Real World Evidence (RWE) is aggregation and analysis of real world data (RWD), collected outside the constraints of conventional RCTs. RWE is used to assess product’s safety, efficacy to effectiveness translation, cost effectiveness and differentiation.1, 2

RWD can be derived from sources such as electronic health records, hospital and registry databases.3 Medical claims and billing databases can contribute to the cost-effectiveness and cost-benefit analysis. These data sources are disparate and of varying quality. As a result, the complexities of accessing, analyzing and drawing conclusions are more challenging than ever.

The stakeholders of RWE include patients, health care providers, patient advocacy organizations, payers, regulators, policy makers and manufacturers. Going forward, RWE will become increasingly more patient centric, as highlighted through the growing emphasis by payers and regulators on advances in this area.

Use of RWE in clinical development and post approval

A value-based, patient outcomes approach is driving the role of RWE in formulating a product’s evidence requirements across the development continuum. In the initial phases (Phase I and Phase II), RWE aids in selection of indication, understanding patient pathway, disease progression, treatment preferences and patient related outcomes (PRO’s).4 RWE facilitates operational aspects of drug development by optimizing patient recruitment and patient access. After drug approval, RWE renders insights about post-marketing safety, prescribing patterns, and adherence, along with real world health outcomes. RWE may potentially explain facets like head to head comparative effectiveness, differentiation in sub population and effects of switching.1 For example, data from an observational study among insulin-naïve patients with uncontrolled Type 2 diabetes was used to assess health outcomes of Toujeo (insulin glargine) compared to basal insulins.5 RWD pooled from U.S. insurance claims databases was used to demonstrate effectiveness of Eliquis (apixaban) among non-valvular atrial fibrillation (NVAF) patients.6

Use of RWE in patient access

When making decisions about new drugs, payers are concerned about the drug’s effectiveness in the real world and its cost effectiveness compared with other drugs on the market. RWD can potentially fill this gap by providing insights into treatments, outcomes and costs in clinical practice. RWE can speed up the initial submission to market and thus time to reimbursement decision, so that products can enter the market faster. The scope of RWE in market access includes achieving optimal price and full reimbursement, favorable recommendation from HTA authority and inclusion in various formularies at hospital, regional and national levels. As an example, EMA label extension was secured by utilizing disease registry data to assess effectiveness of Soliris (eculizumab) for paroxysmal nocturnal hemoglobinuria (PNH).7 Another example is that RWE from US insurance claims helped Zytiga (albiraterone acetate) receive recommendation by National Institute for Health and Care Excellence (NICE) for prostate cancer patients.8

Performance-based risk-sharing arrangements (PBRSA) involve conditional reimbursement by payers based on health outcomes and help improve market access for manufacturers.9 RWE provides insight into the impact of new intervention in the “real” patient population; focusing on efficacy to effectiveness translation. Smart contracts can be utilized to trigger drug reimbursement from insurers only for responders, thus enabling risk sharing between the stakeholders, based on RWD sharing via blockchain technology. There are examples of companies having gone from no risk based contracts in Q3 2017 to a target of having them in over a thousand accounts by Q2 2018.10 RWD is also important for high-priced therapies; wherein “micro-pricing” agreements are fulfilled based on attaining continuous outcomes and quality of life targets. There is an example of a pay for performance agreement in the cardiovascular area; wherein reimbursement will depend on reduction in heart failure hospitalizations.11

Continuum of RWE from clinical development to patient access

The continuum of RWE refers to bridging the evidence gap between clinical development and patient access requirements. Manufacturers must include value demonstration pro-actively in their research and development strategy. The value-development plan should include evidence-based recommendations on the way the product’s value is determined, demonstrated, communicated and realized in the market.12 The plan should be formulated during the proof of-concept phase, and later include new information over the product lifecycle as it evolves.

