REGULATORY PERSPECTIVES FROM THE UNITED STATES

Robert Califf, Commissioner of Food and Drugs at the FDA, said that within the FDA, there is a shared view that the best medical outcomes occur when doctors and other health care providers and patients are armed with high- quality evidence to support what they do, and this is most likely to happen when the clinical trials and observational studies are actually done in practice. The FDA is tasked with providing instructions in the label on how to use the product in practice, not in theory, said Califf, so making an extrapolation from a rarified clinical trial to real practice does not make much sense. He acknowledged, however, the difficulty of collecting data from real-world situations, which has led to a “parallel universe” of data collected specifically for clinical trials. In addition, there is a disconnect between the instructions for use provided in the product label and actual use in clinical practice, such that, according to a recent study in Canada, more than 25 percent of drugs prescribed for CNS conditions were for “off-label” uses, and 21 percent were off label with no credible evidence of the drug's effectiveness for that condition (Eguale et al., 2016). For some CNS drugs, including clonazepam¹ and amitriptyline,² more than 70 percent of use was off-label. Interestingly, the adverse event rate for drugs used off label was twice as high as for drugs used on label, but when considering only drugs used off label but with good evidence of effectiveness, the rate was the same as the on-label rate.

Califf offered a glimpse at what he thinks the system might look like. It begins with good proof-of-concept studies, which lead to representative clinical trials. The best knowledge from those trials is then used to craft clinical practice guidelines and performance measures. When what happens in practice deviates from what was expected, revisions may be needed in the clinical trials process. Underlying all of these steps, said Califf, is measurement and education both in the clinical trials arena and in clinical practice, which he described as a learning health care system (see Figure 5-1).

FIGURE 5-1

Learning health care system. SOURCES: Presented by Robert Califf at the Workshop on Neuroscience Trials of the Future, March 4, 2016. From Annals of Internal Medicine, Greene, S. M., R. J. Reid, and E. B. Larson. Implementing the learning health system: (more...)

Califf also addressed concerns about sustainability, citing a recent study showing that the cost of clinical trials is rising twice as fast as the rest of the American economy (Berndt and Cockburn, 2014). He noted that the driver of this unsustainable growth in the cost of conducting clinical trials is complexity, which also drives a reduction in the number of people who enroll in trials—a trend that is worsening in the United States and is leading to increased inefficiency. His FDA colleagues in the CNS space reiterated many suggestions raised throughout the workshop, to include the need to simplify and enroll relevant, not rarified, populations; make trials more inclusive; stop the collection of non-serious adverse events for every patient; reduce the number of clinic visits required for research studies; and invest in technologies that provide the clearest answers to critical questions.

The FDA continues to optimize trial design approaches to achieve its goals, according to Peña. CDRH uses a risk-based approach, requiring increased oversight for products deemed to present a greater possible risk. The drug and biologic divisions of the FDA, CDER, and the Center for Biologics Evaluation and Research (CBER) use similar approaches. The FDA has published numerous guidance documents to clarify the considerations that should be taken into account by sponsors through the approval process, beginning with presubmissions. They also strongly encourage sponsors to initiate dialog with them at the earliest stages, so that the agency can provide feedback and suggestions on the anticipated designs before a study is initiated and data collection has begun.

REGULATORY PERSPECTIVES FROM ITALY

Luca Pani, director general of the Italian Medicines Agency (AIFA), also addressed sustainability. Because AIFA functions as a regulatory, payer, and HTA institution, it must grapple with all its roles to achieve better outcomes and controlling costs, he said. Sustainability and real-world effectiveness are thus central tenets of the Italian regulatory system. To meet these challenges, AIFA has invested more than €22 million (about $25 million) in information technology and the development of drug-product monitoring registries in the past 5 years. Given the importance of the investments made in this space, the National Health Service Information Technology Law was passed in Italy in 2012. It mandated the implementation of Web-based registries after marketing authorization to measure drug safety and effectiveness for approved therapeutic indications and some selected off-label uses (Montilla et al., 2015). As of February 2016, data from 850,000 patients have been captured by the registries.

