US 21st Century Cures bill vaults second hurdle

A new bill aimed at promoting and speeding up the development of drugs has sailed through the House of Representatives in the US, despite concerns that it could compromise the FDA's oversight of new applications.

The broad-ranging proposals in the 21st Century Cures Act (HR 6) had already been cleared in committee and passed by a vote of 344 to 77 in the House with broad support from both Republicans and Democrats.

The bipartisan support was helped by a welcome 3 percent increase to the $30 billion annual budget of the National Institutes of Health (NIH) - after years of stagnation - as well as $1.75bn per year over five years for an NIH Innovation Fund that will foot the bill for special projects agreed by Congress and investment in young scientists.

Meanwhile, the FDA would get another $110m a year over five years under the proposals to make sure that the special projects do not get impeded by budgetary constraints at the agency.

The investment in research is designed to overcome a steep decline in the funding power of the NIH, which provided money to one in three applications 12 years ago but can now cover just one in six, according to comments made by a representative of the American Association of Medical Colleges (AAMC) in this NPR post.

While the top-line message on medical research has helped garner cross-party support, other elements of the bill are raising eyebrows.

Complicating the picture is the detail in HR 6, including tweaks to the FDA's role that could have significant consequences on both the development of new drugs and medical devices as well as the way they are reviewed and regulated.

An overarching theme is the need to accelerate approval of new therapies, through the adoption of non-traditional study designs such as adaptive trials observational studies and patient registries - as well as the use of new statistical methods - and by allowing some products to be approved on the back of shorter, smaller trials.

The bill would encourage the FDA to accept applications based on biomarkers and other surrogate endpoints, promote screening of patients based on their genetic profiles and introduce a 'patient-centric' review process at the agency. It would also introduce a truncated clinical development and approval process for new antibiotics and antifungals as well as therapies for rare diseases.

These are all great reforms, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), which says the bill will "help to enhance the FDA's ability to adapt to cutting edge technologies utilised by America's biopharmaceutical companies to bring new medicines to patients and their healthcare professionals".

Dissenting voices

Not all are happy with the proposals. In May - shortly after the House Committee on Energy and Commerce unanimously voted HR 6 through - an editorial by Jerry Avorn and Aaron Kesselheim in the New England Journal of Medicine (NEJM) warned that the changes could "bring back some of the problems we thought we had left behind in the 20th century."

The FDA is already one of the most efficient regulators in the world at approving new therapies, they argue, but the current regulatory review process already has problems with a third of new products given the nod after just on randomised clinical trial and more than two-thirds cleared with studies of six months or less " a potential problem for medications designed to be taken for a lifetime."

They are concerned that increased use of adaptive trials and evidence based on clinical experience will not be worthy substitutes for clinical trials, noting that "there is considerable evidence that these approaches are not as rigorous or valid as randomised trials in assessing efficacy."

The increased reliance of biomarkers could also introduce problems, they write, pointing out that surrogate endpoints are already used in about half of new drug approvals. These may not always be reliable predictors of clinical efficacy, they add, giving the example of Roche's Avastin (bevacizumab) which delayed tumour progression in advanced breast cancer but was shown not to benefit patients.

Meanwhile Avorn and Kesselheim are also worried about the fast-track for new antimicrobials, saying that plans to add disclaimers on their labels provides "no evidence that such a precaution would restrict prescribing to only the most appropriate patients."

They conclude that "political forces have also introduced other provisions that could lead to the approval of drugs and devices that are less safe or effective than existing criteria would permit."

Meanwhile, medical charity Breast Cancer Action has also voiced its concerns about HR 6, with executive director Karuna Jaggar writing in a blog post that the bill is a give-away to pharma and biotech that threatens to reduce standards of safety and efficacy necessary to protect patients."

Lowering standards for safety and efficacy will not speed up innovation, and instead threatens to lower the quality of treatments that come to market, she asserts.

Over to the Senate

While HR 6 has wide support in the House, it is still a long way from becoming law. The US Senate is currently drawing up its own bill - with a first draft expected before the end of the year - and only once that is agreed the process of trying to converge HR 6 with the Senate text can start to occur.

Even if a consensus text can be agreed, it would still need to be approved by both houses and signed by President Obama before it can pass into law.