National Academies Press: OpenBook

Neuroscience Trials of the Future: Proceedings of a Workshop (2016)

Chapter: 5 The Regulatory Landscape: International Opportunities and Challenges

« Previous: 4 Transforming Clinical Trials with Technology
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

5

The Regulatory Landscape: International Opportunities and Challenges

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

Many of the challenges raised in the previous chapters with regard to integrating novel tools, trial designs, and statistical approaches into neuroscience trials have regulatory implications. Regulatory agencies around the world have developed strategies to keep pace with the evolving product development in the context of each country’s particular political, legal, economic, social, cultural climate. Yet despite their geopolitical differences, the goals of these countries remain essentially the same. As articulated by Carlos Peña, director of the Division of Neurological and Physical Medicine Devices in the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health (CDRH), one central goal is to optimize trial design approaches to get products to patients who desperately need them while ensuring that these products undergo appropriate evaluation for safety and effectiveness.

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.

___________________

1 Clonazepam is used to treat seizures and panic disorder.

2 Amitriptyline is a tricyclic antidepressant used to treat symptoms of depression.

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

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).

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

Image
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: From concept to action, 157, 3, 207–210. Copyright © [2012] American College of Physicians. All Rights Reserved. Reprinted with permission of American College of Physicians, Inc.
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

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

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

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.

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

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.

___________________

3 For more information, go to http://www.fda.gov/Safety/FDAsSentine/Initiative/ucm2007250.htm (accessed June 3, 2016).

4 For more information, go to https://www.nihcollaboratory.org/about-us/Pages/default.aspx (accessed June 3, 2016).

5 For more information, go to http://www.pcornet.org (accessed June 3, 2016).

6 For more information, go to https://www.whitehouse.gov/precision-medicine (accessed June 3, 2016).

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

Encouraging Data Sharing

A potential roadblock to these efforts is the privacy protections on data, particularly mental health data, noted Robert Bilder. Califf said the expert community and patients would need to push for solutions that enable data sharing with appropriate protections. In Italy, said Pani, there has been a push for sharing data from control arms (which is often the standard-of-care treatment) in clinical trials; in the United States, the FDA is close to publishing the Final Rule for www.ClinicalTrials.gov, which will require sponsors to share results from clinical trials or potentially face fines of up to $10,000 per day, according to Califf. While several potential barriers exist to sharing clinical trial data, several participants acknowledged the many benefits. For example, sharing clinical trial data

  • “has great potential to accelerate scientific progress and ultimately improve public health by generating better evidence on the safety and effectiveness of therapies for patients;
  • increases patients’ contributions to generalizable knowledge about human health by potentially facilitating additional findings beyond the original, prespecified clinical trial outcomes;
  • could provide a more comprehensive picture of the benefits and risks of an intervention and allow health care professionals and patients to make more informed decisions about clinical care; and
  • could potentially improve public health and patient outcomes, reduce the incidence of adverse effects from therapies, and decrease expenditures for medical interventions that are ineffective or less effective than alternatives” (IOM, 2015, pp. 31–32).

No company has the power (or desire) to implement universal data sharing by itself; it will more likely come from legislation, said Pani. Other possible solutions include having the FDA serve as an honest broker to manage shared data, or forming a consortium that hosts a clinical data repository. A model for this in Europe could be the Innovative Medicines Initiative (IMI) called Novel Methods leading to NEWMEDS,7 an international public‒private partnership that encourages data sharing

___________________

7 For more information, go to http://www.newmeds-europe.com (accessed June 3, 2016).

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

from companies and investigators with the goal of identifying new methods for drug development for depression and schizophrenia. Califf said ECG data were shared in this way years ago, after overcoming legal hurdles. This resulted in a much better understanding of cardiac events associated with prolonged QT interval8 issues. Califf added that part of the solution has to be a firewall and an audit trail to protect data that are contributed to such initiatives.

A New Regulatory Framework for Combining Passive and Experiential Data

In 1962, the U.S. Congress passed the Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetics Act, for the first time requiring trials to demonstrate substantial evidence of effectiveness prior to market approval. With the passage of the Orphan Drug Act in 1983, the FDA recognized the need for a different regulatory framework around rare disease entities. Since then, the identification of specific genetic mutations that could predict prognosis or response to the therapy, as well as the emergence of the Internet and the digital revolution, have highlighted the need for a new regulatory framework appropriate for the 21st century, according to Karl Kieburtz.

