Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth
Hans-Georg Eichler, Francesco Pignatti, Brigitte Schwarzer-Daum, Ana Hidalgo-Simon, Irmgard Eichler, Peter Arlett, Anthony Humphreys, Spiros Vamvakas, Nikolai Brun, Guido Rasi, Hans-Georg Eichler, Francesco Pignatti, Brigitte Schwarzer-Daum, Ana Hidalgo-Simon, Irmgard Eichler, Peter Arlett, Anthony Humphreys, Spiros Vamvakas, Nikolai Brun, Guido Rasi
Abstract
Compared with drugs from the blockbuster era, recently authorized drugs and those expected in the future present a heterogenous mix of chemicals, biologicals, and cell and gene therapies, a sizable fraction being for rare diseases, and even individualized treatments or individualized combinations. The shift in the nature of products entails secular trends for the definitions of "drugs" and "target population" and for clinical use and evidence generation. We discuss that the lessons learned from evidence generation for 20th century medicines may have limited relevance for 21st century medicines. We explain why the future is not about randomized controlled trials (RCTs) vs. real-world evidence (RWE) but RCTs and RWE-not just for the assessment of safety but also of effectiveness. Finally, we highlight that, in the era of precision medicine, we may not be able to reliably describe some small treatment effects-either by way of RCTs or RWE.
Conflict of interest statement
The authors declared no competing interests for this work.
© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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References
- Collins, R. , Bowman, L. , Landray, M. & Peta, R. The magic of randomization versus the myth of real‐world evidence. N. Engl. J. Med. 382, 674–678 (2020).
- Trusheim, M.R. , Berndt, E.R. & Douglas, F.L. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat. Rev. Drug Discov. 6, 287–293 (2007).
- Alliance for Regenerative Medicines website: ARM Annual Report & Sector Year in Review <> (2019).
- Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies <> (2019).
- Chasman, D.I. , Posada, D. , Subrahmanyan, L. , Cook, N.R. , Stanton, V.P. Jr & Ridker, P.M. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 291, 2821–2827 (2004).
- Kitzmiller, J.P. , Mikulik, E.B. , Dauki, A.M. , Murkherjee, C. & Luzum, J.A. Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers. Med. 9, 97–106 (2016).
- Tambuyzer, E. et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat. Rev. Drug Discov. 19, 93–111 (2020).
- EMA website: Kymriah EPAR – Public Assessment Report <>.
- EMA website: Yescarta EPAR – Public Assessment Report <>.
- Neelapu, S.S. CAR‐T efficacy: is conditioning the key? Blood 133, 1799–1800 (2019).
- Majzner, R.G. & Mackall, C.L. Clinical lessons learned from the first leg of the CAR T cell journey. Nat. Med. 25, 1341–1355 (2019).
- Kim, J. et al. Patient‐customized oligonucleotide therapy for a rare genetic disease. N. Engl. J. Med. 381, 1644–1652 (2019).
- Woodcock, J. & Marks, P. Drug regulation in the era of individualized therapies. N. Engl. J. Med. 381, 1678–1680 (2019).
- EMA webstite: Zynteglo EPAR – Public Assessment Report <>.
- Eichler, H.G. et al. Data rich, information poor: can we use electronic health records to create a learning healthcare system for pharmaceuticals? Clin. Pharmacol. Ther. 105, 912–922 (2019).
- EMA website: Qualification opinion on Cellular therapy module of the European Society for Blood & Marrow Transplantation (EBMT) Registry <>.
- European Cystic Fibrosis Society Patient Registry website <>.
- Cystic Fibrosis Foundation website: Annual report 2018. <>.
- Eichler, H.G. et al. "Threshold‐crossing": a useful way to establish the counterfactual in clinical trials? Clin. Pharmacol. Ther. 100, 699–712 (2016).
- Mulberg, A.E. et al. Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders. Orphanet. J. Rare Dis. 14, 36 (2019).
- Carrigan, G. et al. Using electronic health records to derive control arms for early phase single‐arm lung cancer trials: proof‐of‐concept in randomized controlled trials. Clin. Pharmacol. Ther. 107, 369–377 (2020).
- Wainwright, C.E. et al. Lumacaftor‐ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N. Engl. J. Med. 373, 220–231 (2015).
- FDA website. Highlights of prescribing information <>.
- Carpten, J.D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439–444 (2007).
- Bleeker, F.E. et al. AKT1(E17K) in human solid tumours. Oncogene 27, 5648–5650 (2008).
- Hyman, D.M. , Taylor, B.S. & Baselga, J. Implementing genome‐driven oncology. Cell 168, 584–599 (2017).
- Flynn, R. et al. Ability of primary care health databases to assess medicinal products discussed by the European Union Pharmacovigilance Risk Assessment Committee. Clin. Pharmacol. Ther. 107, 957–965 (2020).
- Tervonen, T. , Angelis, A. , Hockley, K. , Pignatti, F. & Phillips, L.D. Quantifying preferences in drug benefit‐risk decisions. Clin. Pharmacol. Ther. 106, 955–959 (2019).
Source: PubMed