Currently, FDA approval is pretty much an all-or-nothing deal. Drugs are approved for specific indications, of course. But once a drug is approved, if a patient can find a way to pay for it, with rare exceptions any doctor can prescribe it off-label for any reason.
But not everybody thinks that's the best way to license drugs.
The current system, political science expert Kenneth Oye told BioWorld Insight, has several problems. For one, "the information you have when you make the licensing decision is not necessarily the best predictor of safety, efficacy or effectiveness."
The reason is that randomized, controlled trials use what he termed "cleansed" patient populations – that is, enrollment criteria that keep certain patients from participating. But "in cleansing the patient population, you're also taking out a lot of the factors that affect safety and efficacy, as well as compliance," once an approved drug is being used in the general population.
For another, the current system encourages patients to think of safety and efficacy as an all-or-none phenomenon: That the reality is more complex is no secret to anyone in the biopharmaceutical industry. But to many patients, if a drug is approved, that implies it is safe and will work, with little to no attention paid to the caveats.
In the Feb. 15, 2012, online issue of Clinical Pharmacology & Therapeutics, Oye, who holds a joint appointment in Political Science and Engineering Systems and directs the Program on Emerging Technologies at the Massachusetts Institute of Technology, suggests adaptive licensing as a possible alternative. His collaborators on the paper represent an extremely broad range of like-minded luminaries from academia, industry and regulatory agencies.
Adaptive licensing would work differently for different classes of drugs. But basically, the idea is to approve drugs bit by bit.
Initial approval would be faster than under the current system, but in addition to being restricted to certain patient groups, prescribing privileges would also be restricted, to make sure that only those patients who are most likely to benefit from a drug actually receive it. Observational data from those initial patients, as well as further randomized controlled trials where appropriate, would then be used to slowly expand a drug's domain as appropriate.
Adaptive licensing is sometimes also called progressive approval. The Biotechnology Industry Organization had proposed a progressive approval path in 2011, though the trade group is now pushing for widening the existing accelerated approval path instead of creating a new one. (See BioWorld Today, Jan. 24, 2012.)
Oye noted that his team's paper is not meant to be a call to reform at this instant. "We want to be careful," he said. "We are offering a set of ideas that are worth considering. At the same time, we've specified areas of uncertainty . . . the article could have been punchier if we'd left out all the caveats and asterisks. But we didn't want to run ahead of the data."
In their paper, Oye and his colleagues described how adaptive licensing might work in five different scenarios. Those scenarios include adaptive licensing based on small sample sizes, as for rare diseases, surrogate endpoints such as biomarkers in cancer, and others. Oye said that whether drug development would be cheaper or more expensive under adaptive licensing than the current regulatory system would likely depend on the indication.
One area where adaptive licensing could improve efficiency in the approval process is drugs for chronic conditions such as obesity. There is an undisputed need for drugs for chronic conditions. But since they are not immediately life-threatening, safety concerns are greater than for acute diseases. And this leaves the approval process in a bind: Such safety concerns are clearly legitimate, but at the same time, "how long do you want to hold up the approval process?"
The area where adaptive licensing might get traction most easily, however, is oncology. For one thing, accelerated approval, like adaptive licensing, is based on the idea that for some patients, higher-than-average risk is an acceptable tradeoff for the potential benefits to them.
For another, many of the most promising results in cancer treatments are being achieved through the use of combination treatments – which can quickly turn randomized controlled trials into huge productions. An observational approach, Oye said, might be "particularly suited" to identifying promising drug combinations. In fact, he argued, currently such combination treatments "are often developed by physicians who are, in effect, experimenting."
On the implementation side, whether physicians and patients would be willing to refrain from prescribing, or taking, partially licensed drugs is an open question. "Physicians like maximum freedom. And so do patients, actually," Oye acknowledged.
One possibility is to back up prescribing limitations with a legal requirement. And even if prescribing restraints end up being closer to an honors system, here, too, switching to adaptive licensing might not so much create new problems as expose already existing ones.
"As you know, right now, lots and lots of people go against medical advice," Oye said. "And in fact, if they fully understand the risks . . . maybe that should be their call."