Between 2005 and 2011, nearly half of all new drug formulations in the US were approved without companies having to demonstrate a tangible benefit, such as relieving disease symptoms, extending life, or improving someone’s ability to go about normal activities.

What patients really want is evidence that the drug they are taking will actually improve their condition. But the FDA, the American drug regulator, doesn’t routinely consider this for new molecular entities (NMEs) – drugs that have innovative chemical structures that have never been marketed before.

The findings come in a new paper by Nicholas Downing of Yale University and colleagues, part of a series on the drug approval process published in the Journal of the American Medical Association (JAMA), that found there was wide variation in the quality of evidence considered by the FDA. They also found that nearly two out of five drugs approved by the FDA was brought to market after a single pivotal trial.

A second paper in the series documented the lack of data required by the FDA when it considers approvals for medical devices – the study found that only 14% of high-risk medical devices, such as pacemakers and other cardiovascular implants, were assessed in one randomised control trial.

Both studies strongly suggest that the FDA is approving products that may not have accurate risk-benefit profiles, which could place patients at risk.

Sleeping watchdog?

While patients and physicians rely on the FDA to serve as an appropriate gatekeeper and watchdog, opinion polls reveal the public is misinformed as to what the FDA seal of approval actually means. For example, a national randomised trial conducted in 2011 found that 39% of US adults believe the FDA approves only “extremely effective” drugs, and 25% believe the agency only approves drugs that do not have serious side effects.

In addition to debunking these commonly held myths, the Downing paper is part of a long line of comprehensive studies that have highlighted the limitations of the FDA’s review process for new drugs before they hit the market.

Because pre-market studies are limited in duration and scope, they often fail to capture later adverse events, or adverse effects that only happen to a small percentage or sub-population of patients. At the same time, pre-market studies often include research subjects who are not representative of “real-world” patients. For example, studies typically don’t include patients who are taking multiple medications.

The findings also affirm what commentators and FDA Commissioners have long argued – that the FDA should take a more proactive role in reviewing drugs and medical devices once they hit the market, to make sure adverse events are logged and considered.

No one wants an approval process that drags on for a long time. So when it comes to catching later problems, the only meaningful alternative is to require that drug and medical device manufacturers actively review post-market data and report their findings to the FDA – something that needs manufacturers to actively engage with.

Inside the FDA

Since the 1960s, the total number of drugs approved has been falling on average, according to data collated by The Conversation. This is happening at the same time as the cost of research and development is going up. In another study in the JAMA series, six FDA scientists looked at the reasons why approvals for drugs might be delayed or denied. According to the paper, between 2000 and 2012 a half of NMEs were approved when first submitted to the agency and nearly 75% were ultimately approved. Some of the reasons why new compounds failed to earn FDA approval included inadequate performance and problems with doses.

It’s a hugely important paper because information from the FDA on why drugs aren’t approved is limited, due to data sharing issues (despite recommendations from its own transparency taskforce).

The study is sure to provide meaningful guidance to pharmaceutical companies as they contemplate, prepare or conduct pre-market studies. At the same time, however, the article raises complex questions as to the proper role of the FDA as regulator, industry collaborator, and promoter of public health. In many respects the FDA and industry are collaborators – industry’s responses to new regulations are taken seriously by the agency, and lobby groups have long had significant influence over the legislation that sets the legal limits of FDA’s authority. Yet, the agency’s primary mission is to ensure that marketed products are safe and effective, though the FDA characterises itself as a public health agency that must “promote health, prevent illness, and prolong life”.

As Marcia Angell, former editor of the New England Journal of Medicine, has observed, “there is growing evidence that … [the FDA] has become the servant of the industry it regulates.”

Taken together, the articles support calls for the FDA to be more robust in the surveillance of marketed drugs and medical products. Simply stated, we need to know if the products we are using actually work. As the Downing study shows, the FDA’s pre-market review process isn’t clear on this and the public remain none the wiser.

Related: Why there may be fewer truly new drugs hitting the market