Several speakers throughout the workshop looked to the future, focusing on approaches and lessons learned that could be applied to improve and speed the development of treatments for prevalent chronic diseases. Michelle Rohrer, global head of product development regulatory and policy at Roche, provided an industry perspective, offering a suite of suggestions to foster more innovative trial design and better incorporate patient input. Joseph Menetski, associate vice president of research partnerships at the Foundation for NIH, spoke about ways the foundation is helping to open up new possibilities for understanding and treating prevalent chronic diseases. Chronis Manolis, senior vice president of pharmacy at the University of Pittsburgh Medical Center (UPMC) Health Plan, discussed examples of success in innovative treatments for chronic diseases and how changes in reimbursement policies could encourage more innovation. James Smith, deputy director in the Division of Clinical Policy and Office of New Drugs at the Center for Drug Evaluation and Research at FDA, discussed some of the regulatory considerations and laid out a few opportunities for innovative trial design and data collection.
Rohrer spoke from an industry perspective. Despite the availability of many promising innovations, clinical trials are currently taking longer and are more expensive to carry out than previously. A recent calculation indicated that new molecular entities cost an average of $2.6 billion to bring
to market, and the average success rate for developing new drug treatments is less than 12 percent (DiMasi et al., 2016).
Specifically, she described a few challenge areas that will be of particular importance in developing treatments for prevalent chronic diseases in the future:
- Trials are growing more complicated, with more procedures and more endpoints, with data from the Tufts Center for the Study of Drug Development indicating that between 2005 and 2020, the average number of data points for a phase III trial grew from 494,000 to 3.56 million (Tufts Center for the Study of Drug Development, 2021).
- There is a lack of investment in chronic diseases other than cancer. While there have been growing numbers of initial public offerings (IPOs) in the biopharmaceutical area, Rohrer said, and a record number—more than 100—of such companies went public in 2020, a large percentage of those IPOs were in the area of cancer, with relatively little investment in other chronic diseases.
- Although progress has been made toward community outreach and engagement with minority populations when recruiting for clinical trials, mistrust of the medical research community remains an ongoing barrier to carrying out clinical trials that include representative populations.
Turning from challenges, Rohrer then spoke of opportunities for research and development in the area of prevalent chronic diseases. The current environment is promising, she said, given that there is more investment in the biopharmaceutical industry than ever, even if not enough of that investment has yet been channeled toward prevalent chronic diseases. Furthermore, advances in digital health technology are opening up many opportunities. “There has never been a time when technology can so complement the therapeutic space,” she said, mentioning as an example the stride velocity ankle bracelet, which is currently being validated to replace the burdensome 6-minute walk test. Additionally, the regulatory environment is more mature than ever before. More countries are joining the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use,1 she said, “and we have regulatory flexibility that can also maintain high standards of quality, safety, and efficacy.” The rapid response to the COVID-19 pandemic has provided an opportunity to implement new paradigms for drug R&D that can help bring treatments to patients faster.
With those opportunities in mind, Rohrer discussed five specific areas that she suggested will be important for more effectively dealing with prevalent chronic diseases:
- Collaborative investment in technology and biopharmaceuticals should be targeted for the treatment of prevalent chronic diseases.
- There should be focused research programs to address the early stages of chronic diseases to support therapeutics for disease prevention and the slowing of disease progression. “Treating early is cost effective and has high impact on patients,” Rohrer said. “But today, we have to admit that most of our therapeutics are being developed for late-stage disease.”
- In the case of COVID vaccines, companies were required to enroll diverse patient populations. Rohrer said, “It is incumbent on sponsors and regulators to not just keep running the same experiment and having the same result with 2 percent of our clinical trial population being diverse.” Sponsors should recruit diverse participants to clinical trials and be held accountable for doing so.
- There are many innovative approaches beyond randomized clinical trials that could be considered for regulatory decision making. These include model-informed drug development, adaptive clinical trials, Bayesian approaches, the inclusion of novel and digital endpoints, platform studies, testing multiple agents, the use of external controls, and the use of real-world data in assessing quality, safety, and efficacy. There may be resistance from regulators and investors, Rohrer acknowledged, but adopting new approaches will be crucial “because it is just not sustainable to insist on randomized clinical trials for absolutely every condition when we have these other perfectly valid innovative approaches to use.”