Thomas Laughren cited some of the 21st century approaches that present challenges to be addressed in this new framework:

  • Incorporating novel designs and methods into clinical studies, and how sponsors can gain regulatory guidance on the adoption of new methodologies in a drug development program;
  • Using the Internet and social media for patient recruitment and assessment;
  • Conducting trials at geographically dispersed sites; and
  • Incorporating more clinically meaningful endpoints into trials.

Pani added that the shifting classification boundaries for therapeutics present a challenge for regulators with respect to considerations of both efficacy and safety. A drug may first be developed for the treatment of psoriasis, for example, and then be used to treat arthritis, Crohn’s dis-

___________________

8 The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. A long QT interval is a risk factor for sudden death, while a short QT interval indicates a genetic condition (http://www.tga.gov.au/file/1140/download, accessed June 23, 2016).

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

ease, or even cancer, said Pani. In addition, particularly for precision medicine but for other drugs in development as well, variability in response needs to be better understood. Thus, rather than striving for homogeneity in clinical trials to reduce variability, it may be more advantageous to enroll very large heterogeneous populations and then use analytics to discover commonalities and differences. However, the enrollment of large heterogeneous populations in the RCTs is the opposite approach of the adaptive pathway, said Pani. He added that enrolling large population from an academic point of view is acceptable, but on the other hand, is very expensive and it may delay the access of new drugs.

As the range of treatment targets expands, there will be an increasing need for collaboration among regulators, other governmental agencies, and the research community, added Tiffany Farchione.

Drug Product Registries

Registries are an enormously useful source of information that could generate many hypotheses that might lead to randomized trials, according to Laughren. For example, a registry was required for the clozapine9 registration trials, which enabled generating data regarding the hazard curve for the potentially fatal adverse event agranulocytosis, in which the level of white blood cells called neutrophils drops to dangerous levels, causing suppression of the immune system (Alvir et al., 1993). It also suggested that clozapine reduced suicides in patients with schizophrenia.

Italy also has established registries for many medications, including the treatment-resistant depression registry mentioned earlier. These registries provide information about the effectiveness and safety of a treatment. In addition, because registries collect fairly rigorous data, they are an ideal place to embed randomization, said Califf. For example, Sweden is doing a series of registry trials where everyone gets randomized as part of routine care. As a result, they were able to conduct a trial of a thrombectomy device, which removes a clot from a blood vessel, for a tiny fraction of what it would have cost to run such a trial in the United States. Randomization with real-world data is done every day in the business world, but has encountered roadblocks in medicine, said Pani.

However, Laughren cautioned that many registries that have been set up are failing to generate useful data because they were poorly designed. Italy has addressed this by requiring that registry databases meet International Organization for Standardization standards and by continuously

___________________

9 Clozapine is an atypical antipsychotic agent.

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×

and randomly checking the data, according to Pani. One challenge is the quality of data; the data must be well structured but the quality may depend by other factors, he added. Califf commented that there are excellent models in the United States, such as one developed by the Society of Thoracic Surgeons, where data are checked and audited. They were designed that way because surgeons realized they would not be reimbursed unless they produced reliable outcome data. Several health systems are investing heavily in integrated data warehouses; there are also efforts to enable these data warehouses to communicate with each other while retaining local control.

Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 43
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 44
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 45
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 46
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 47
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 48
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 49
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 50
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 51
Suggested Citation:"5 The Regulatory Landscape: International Opportunities and Challenges." National Academies of Sciences, Engineering, and Medicine. 2016. Neuroscience Trials of the Future: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502.
×
Page 52
Next: 6 Ethical Considerations »
Neuroscience Trials of the Future: Proceedings of a Workshop Get This Book
×
Buy Paperback | $46.00 Buy Ebook | $36.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

On March 3-4, 2016, the National Academies of Sciences, Engineering, and Medicine’s Forum on Neuroscience and Nervous System Disorders held a workshop in Washington, DC, bringing together key stakeholders to discuss opportunities for improving the integrity, efficiency, and validity of clinical trials for nervous system disorders. Participants in the workshop represented a range of diverse perspectives, including individuals not normally associated with traditional clinical trials. The purpose of this workshop was to generate discussion about not only what is feasible now, but what may be possible with the implementation of cutting-edge technologies in the future.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!