A second key aspect of the AIFA system that addresses sustainability is pricing and reimbursement, said Pani. He described a range of possible reimbursement outcomes that await Market Authorization Holder who seek registration by AIFA, ranging from a refusal to reimburse, reimbursement without particular conditions, reimbursement with a control on prescription (adherence to an optimized therapeutic plan) to a Managed Entry Agreement (MEA). MEAs are a heterogeneous group of instruments that are being increasingly implemented to guarantee sustainability of innovative and expensive medicines. MEAs can be purely financial based (price/volume agreements) or health-outcome based (Ferrario and Kanavos, 2015). Most frequently a combination of the two may be applied. For example, AIFA has signed contracts with pharmaceutical companies that set payment based on treatment effectiveness (performance-based risk sharing agreements), with companies refunding costs if the medication fails, said Pani.

Pani described how the AIFA strategy was applied to the approval of new treatments for hepatitis C (HCV), which are highly effective, but extremely expensive. Like the United States, Italy has a high incidence of HCV, and the cost of treating them all would be prohibitive. Thus, AIFA created a permanent national working group to develop a strategy for providing HCV drugs. After developing seven prioritization criteria that would provide the drug to patients with the greatest clinical need, AIFA used data from their registries to calculate the total number of treatments needed, and thus to negotiate a price/volume discount with the manufacturer.

AIFA also used earlier versions of the registries to determine how best to use new diabetes therapies (incretins) most effectively. In 2008, they approved the reimbursement of three drugs—exenatide, sitagliptin, and vildagliptin—in which patients were subject to enrollment in the real-world data. Data from the post-marketing registry revealed substantial off-label use, little adherence, as well as inconsistent effectiveness. However, the data also showed that when used appropriately in combination with exercise, the effectiveness of the drugs was consistent with the results seen in the registration trials (Montilla et al., 2014).

In the area of psychiatry, AIFA used the national drug utilization database (Osmed Health-DB) to study treatment-resistant depression. They developed an antidepressant usage index, which revealed that the higher the degree of “resistance” along a continuum, the higher the cost of both depression-related and depression-unrelated resources for the National Health System, said Pani.

POTENTIAL REGULATORY IMPLICATIONS FOR CLINICAL RESEARCH INNOVATIONS

Recognizing the inefficiencies of the historical model of clinical research, where a single coordinating center manages a trial with top-down decision making with independently operated sites, Califf proposed a different model of interoperable networks that share sites and data. Integrating clinical research networks not only ensures more efficient trials, but also enables patients, physicians, and scientists to form true “communities of research.”

Indeed, such systems are already being built. The FDA's Sentinel Initiative,³ launched in 2008, is a national electronic system that will enable postmarket safety monitoring of FDA-approved drugs by providing access to claims data from more than 100 million people. Linked to Sentinel is the National Institutes of Health (NIH) Health Care Systems Research Collaboratory,⁴ which has initiated 10 demonstration projects spanning 12 NIH institutes and centers to reduce the cost of clinical trials by capturing electronic health record data. Another network, the National Patient-Centered Clinical Research Network (PCORnet),⁵ brings patients into the process as full partners. With the support of user fees from the Prescription Drug User Fee Act (PDUFA), a national evidence generation system is being built to combine data from different networks through collaborations with industry, academia, and integrated health systems.

The culmination of all of this, said Califf, is the Precision Medicine Initiative.⁶ The FDA is integrally involved in this NIH-led effort to get volunteers to participate in research as a normal part of their patient care. He noted that this initiative was fueled by a recognition by the U.S. President and Vice President that what is holding the country back from exploiting the computational power currently available is culture, not technology, which has resulted in people hoarding rather than sharing data.