21st Century Cures Act Passes House: Could Usher In Broad Reforms to Drug Approval Process

July 13, 2015 | By

On Friday, July 10th the U.S. House voted overwhelmingly to streamline the approval process of prescription drugs and medical devices by the FDA. If passed in the Senate and signed by President Obama, the “21st Century Cures Act” (the “Act”) would foster significant regulatory changes in the introduction of new drugs to the market. The legislation passed 344-77 with strong, bipartisan support, though opponents raise concerns about the Act’s lack of assurances of patient safety.

The main focus of the 352-page Act is a reduction of bottlenecks in the regulatory process that, supporters claim, slow the development of new drugs. The Act would trim regulations by allowing for shorter clinical studies involving fewer individuals for certain kinds of drugs. It would also allow for expanded use of surrogate endpoints as evidence of the efficacy of drugs. Surrogate endpoints are biomarkers (such as blood pressure for hypertension), which are thought to predict clinical benefit, but are not outright measures of such benefit. Use of surrogate endpoints can significantly decrease the time of clinical trials. For example, instead of having to wait to learn if a drug actually extends survival for diabetic patients, the FDA could approve a drug based on evidence that it reduces hemoglobin A1C levels. The onus remains on drug makers to then prove that reductions in A1C levels lead to a longer lifespan.

If a drug that is already on the market is shown to have a new use, the Act will allow case studies to suffice as evidence of the new benefit rather than require additional clinical trials. The Act will also increase the use of patient registries and existing health care data to speed up clinical trials. These regulatory changes would be enhanced by a five-year, $8.75 billion increase in funding to the National Institutes of Health – a major financier of biomedical research in the U.S. The NIH would also host a new Cures Innovation Fund which would support breakthrough biomedical research. The Act would enhance funding to the FDA by $550 million.

The Act includes several controversial measures that are beyond a general concern for patient safety. Informed consent has been a hallmark of clinical trials since the fallout following the Tuskegee syphilis trials. Exceptions are granted only when it is impossible to obtain informed consent or when doing so is contrary to a patient’s best interest. The Act adds a measure whereby informed consent can be denied when “clinical testing poses no more than minimal risk” to the study’s participants. Further, the Act does not define who shall determine what constitutes “minimal risk.” The Act would also speed up the regulatory process for antibiotics that treat drug-resistant infections by allowing for approval based on laboratory and animal testing with smaller clinical trials and would provide financial incentives to hospitals that prescribe these antibiotics. The Act also includes a six-month extension of market exclusivity for already-approved drugs that treat rare diseases. Finally, the Act would allow the FDA to grant breakthrough status based on early stage testing, with drug makers performing clinical trials following approval of the drug.

Opponents of the Act have expressed concerns over how these reforms will compromise patient safety. They claim that a less rigorous review process could introduce the possibility of faulty drugs entering the market and that effectiveness can be proven only when there is substantial evidence from well-controlled clinical trials – not from alternative measures like surrogate endpoints. Opponents recall that regulatory fast tracking has been traditionally reserved for only urgent circumstances where no other reasonable clinical alternative exists, and that this Act turns the exception into the rule.

It has been a longtime statutory requirement for drugs to be proven safe and effective before entering the U.S. market. Some believe that the reforms in the Act are a departure from decades of regulation that guarantee safety and efficacy through a sometimes burdensome and lengthy regulatory process; however, this is by no means the first time that Congress has acted to speed up the drug approval process.

In 1950, over half of medications in common use in the U.S. had been unknown a decade earlier, according to Siddhartha Mukherjee, author of The Emperor of All Maladies: A Biography of Cancer. That rate of growth slowed tremendously following a 1962 scare in Europe when pregnant women were prescribed Thalidomide which led to birth defects. The Kefauver-Harris Amendments were passed which made proof of efficacy and rigorous clinical trials explicit requirements for approval of new drugs by the FDA. These new regulations significantly increased R&D costs to pharmaceutical companies, which soon stopped developing drugs to treat rare diseases, as the new regulations made such drugs unprofitable. Congress responded by passing the Orphan Drug Act in 1983 which introduced market exclusivity periods (aka “patent protection”) for drugs treating rare diseases to allow for a return on pharmaceutical R&D investments before other drug makers could compete. The HIV/AIDS epidemic fostered in a series of reforms aimed at speeding up the regulatory process. A fast track designation was approved in 1988 for drugs treating serious or life-threatening illnesses for which there were no approved treatments and unmet need. Congress again acted in 1992 to introduce priority review, which shortened the review process to six months for drugs that hold a promise of significant improvement over existing therapies for serious or life-threatening illnesses. That same year, accelerated approval regulations were introduced which allowed for the use of surrogate endpoints as evidence of drug efficacy for drugs treating serious conditions that filled an unmet need. The FDA Modernization Act was passed in 1997 which codified many of these regulatory designations and also cleared a path for a single clinical investigation for some drugs which previously were required to go through multiple phases. Finally, in 2012, Congress passed a breakthrough therapy designation, which expedited the approval process for drugs which demonstrate preliminary clinical evidence of substantial improvement over existing therapies.

In some ways, the Act represents a paradigm shift in our thinking about the drug approval process. Unlike the reforms introduced in past decades, we are now entering an age of electronic medical records and health information exchanges, which provide unprecedented opportunity to use biometric data to capture the impact of new drugs and devices and share that data with researchers, providers, and patients. The traditional large scale clinical trial, which has been the anchor of an often burdensome, lengthy regulatory process, is now supplemented by our ability to see data in new ways which can shorten and strengthen that process. This has the potential to reduce the cost and quicken the pace of clinical trials, providing Americans with faster access to new therapies.

Reforms to the drug approval process represent a societal tradeoff between the risk of serious, adverse consequences following the introduction of a faulty drug and improvements in the quality or length of life for those who need new drug therapies. Stated in the form of a question, can we quantify how many quality-of-life-years we are willing to sacrifice in order to prove that a new drug is safe and effective? Any delay in the introduction of a new drug represents our tolerance for loss of life just as much as allowing the introduction of drugs which may not meet traditional thresholds of proven efficacy. Patients die while waiting for drugs to be approved. However, there is a major difference between statistical, unidentifiable persons who could have been helped and identifiable persons who died or suffered as a result of faulty drugs.

When the disease in question is infectious and we are all at risk, our societal tolerance for uncertainty of drug safety rises. This is illustrated in both the HIV/AIDs epidemic of the 1980s and 1990s as well as in the Ebola outbreak of 2014 when ZMapp was approved on an experimental basis with no clinical evidence of its effectiveness. However, in times between outbreaks, we tend to hold a lower tolerance for the risk of an unproven drug entering the marketplace. Examples abound of Congressional hearings following the discovery of inefficacy of drugs.

The Act will now go to the Senate, where revisions are likely. President Obama has expressed concerns and has not been a vocal supporter of the Act, although its strong bipartisan support, if continued through the Senate, would make a veto improbable.

Author: Brandon Danz, M.H.A., M.P.A. is a former Special Advisor to the Secretary of the Pennsylvania Department of Human Services. He is a graduate of the Master of Health Administration program at Penn State University with a focus on health care policy development and cost containment, and graduate of the Master of Public Administration program at Shippensburg University of Pennsylvania. Danz can be reached at bwdanz@gmail.com.