to the advantage of drug companies and desperate patients alike.
Introduced in 1992 and modified in 2012, accelerated approval allows the FDA to base approval of drugs for “serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.” In other words, marketing approval can be based on clinical trials that do not yet show an improvement of a definitive endpoint such as increased longevity, reduction in the incidence of heart attacks or healing of an infection.
A “surrogate endpoint” is a marker of some kind — a laboratory test, radiographic image, physical sign or other finding — thought to correlate with definitive clinical benefit. Examples include the lowering of blood pressure or improvement in a laboratory value such as “good” cholesterol. Similarly, an intermediate endpoint is “a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug,” such as the shrinkage of a tumor.
After accelerated approval, the drug sponsor (company) must perform confirmatory trials to prove that the medicine is effective in meeting a definitive clinical endpoint, at which time the approval is converted to a standard, unconditional approval. If the studies fail to provide such confirmation, the FDA can pull the drug from the market.
The vast majority of drugs marketed after accelerated approval are found in subsequent studies to be safe and effective. And given that only medicines for serious conditions that address an unmet medical need are eligible for this pathway, accelerated approval offers significant benefits to patients by making important medicines available far earlier than would otherwise have been the case.
A journal article (G. Raghu et al; doi:10.1001/jama.2018.6129) by a large multinational team that reported a mid-stage (Phase 2 of the usual three) clinical trial of human pentraxin 2, a new drug for a serious lung disease called idiopathic pulmonary fibrosis (IPF), illustrates that the issues surrounding accelerated approval are not always straightforward.
IPF is marked by scarring, or fibrosis, of the lungs, the cause of which is unknown. Over time, the scarring gets worse and it becomes hard to take in deep breaths and the lungs cannot take in and transfer enough oxygen to the bloodstream.
During the past few years, the FDA has approved two other drugs on the basis of clinical data showing that they slowed the rate of deterioration of a surrogate endpoint — measurement of forced vital capacity (FVC) — the largest amount of air that a person can blow out after taking in the biggest breath possible. But neither of them convincingly enhances survival or quality of life.
The Raghu et al clinical trial, which involved 117 patients and compared pentraxin 2 to a placebo, found that the drug was superior in two ways: the rate of deterioration in FVC was slowed, and there was a marked effect on how far a patient could walk in six minutes: The distance achieved by patients in the drug-treatment group decreased less than two feet during the 24 weeks of the study, while the distance patients in the placebo group could walk decreased an average of 104.3 feet.
The improvement over placebo of these two endpoints — FVC and the six-minute walk – for a serious disease without good therapeutic alternatives would seem to make pentraxin 2 a good candidate for accelerated approval.
Even in the absence of definitive evidence of prolonged survival, the drug could make a big difference to the retention of lung function and mobility of the roughly 100,000 Americans who suffer from IPF. So, why not grant accelerated approval for pentraxin 2 now?
Henry I. Miller, a physician and molecular biologist, is a Senior Fellow at the Pacific Research Institute. He was an FDA medical reviewer and the founding director of the Agency’s Office of Biotechnology. Follow him on Twitter @henryimiller
A version of this article was originally published on Pundicity’s website as “FDA’s ‘Accelerated Approvals’ Are Critical But Raise Thorny Issues” and has been republished here with permission.