RWE: The Path Ahead

Going forward, drug pricing will be based on health outcomes rather than payment per pill. The current constraints of using and leveraging RWE will be mitigated by use of technologies like big data, machine learning and block chain technology. Linking and sharing RWD like EHR and real time Internet of Things (IoT) data via blockchain technology can help execute smart contracts between stakeholders and incentivize the right health outcomes in health system. Also, Precision Health Economics Outcomes Research (HEOR) through big data can aid healthcare decision-making tailored to specific clusters (e.g., within oncology patients), so as to provide the most optimum and cost effective individualized treatment. RWD obtained from wearable technology can be used for regulatory and health technology assessment (HTA) to determine drug effectiveness. Perhaps the biggest impact of these future trends will be felt in the emerging markets by ‘leapfrogging’ the aforementioned innovations.

With increasing emphasis on using RWE seamlessly across the entire product lifecycle, from development to patient access and back to discovery and development, there’s a distinct advantage to having cross-skilled teams. Solid experience in clinical trials with a strong orientation to the needs of real world studies and the peculiarities of real world data is the need of the hour. Since the volume of work to be done in the RWE, HEOR and MA areas is growing, largely due to vast amounts of data being available and the advances in data analytics, there is an interest in partnering with service providers with the required domain understanding and robust analytical and scientific writing skills. Partners who have the right blend of clinical development and patient access experience will be well-poised to provide value-added support to their clients.

References
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2. U.S. Department of Health and Human ServicesFood and Drug Administration, 2017.Use of Real-World Evidence toSupport Regulatory Decision-Makingfor Medical Devices(Internet)https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf [Accessed 9/01/2018]
3. U.S. Department of Health and Human Services Food and Drug Administration, 2017.Real WorldEvidence(Internet)https://www.fda.gov/ScienceResearch/SpecialTopics/RealWorldEvidence/default.htm [Accessed 9/01/2018]
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5. Sanofi, 2017. Switching to Toujeo® in a real-world setting produced a similar number of severe low blood sugar events as insulin Degludec. (Internet) http://www.news.sanofi.us/2017-11-30-Switching-to-Toujeo-R-in-a-real-world-setting-produced-a-similar-number-of-severe-low-blood-sugar-events-as-insulin-degludec. [Accessed 22/01/2018]
6. Bristol-Myers Squibb Press Release, 2017. Bristol-Myers Squibb and Pfizer Present Observational Real-World Data Analysis on the Effectiveness and Safety of Eliquis® (apixaban) Compared to Warfarin in Select High-Risk Patients with Non-Valvular Atrial Fibrillation. (Internet) https://news.bms.com/press-release/partnering-news/bristol-myers-squibb-and-pfizer-present-observational-real-world-data- [Accessed 23/01/2018]
7. Alexion Pharmaceuticals Inc, 2009. Alexion’s Soliris(R) (eculizumab) Receives Marketing Approval in Canada for All Patients with PNH. (Internet) http://ir.alexion.com/releasedetail.cfm?releaseid=362191 . [Accessed 22/01/2018]
8. Ramaekers, B.L.T., Riemsma, R., Tomini, F. et al, 2017. Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal PharmacoEconomics (2017) 35: 191. (Internet) https://doi.org/10.1007/s40273-016-0445-5 . [Accessed 22/01/2018]
9. Garrison, Louis P., et al, 2013. “Performance-based risk-sharing arrangements—good practices for design, implementation, and evaluation: report of the ISPOR good practices for performance-based risk-sharing arrangements task force.” Value in health 16.5 (2013): 703-719. (Internet) https://www.ispor.org/ValueInHealth/ShowValueInHealth.aspx?issue=5E4EB78D-D58F-48A3-9FD7-E96C7B626C11 [Accessed 22/01/2018]
10. Omar Ishrak. Medtronic. 2018, Jan 8. 36th Annual J.P. Morgan Healthcare Conference, San Francisco. (Internet) file:///C:/Users/ppal/Downloads/Release0463fc6e-d125-459e-a1e0-4f83a78b9ad9_2324263.pdf [Accessed 22/01/2018]
11. Business wire, 2016. Cigna Implements Value-Based Contract with Novartis for Heart Drug Entresto (Internet) https://www.businesswire.com/news/home/20160208005778/en/Cigna-Implements-Value-Based-Contract-Novartis-Heart-Drug [Accessed 22/01/2018]
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