The route from discovery to approval for a new investigational medicine can be long and difficult. For the U.S. Food and Drug Administration (FDA) to grant approval, there must be convincing evidence that the medicine is safe and effective. And yet the desire for certainty must be balanced with the urgent needs of people whose diseases can’t wait.
The Prescription Drug User Fee Act (PDUFA), first passed in 1992, revolutionized the way medicines are reviewed and approved in the United States, enabling life-saving treatments to more quickly reach people with devastating diseases like cancer. But just as science and patient needs continue to evolve, so must our regulatory policies. Fresh approaches are needed to capture a more complete and up-to-date picture of how new medicines can potentially help people.
To that end, PDUFA was designed to be updated every five years, and the 2017 Food and Drug Administration Reauthorization Act (FDARA) includes the latest enhancements to PDUFA that should have a big impact for people with cancer. These enhancements will build upon previous regulatory advances while maintaining the FDA’s high standard of rigorous review. The changes ahead are laudable not only for their breadth but also their focus on patient-centricity — never before has such a broad range of initiatives been undertaken at such a high level to integrate the patient voice into the development process.
To understand some of the key PDUFA updates, how they fit together and how people living with serious diseases are involved, it can be helpful to think of the route to approval as a subway map.
Surrogate Endpoints
PDUFA has always sought to balance the need for thorough evaluation of potential medicines versus the need to get new treatments to people with life-threatening conditions in a timely manner. It’s a mission that’s never really complete, and ongoing efforts include changes to the measurements (endpoints) used in clinical trials. The choice of endpoints is crucial. For example, as cancer medicines improve and more options become available, the total length of time that people survive may increase – in some cases to many years. That means it can become increasingly difficult to measure the “gold standard” endpoint of overall survival within a reasonable timespan in a clinical trial.
For these reasons, surrogate endpoints are often used to provide an earlier indication of efficacy. These are like earlier stops on the route to approval, potentially allowing medicines to reach people who need them sooner. With the new PDUFA, the FDA is redoubling its efforts, offering early consultation about the use of new surrogate endpoints as a primary basis for approval.
Rare Diseases
Rare diseases, including some types of cancer, often don’t receive the same attention as other areas when it comes to medical advances. This can occur for myriad reasons, including the difficulty of recruiting enough people for robust clinical trials. To address these unmet needs, the FDA is intensifying its focus on fostering collaborations to develop new treatments for rare diseases. Importantly, patient engagement through avenues like patient reported outcomes and open dialogue with the agency is recognized as an essential part of the process.
The FDA is also pushing to accelerate the development of treatments for pediatric cancers. Beyond PDUFA VI, FDARA includes crucial updates from the Research to Accelerate Cures and Equity (RACE) for Children Act. One of the main provisions is that investigation of new potential treatments be guided by specific disease biology rather than just copying the way a medicine is used in adults. This is an important step reflecting the scientific reality that children are not just small adults – their diseases are often biologically distinct. The legislation also ensures that pediatric investigation is included in the development of more types of cancer medicines.
Real-World Evidence
An ever-expanding variety of sources, including electronic health records (EHRs), health insurance claims, medical devices and even smartphone apps, are generating a staggering amount of data about treatments and outcomes outside of clinical trials. Yet it’s historically been very difficult to harness this information in a meaningful way. Insights gleaned from many diverse types of real-world data have the potential to further expedite the speed at which new medicines get to the people who need them. As such, a key priority in the new PDUFA is expanding the FDA’s ability to consider real-world evidence, enabling new possible connections to and from the route to approval.
Innovative Trial Design
New types of complex, innovative trial designs have the potential to make clinical development significantly more efficient, which means new medicines reach the people who need them sooner. These novel approaches can enable researchers to collect data earlier and faster, or even adjust a trial continuously based on evidence as it becomes available. Innovative trial designs can also potentially lead to new uses for existing medicines, perhaps providing new options for more people with rare diseases. This is a fairly nascent area full of possibilities. Promising approaches include use of preclinical data, earlier clinical data and new statistical methods.
Patient Voice
All of the above focus on data and methodology, laying the tracks for the route to approval. What about the people involved in clinical trials? The evidence on the route to approval has typically only included clinical measurements of efficacy and safety, not taking into account how a person feels or functions during treatment. This is changing, however, with the rise of a focus on patient-centricity. The FDA is actively encouraging systematic approaches to capturing the patient voice – as well as the experience of caregivers – and using that data to inform regulatory decisions. Measuring what matters most to patients and their caregivers in a rigorous and reliable way is a major priority for us at Genentech. We believe it’s an effort that will ultimately require input and involvement of all stakeholders, from regulatory authorities to industry to patient advocacy groups.
From its very inception, PDUFA was meant to be a living document that evolved and improved to keep pace with advances in science and medicine. Many of the latest PDUFA updates are themselves fluid and will continue to unfold over the coming months based on public workshops and input from doctors, academia, industry and advocacy groups. At Genentech, improving outcomes for patients is at the center of everything we do, and we look forward to continuing to contribute to these important efforts.