- “We must continue to partner with patients to further make sure their voice and concerns are front and center in our clinical trial and regulatory decision-making forums,” she said. With telemedicine and other digital health technologies, patients can participate in one or more aspects of trials without having to step foot in a clinical site. Rohrer added that researchers should consult with patients on whether particular trial designs are workable for them or if the endpoints are truly meaningful in assessing their quality of life.
“This is a huge burden on our society as well as our families and individuals whom we love,” she said in conclusion, “and if we can put rovers on Mars, we certainly can do better for patients with chronic disease.”
Speaking from a payer’s perspective, Manolis offered his own perspective on how best to mobilize the R&D research engine to deal with prevalent chronic disease. He began with the observation that the pharmaceutical industry is currently facing unprecedented levels of complexity due to a number of factors: transformative drugs, the impact of digital health technologies, drug pricing, industry consolidation, the regulatory environment, and the evolution of values. Any one of these factors alone could create a daunting environment, Manolis said, but all of them together “creates one of the more challenging environments I have seen in my 30 years in this business.”
Specialty drugs, which include most injectable drugs, biologics, and other medications that require special administration or ongoing clinical assessment, account for nearly 38 percent of all spending on retail drugs, even though only 5 percent of the population uses a specialty drug (Hill et al., 2020). This is reflected in the drug pipeline which, again, shows a disproportionate emphasis on rare diseases, cancer, and neurologic disorders—with the traditional chronic diseases very much underrepresented (see Figure 6-1). Indeed, Manolis said, for years clinicians have been relying on generic classes of drugs to treat conditions such as hypertension, mental health, high cholesterol levels, and peptic ulcers, and there has been little
innovation in these areas. Managed care payers are reluctant to pay for new drugs for these conditions, which contributes to the lack of innovation, Manolis said. This, in turn, impacts whether a company might be willing to support research programs for prevalent chronic diseases.
Another issue is what Manolis called the “pharmacy benefit managers rebate machine”—the current practice of pharmaceutical companies paying rebates to pharmacy benefit managers to favor their drugs, which can skew the choice of drugs put on a formulary.
Nonetheless, Manolis continued, there have been some recent innovation successes in dealing with prevalent chronic diseases. SGLT2 inhibitors and GLP-1 agonists have proven valuable in treating diabetes (Nauck and Meier, 2005; Whalen et al., 2015). Direct-acting oral anticoagulants have proven effective in treating and preventing blood clots and now account for more than 97 percent of the individuals in the UPMC Health Plan Medicare program who are on blood thinners (Chen et al., 2020). Similarly, a number of new products are now available to treat migraines (Han et al., 2019), and are replacing triptans, which were the standard of care for years. In short, he said, it is clear that there is room for innovation even in the prevalent chronic disease space.
Furthermore, he said, there is no question that payers will get behind innovation and that deserving drugs will be accepted onto formularies so that payers will reimburse for them. “I can tell you as someone who leads a $4 billion pharmacy operation, mechanism of action, clinical materiality, and differentiation—they always have a place,” he said. “They will always get a look, and it is all about the data.” Ultimately, he added, payers are focused on the total cost of care (see Box 6-1).
One approach for encouraging innovation will be to take advantage of increasing demand for new, more targeted and more effective drug therapies. The numbers of physicians in accountable care organizations—in which compensation is tied to the quality of care and reductions in cost of care—is rapidly increasing, and these physicians, Manolis said, are particularly interested in new differentiated therapies that can be matched to individual patients. Those patients, if they are educated and engaged, may demand new and better treatments. The key, Manolis said, will be in harnessing this demand to encourage more innovation in drug R&D for prevalent chronic disease.
The Foundation for the NIH is an independent, not-for-profit organization that was established by Congress to support the mission of NIH. Menetski highlighted two Foundation for the NIH partnerships: the
Accelerating Medicines Partnership (AMP)2 and the Biomarkers Consortium.3 Each of these partnerships has focused on precompetitive research with implications for drug development. The foundation will typically require a partnership to include at least three private partners and two research institutions. The expectation is that the field will benefit from the knowledge generated by these partnerships.
