Posts Tagged RWE

Changing the Clinical Trial Paradigm for Rare and Orphan (R&O) Diseases using Real-World Evidence

Interview with Flora Sandra Siami, MPH. Vice President of Clinical Research, Regulatory Affairs, and Quality Assurance at HealthCore-NERI.

Dr. Patti Peeples, CEO of HealthEconomics.Com, sat down with Flora Sandra Siami, MPH, Vice President of Clinical Research, Regulatory Affairs, and Quality Assurance at HealthCore-NERI, to discuss changing the clinical trial paradigm for rare and orphan diseases using real-world evidence. The mission of HealthCore-NERI is to provide clarity that empowers decision makers to act with precision to improve quality, safety, and affordability in healthcare. HealthCore-NERI works with life science companies, payers and providers, and government and academic organizations to provide real-world evidence in support of a wide variety of healthcare decisions.  

Dr. Peeples: Millions of people are affected by rare diseases worldwide, yet few treatments are available to address these diseases. What are some of the unique challenges that researchers face when designing a clinical trial for rare and orphan diseases?

Sandi Siami: There are many challenges unique to developing and testing treatments for rare and orphan diseases. First and foremost is understanding the natural history of the disease. Because there are a limited number of people with the disease/condition, physicians may not be aware of the most appropriate way to diagnose the condition. Even if the disease/condition is diagnosed, there may be limited clinical information available to understand the disease/condition outside of published case studies.

Once sufficient information is available about the natural history, then products can be developed to treat the disease/condition because there is some level of understanding of the disease, its mechanism of action, how it progresses, and the population it may affect, but the population is also heterogenous. However, this information is needed to design the clinical trial to define eligibility (i.e. inclusion/exclusion criteria), evaluation measures (i.e. study procedures), identify endpoints (i.e. outcomes), and lend to the statistical assumptions for the trial design/methodology.

At HealthCore-NERI, we’ve grappled with a number of these rare/orphan disease trials, and have gained substantial insight into challenges and solutions. One approach we’ve used is to arrange and execute state-of-the-science Consensus Conferences. We’ve held several of these for our clients. These are usually 1-2 day conferences with CME accreditation as put forth by the ACCME that focus on major topic areas, such as pathophysiology and diagnostic criteria, unmet need and available treatment, clinical management, and quality of life and health outcomes that related to internationally available treatment and management of the disease. These conferences present current evidence and discuss how the disease is currently treated and managed either in primary care or a specialty, as well as quality of life and potential psycho-social impact of the disease or its associated symptoms and provide guidance for appropriateness of establishing disease-specific treatment guideline and strategies. A white paper-style report from the conference is generated and submitted to a peer-reviewed publication in a relevant top-line journal. This would serve as the basis of evidence to overcome the above challenges.

Dr. Peeples: The Orphan Drug Act was able to put a spotlight on rare and orphan diseases, encouraging more research to address the unmet need of patients impacted by these diseases. However, traditional clinical trials remain challenged in addressing this need. How do you see the growth in large data sets and real-world evidence impacting the ability to improve the volume and efficiency of research studies focused on rare and orphan diseases?

Sandi Siami: Identifying investigators that treat a rare disease is a major challenge, in addition to identifying the patients themselves. Therefore, having access to large integrated data sets and the use of real-world evidence is essential, but also represents a major clinical trial paradigm shift. In the past we have used disease registries that collected information about rare/orphan/underserved/neglected diseases/conditions. These registries are designed to learn more about the natural history, diagnostic patterns, medical interventions, and outcomes in order to determine the types of treatments/interventions that will be suitable for that particular patient population. Our registries have included as few as 40 patients to as many as 19,000 patients in diseases from sickle cell anemia and thalassemia to pediatric cardiomyopathy and congenital heart disease.

Click to view a larger image.