The Accelerating Medicines Partnership
AMP launched in 2014 as a public–private partnership among NIH, FDA, multiple biopharmaceutical and life science companies, nonprofits, and other organizations to transform the current model for developing new diagnostics and treatments
Based on input from NIH director Francis Collins and representatives from biopharmaceutical companies, AMP has focused on identification of drug targets. In particular, Menetski said, AMP focused on making sure that targets that had been identified in animal models translated to humans. Initially, AMP started such programs on type 2 diabetes, AD, rheumatoid arthritis, and systemic lupus erythematosus. These initial programs have
3 For more information, see https://fnih.org/our-programs/biomarkers-consortium (accessed June 29, 2021).
since been joined by several others, including programs on Parkinson’s disease and schizophrenia, with others under development.
The teams developing the programs include members from “industry, patient groups, NIH, academia, pretty much anybody that had a stake in that space,” Menetski said, with each member having input on the plan going forward. That was important, he said, because success depended on industry and NIH support. The projects are designed with milestones and go/no-go decision points.
Menetski shared two examples of success:
- AMP—rheumatoid arthritis, systemic lupus erythematosus.4 This project focuses on understanding the immunological underpinnings of the disease at the individual cellular level, and has defined standards for collecting tissue, isolating cells, collecting data from multi-omics platforms, and analyzing the data. For both diseases, Menetski said, research teams identified a number of cell types that have a strong pathologic effect on the disease—not only the usual suspects, but a number of new low-prevalence cell types as well. This type of work could not have been done by any one company, he said, and it was even tricky for NIH to carry out.
- AMP—AD5 and type 2 diabetes.6 AMP’s work on AD generated a set of new targets by standardizing the collaborative analysis of large datasets from multiple different cohorts. The project on type 2 diabetes produced a publicly available repository of genetic data to help researchers identify genes of interest and validate drug targets.
The Biomarkers Consortium
The Biomarkers Consortium, by contrast, has focused on generating drug development tools that can be used to enhance the results from clinical trials. Janet Woodcock, acting commissioner of FDA, commented that although thousands of papers are published each year on biomarkers, few of them are useful for clinical decisions. There are generally too few data to be confident about a decision and too much ambiguity. Especially given the current emphasis on precision medicine, it is important, Menetski said, to develop better tools for clinicians to assess factors such as who is sick
5 For more information, see https://www.fnih.org/our-programs/amp-alzheimers-disease-phase-2 (accessed July 16, 2021).
6 For more information, see https://fnih.org/our-programs/AMP/accelerating-medicines-partnership-type-2-diabetes-project (accessed July 16, 2021).
with what disorder, what the future outcome is likely to be for that person, what drug would work best, and whether a given therapy is producing the expected results. Biomarkers can play a role in all of these areas as well as in drug development and testing.
The approach of the Biomarkers Consortium is similar to that of the AMP, Menetski said. Over its 14 years of operation, the consortium has started more than 30 projects. He added that an important contribution of the Biomarkers Consortium, in addition to biomarker identification, has been in advancing a promising idea to a definitive tool in the regulatory context.
As an example, Menetski pointed to the Osteoarthritis Biomarkers Project.7 Osteoarthritis is a highly prevalent disease, but available therapies only provide symptomatic relief. Traditional measures of disease progression and response to treatment were limited and the existing research base was small. Before the consortium got involved, there had been some initial work on biomarkers, but none could be confidently used in the clinic. The consortium team, which includes companies looking for disease-modifying therapies and academic research leaders, has since identified several new biomarkers for predicting disease progression and treatment response in clinical trials, which were submitted to FDA’s Biomarker Qualification Program.8
Menetski emphasized the value of public–private partnerships in spurring innovation in drug R&D for prevalent chronic diseases. Collaboration enables risk sharing and can increase the probability of success.
Smith highlighted the heterogeneity of chronic diseases from a drug development perspective, stating that, “with respect to available therapies, some disorders have hardly any truly effective available therapies, whereas others have multiple classes, sometimes with substantial availability of generic products.” He recognized there could be variability across chronic diseases in terms of the pathophysiology and how well the underlying disease biology is understood, and in terms of the degree of regulatory precedent with respect to suitable endpoints for clinical trials. On top of these considerations, Smith suggested that in many cases, drug R&D for prevalent chronic diseases may require large clinical trials to detect the treatment effect or ensure an adequate safety database, particularly if existing safe and available therapies are available.
7 For more information, see https://fnih.org/our-programs/biomarkers-consortium/osteoarthritis-project (accessed July 16, 2021).