But in addition to registries and datasets, the HealthCore Integrated Research Database (HIRD®), for example, is a large administrative healthcare database maintained by HealthCore for use in health outcomes and pharmacoepidemiologic research. The HIRD is a broad, clinically rich, and geographically diverse spectrum of longitudinal medical and pharmacy claims data from health plan members across the U.S. Member enrollment, medical care (professional and facility claims), outpatient prescription drug use, outpatient laboratory test result data, and health care utilization may be tracked for health plan members in the database dating back to January 2006, and with diagnoses recorded in International Classification of Disease, Version 10 (ICD-10) since October 2015. The HealthCore Integrated Research Environment (HIRE) has the ability to link the claims data in the HIRD to complementary data sources, including inpatient and outpatient medical records, national vital statistics records, cancer and vaccine registries (state-by-state), disease and device registries, member and provider surveys, and point of care clinical data, which is especially critical for rare, orphan, and underserved diseases/conditions. Using these resources, HealthCore conducts real-world research designed to meet various client needs, including retrospective database studies, medical record review studies, cross-sectional and longitudinal patient and PRO surveys, electronic data linkage studies (including linkage of patient survey data with electronic claims), randomized controlled trials (RCTs), pragmatic clinical trials (PCTs), and site-based enrollment for prospective observational studies using electronic data capture.

Dr. Peeples: There has been substantial growth in interest and research around genetics and genomics. In many cases, genetic diseases are being described alongside rare and orphan diseases. Do you see genomics research as a way to further accelerate research for other rare and orphan diseases?

Sandi Siami: Genomics is an integral part of rare/orphan disease research and has been for over a decade. There are different approaches to genomic studies such as genome wide association, copy number variation, pathway analysis, and next generation studies, all of which have been used to identify genetic variants in the pediatric population. A great example is the Bench to Bassinet Program (B2B) funded by the National Heart, Lung, and Blood Institute, for which HealthCore-NERI served as the initial Coordinating Center. One of the studies, referred to as CHD GENES, collected phenotype and biospecimens from children, their biological parents, and siblings to determine the primary and secondary aims which include genome-wide association studies, whole exome sequencing, and whole genome sequencing to discover genes responsible for congenital heart disease. Secondary aims included identification of mutations responsible for CHD in large numbers of participants, and genotype/phenotype correlation including long-term clinical follow-up of enrolled participants to determine how genetics influences the clinical outcome in CHD.

Another example, for which HealthCore-NERI was a Coordinating Center is the Cooperative Study of Sickle Cell Disease that identified genetic variants associated to the severity of sickle cell disease and fetal hemoglobin expression. Results of these genomic studies can then be used to guide prospective clinical trials to sub-divide patient populations (by genotype/phenotype) to predict those that are responsive to some active drug substances or to use genetic variants as surrogates for diagnosis or outcomes. This is especially important as we are moving toward patient-centric personalized medicine.

Dr. Peeples: Similar to genomics research, special populations such as pediatrics are singled out as areas of importance in the R&O research world. Do you see this as a benefit in that it provides visibility for a broader class of research into R&O, or does this disadvantage other R&O diseases that may not be ‘trending’? On the other hand, how do you see R&O research benefiting such special populations?

Sandi Siami: Most rare diseases are also life-threatening or aggressively progressive in nature, and many also affect the pediatric population. Thus, once a potential therapy is targeted, identifying potential participants for clinical trials becomes challenging not only because of the rare nature of the disease and the limited number of physicians/investigators that may treat the disease but the special ethical considerations that must be given to children who are considered part of the vulnerable population.

More than half of the rare/orphan diseases/conditions affect the pediatric population, and as you know, research in this vulnerable population also has its own challenges. Certainly there are the standard regulatory pathways such as the Humanitarian Device Exemption, Accelerated Approval, Breakthrough Designation, or Regenerative Medicine Advanced Therapy Designation to reduce the regulatory, economic, legal, technical, and logistical burdens associated with development of interventions. And the additional regulations encouraging interventions in pediatric populations under the Best Pharmaceutical for Children Act (BPCA) and Pediatric Research Equity Act (PREA) may account for concentration in pediatric research over other populations. Section 529 of the Food, Drug, and Cosmetic Act (FDCA) specifically encourages development of new interventions for the prevention and treatment of certain rare pediatric diseases.

But the reality is that 50-75% of rare diseases begin in childhood1, and thus it would be expected that there would be more research centered around pediatric rare diseases. According to Children’s Wish Foundation International there are 7,000 different types of rare diseases, 80% are genetic in origin, 50% are children, and 30% of the children don’t live past the age of 5 years of age. Organizations such as this, as well as Global Genes and National Organization for Rare Disorders provide resources to patients, families, researchers, and clinicians on rare diseases. HealthCore-NERI has over 30 years of experience in conducting research in this challenging population engaging more than 490 sites globally and close to 25,000 pediatric subjects in diseases ranging from sickle cell disease, thalassemia, Marfan syndrome, pulmonary hypertension, and spinal muscular atrophy to name a few. Given the unique nuances in conducting pediatric research, on top of the challenges of rare/orphan diseases, our digital strategies have produced award-winning products to aid in educating children, their parents, and pediatricians on clinical trials and participating in clinical trials from websites, to DVDs/posters, YouTube videos, Facebook, video games, and national broadcast film.

Works Cited

  1. 1-Bavisetty S, Grody WW, Yazandi S. Emergence of pediatric rare diseases: review of present policies and opportunities for improvement. Rare Dis. 2013;1:e23579.

Flora Sandra Siami, MPH, is Vice President of Clinical Research, Regulatory Affairs, and Quality Assurance at HealthCore-NERI with close to 25 years of industry experience. She oversees the Clinical Research business unit that includes early and late phase trials, including pragmatic clinical trials, across all therapeutic areas with specific interest and passion in rare, orphan, and underserved diseases as well as pediatric and minority populations. As part of her clinical research oversight, she directs the pharmacovigilance/medical device safety activities including management of Data and Safety Monitoring Boards and Clinical Events/Endpoints Committees. She leads all domestic and international regulatory affairs activities in over 37 countries worldwide. She oversee the quality assurance team overseeing SOPs, internal/external and client/regulatory agency audits, and quality systems.

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Real-world evidence and value-based contracting – swipe left or swipe right?

As biopharma makes the shift toward a personalized healthcare system, it is also transitioning towards a pipeline full of innovative, high-cost therapies. We are moving to a value-based system, with two of the biggest ideas for this decade becoming more and more important: value-based contracting (VBC) and real-world evidence (RWE).

RWE and VBC are key parts of a new era in healthcare

RWE represents outcomes derived from a diverse patient population in a real-world environment. Data sources can include administrative claims, electronic health records (EHR), laboratory data, information and communication technologies (ICT), genomics, health app data, biometric devices and survey reports.

VBC uses RWE to allow both biopharma and health insurers to spread risk and make high cost therapies more available to patients. These arrangements aim to tie contracted drug prices and reimbursement rates more closely to clinical outcomes by collecting and analyzing RWE after a drug has been launched. Prices are linked to how a drug performs in the real world and an insurer will not pay the full cost of a drug that does not work as intended. Moreover, if a drug performs better than projected, the biopharma company may get a higher reimbursement rate.

RWE and VBC are becoming commonplace

Deloitte’s 2nd annual RWE Benchmarking Survey in 2018 found that 14 out of the 20 biopharma companies polled are currently engaged in VBC and 9 of these stated they are using RWE in contract design.1

In 2018, PhRMA reported that the list of publicly-announced VBCs had continued to grow over the last quarter from 39 to 43. In reality, this is a conservative estimate as many VBCs are not publicly announced.2 The U.S. government has shown interest in RWE as well. In December 2018, the FDA released its Framework for RWE3 which paves the way to use RWE to support the approval of a new indication for a pre-approved medicine and satisfy post-approval study requirements, as required by the 21st Century Cures Act of 2016.4 Key elements of the FDA RWE Framework include a broader consideration of RWE data sources, expansion of acceptable study designs (to include observational studies, pragmatic trials, hybrid designs, and RWE control arms), and the use of RWE to assess efficacy and effectiveness (beyond safety).

There are many ways to set up VBC arrangements

VBCs continue to emerge and evolve as payers and manufacturers gain experience in linking payments to measures of outcomes, utilization or spending. Most reviews categorize VBCs as outcomes-based or finance-based.5 RWE will play a pivotal role in outcomes-based VBCs, currently the most common type of arrangement.