8 For more information, see https://www.fda.gov/drugs/drug-development-tool-ddtqualification-programs/biomarker-qualification-program (accessed July 16, 2021).
Smith offered a few thoughts from the perspective of evidence generation. For example, in response to the COVID-19 pandemic, the use of master protocols has offered a faster path to treatment and could be applicable for other therapeutic areas, including prevalent chronic diseases. Smith suggested that there is more openness within FDA to consider new approaches to trial design than is often assumed, and he challenged the clinical research community to “push the envelope a little bit.” As an example, he mentioned a meeting of the Cardiovascular and Renal Drugs Advisory Committee in which the Division of Cardiology and Nephrology expressed an interest in using “graded adjudication” to judge cardiovascular events. In graded adjudication, he explained, instead of adjudicators making a binary, yes/no decision concerning whether an outcome event has occurred, potential negative events could be assigned a likelihood of probability. “We have been doing cardiovascular outcome trials for decades,” he said, “and there might be ways to innovate here that would actually provide more outcome events” and thus improve the efficiency of the trial.
The implementation of decentralized clinical trials, in which some or all trial-related procedures and data acquisition take place at locations remote from the investigator, could also offer new opportunities to reach patient populations who might not otherwise be included in clinical trials.
Another opportunity, Smith suggested, could be leveraging real-world data—information collected through clinical practice (e.g., data acquired from electronic health records, medical claims data, or other such sources) to support regulatory decision making.9 He mentioned in particular that FDA’s guidance for conducting trials during the COVID-19 pandemic noted that it may be necessary to collect safety and efficacy assessments in alternative ways, such as through virtual assessments.
Finally, Smith said it is important to consider which data are absolutely necessary to collect in a trial. Clinical researchers often collect a number of data points on large numbers of patients, which can significantly increase the cost of a trial. “Certainly, patient safety is paramount in clinical trials,” he said. “I would not want to suggest otherwise. But it is fairly typical for us to see protocols that include comprehensive safety data collection regardless of the stage of drug development—even after approval—with the collection of voluminous laboratory data and EKGs and physical exams and non-serious adverse events.” He suggested that there could be opportunities for stakeholders to reconsider what information is relevant and actionable, and then scale back on some data collection while still accomplishing the goals of the trial and meeting the needs of regulators.
Smith stated that FDA remains interested in collaborating with stakeholders to develop new ways to formulate drugs for prevalent chronic diseases effectively and efficiently. He recognized that FDA has not yet seen the data from most COVID-19 trials, but expressed optimism that lessons learned from these trials could and should be applied to answer clinical questions and improve clinical trials for other treatments in the future.
Chen, A., E. Stecker, and B. A. Warden. 2020. Direct oral anticoagulant use: A practical guide to common clinical challenges. Journal of the American Heart Association 9(13):e017559.
DiMasi, J. A., H. G. Grabowski, and R. W. Hansen. 2016. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics 47:20–33.
Han, L., Y. Liu, H. Xiong, and P. Hong. 2019. CGRP monoclonal antibody for preventive treatment of chronic migraine: An update of meta-analysis. Brain and Behavior 9(2):e01215.
Hill, S. C., G. E. Miller, and Y. Ding. 2020. Net spending on retail specialty drugs grew rapidly, especially for private insurance and Medicare Part D. Health Affairs 39(11):1970–1976.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2019. Examining the impact of real-world evidence on medical product development: Proceedings of a workshop series. Washington, DC: The National Academies Press.
Nauck, M. A., and J. J. Meier. 2005. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regulatory Peptides 128(2):135–148.
Pharmaceutical Research Manufacturers of America. 2020. Medicines in development | cell and gene therapies. PhRMA.
Tufts Center for the Study of Drug Development. 2021. Rising protocol design complexity is driving rapid growth in clinical trial data volume. https://www.globenewswire.com/en/news-release/2021/01/12/2157143/0/en/Rising-Protocol-Design-Complexity-Is-DrivingRapid-Growth-in-Clinical-Trial-Data-Volume-According-to-Tufts-Center-for-the-Study-of-Drug-Development.html (accessed November 22, 2021).
Whalen, K., S. Miller, and E. S. Onge. 2015. The role of sodium-glucose co-transporter 2 inhibitors in the treatment of type 2 diabetes. Clinical Therapeutics 37(6):1150–1166.
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