Examples (outcomes based)

VBC is not limited to pharmaceuticals. Medical device manufacturers are also striking deals based on a product or service guarantee, or risk sharing. For example, Stryker, an orthopedics company, offered a guarantee to hospitals on the SurgiCount product to address retained surgical sponges, as well as $5 million in product liability indemnification.6

Rising to the risks and challenges of RWE and VBC

RWE and VBC bring risks and challenges for both biopharma and payers.

  1. Defining populations and outcomes
    1. It is necessary to collaborate with hospitals, providers, and professional societies to define inclusion and exclusion criteria and gain buy-in
  1. Collecting, linking and analyzing the necessary healthcare data
    1. It may be difficult to collect and link data from different sources
    2. Data may be protected by law or be costly
  1. Estimating causality between product and outcome
    1. There may be externalities that affect causality like compliance and provider error
  1. Measuring outcomes
    1. Infrastructure may be in place or it may have to be built
  1. Lack of clear financial incentives to participate in value-based contracts when financial risk may be associated with poor patient outcomes or underperforming products
  1. Trust among payers, providers and manufacturers needs to be created and maintained
  1. RWE data may be heterogeneous, incomplete, lack use agreements, run afoul of privacy regulations, lack data standards, and lack unique patient identifiers
  1. There is a lack of data scientists and outsourcing companies to process and work on RWE data to keep up with the fast growth of the industry
  1. Regulatory and legal barriers
    1. Even with the updates of the 21st Century Cures Act, it is still unclear how RWE usage will be integrated into the FDAMA 114 Act, which regulates the use of information for promotional activities by biopharma and has been the start of law suits about improper use of data for promotion
    2. Anti-kickback statutes in the Center for Medicare & Medicaid Services (CMS) complicate the ability of biopharma to enter into value-based contracts because they may be viewed as inducing providers to prescribe certain medications– additional safe harbor laws could be created by Congress and CMS to prevent this7 (kickbacks are currently being addressed by Health &Human Services Secretary Alex Azar)
    3. Medicare’s “best price” policy requiring that biopharma offer a price equal to the best commercially available discount price is a challenge in value-based contracting8

The RWE and VBC challenge: is there a way to help?

Procuring RWE in support of VBC is vital, complex, and multi-dimensional so it is imperative to find solutions that speed up the delivery of data and address the unique challenges of RWE. Several options are below.

1. Simulations of VBCs using RWE to reduce uncertainty

Optum and Merck are collaborating on a multi-year project using RWE to co-develop and test advanced predictive models that will reduce clinical and financial uncertainty for VBCs.10 This would reduce risk on both the pharmaceutical and payer side entering into VBC agreements, would could increase the uptake of these types of contracts.

According to Curt Medeiros, president of Optum Life Sciences, “this collaboration offers an opportunity to leverage our collective strengths to increase knowledge about the design and implementation of outcomes-based contracts in the U.S. health system.” The companies plan to share their findings. Seeing success in this kind of system could inspire other companies to follow suit.

2. Direct partnerships

Another potential solution is direct partnerships between players in the healthcare field.

Pharmaceutical giant Amgen is currently partnering with pharmacy benefit manager Magellan Rx Management and Texas-based health care system Baylor Scott & White Health (BSWH).11 This allows them to work collaboratively and move beyond a purely transactional model for a cooperation-based approach to problem solving in VBP.

Delivery organizations like Magellan and pharmaceutical companies like Amgen bring the opportunity to develop RWE to feed into these types of approaches to VBP.

In Andrew Masica’s, Chief Clinical Effectiveness Officer of BSWH, words, “I think there is a real opportunity for organizations to use their own data and work with industry partners to help answer [many] types of questions.”

3. A marketplace to connect researchers and suppliers

Another option is more efficient collaboration, using a resource such as the HEOR & RWE Marketplace for researchers and suppliers of RWE services, offered by HealthEconomics.Com and Scientist.Com. HealthEconomics.Com and Scientist.Com are two trusted life science brands who have partnered to connect researchers and suppliers in HEOR, RWE and related areas with the aim to facilitate research, overcome challenges, trim costs and bolster market access.9

As Deloitte’s 2nd annual RWE Benchmarking Survey said, “hiring experts to build and implement advanced systems … can help existing talent derive insights from structured and unstructured disparate RWD [real-world data] sources. But attracting this talent could prove difficult, given the current market demand for data scientists.”1The HEOR & RWE Marketplace is a way for biopharma companies to source that talent and a way for consulting and data companies to offer their services and products so that these value-based deals based on RWE can be implemented and assessed more quickly and efficiently.

Conclusion

VBC and RWE may not be the easy way forward for biopharma or for payers. But this path has the potential to contain costs and allow for the development of more personalized medicines that facilitates better outcomes. RWE holds the promise of collecting and utilizing the vast amount of available data to gain meaningful insight. Regardless, now we must focus on the challenge of how to structure VBC contracts that fairly share risk, how to source robust data and how to use resources like direct partnerships, VBC simulations and the HEOR & RWE Marketplace to drive faster insights.

Works Cited

  1. 2018 RWE benchmark survey. Deloitte Insights Available at: https://www2.deloitte.com/insights/us/en/industry/life-sciences/2018-real-world-evidence-benchmarking.html.
  2. Drozd, M. Number of value-based contracts continues to rise. PhRMA (2018). Available at: https://catalyst.phrma.org/number-of-value-based-contracts-continues-to-rise.
  3. FDA. Framework for FDA’s Real-World Evidence Program. (2018). Available at: https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RealWorldEvidence/UCM627769.pdf.
  4. 114th Congress. 21st Century Cures Act, Public Law No: 114-255. (2015).
  5. Policy, M. C. for H. Developing a Path to Value-Based Payment for Medical Products. Duke University (2017). Available at: https://healthpolicy.duke.edu/sites/default/files/atoms/files/value_based_payment_background_paper_-_october_2017_final.pdf.
  6. Parmar, A. Here’s four types of value-based contracting with providers that companies can pursue. MedCity News (2018). Available at: https://medcitynews.com/2018/09/heres-four-types-of-value-based-contracting-with-providers-that-companies-can-pursue/?rf=1.
  7. Hayes, T. Current Impediments to Value- Based Pricing for Prescription Drugs. AAF (2017). Available at: https://www.americanactionforum.org/print/?url=https://www.americanactionforum.org/research/current-impediments-value-based-pricing-prescription-drugs/.
  8. Comer, B. Pharmaceutical value-based contracting: Collaboration is key. PwC (2018). Available at: https://www.pwc.com/us/en/industries/health-industries/library/pharmaceutical-value-based-contracting-collaboration-is-key.html.
  9. HealthEconomics.Com, Scientist.Com Partner on RWE/HEOR Initiative. HealthEconomics.Com (2018). Available at: https://www.healtheconomics.com/industry-news/healtheconomics-com-scientist-com-partner-on-rwe-heor-initiative.
  10. Optum and Merck Collaborate to Advance Value-Based Contracting of Pharmaceuticals. UnitedHealth Group (2017). Available at: https://www.unitedhealthgroup.com/newsroom/2017/0525optumlearninglab.html.
  11. Value-Based Partnerships: Engaging in Value-Driven Innovative Collaborations. The American Journal of Managed Care (2018). Available at: https://ajmc.s3.amazonaws.com/_media/_pdf/AJMC_A818_06_2018_VBP_Whitepaper(1).pdf.
  12. Staton, T. Lilly’s Trulicity joins pay-for-performance trend with Harvard Pilgrim deal. Fierce Pharma (2016). Available at: https://www.fiercepharma.com/pharma/lilly-s-trulicity-joins-pay-for-performance-trend-harvard-pilgrim-deal.
  13. Staton, T. Novartis defies naysayers with newfangled pay-for-performance deals on Entresto. Fierce Pharma (2016). Available at: https://www.fiercepharma.com/sales-and-marketing/novartis-defies-naysayers-newfangled-pay-for-performance-deals-on-entresto.
  14. Teichert, E. Harvard Pilgrim Scores Discounts on Novartis, Lilly Drugs. Modern Healthcare (2016). Available at: https://www.modernhealthcare.com/article/20160628/NEWS/160629889.

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