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Evidence-based medicine challenges in new anticancer drugs

Cancer caused the death of 9.5 million people in 2018 and its incidence is increasing each year (1). The costs of anticancer drugs are also rising which is impacting healthcare systems all over the world (2).

Health Agencies such as the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA) have made flexible requirements for cancer drug approvals (3). For new cancer treatments, phase 2 and non-randomized studies can be used as a single reference for approval. Increasingly, these trials use surrogate outcomes as the primary endpoints, such as progressive-free survival (PFS) and overall response rate. Surrogate endpoints are used to predict a clinically meaningful outcomes, such as overall survival, however they are not patient-important outcomes.

The majority of papers published in oncology use surrogate outcomes. This can be biased due to various reasons, including:

  1. there are no standard measurements for outcomes (most studies use radiological parameters)
  2. progression or response is subjective and the measurement can be different among researchers
  3. frequency of assessment can influence the results and
  4. demonstrate low or moderate correlations with overall survival (4,5).

Moreover, patients are becoming more involved in healthcare decisions, and surrogate endpoints are barriers to shared-decision making (6,7).

Pressure from patient associations regarding new technologies and treatments is contributing to the challenges. Patients with advanced cancer are facing death and they want fast and effective solutions for their health problems. This social pressure for “unmet medical needs” is, in many times, used as an argument for faster drugs approvals pathways. Access to new technologies is important but a balance between access, the cost of clinical drug trials and ensuring robust evidence,  “relevant, replicable, and accessible to end users” (8) is required.

Currently, when a new drug enters the market, patients and physicians are not fully aware of the risks. Some new treatments are approved based on accelerated pathways, examples include:

a.Drugs approved with single-arm and non-randomized studies (10,11);
b. Drugs approved with no confirmatory data (still in the experimental phase) (12);
c. Drugs approved where the studies have serious methodological limitations (11,13);
d. Drugs approved where there is limited safety information (14).

Possible solutions

Clinical trials and real-world data (prospective and standardized data collection) could be linked to generate information about effectiveness and safety of new drugs in the post marketing phase. This data could be mandatory for a pharmaceutical company to continue selling their drug. The inclusion of patient and public representation would be essential, as stated in AllTrials initiative (9). A multi-disciplinary team to prior study development, including experts in EBM, is necessary.

Patient education about that uncertainty of using new cancer medicines and training for physicians on shared decision making should be at the forefront. Creating an international collaboration, with chapter in all regions (i.e.: Latin America, European etc), would be an important action to discuss and implement practical solutions in EBM ecosystem.


(1)  Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R., Torre, L. and Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), pp.394-424.
(2)  Pricing of cancer medicines and its impacts. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.
(3)  Baird LG, Banken R, Eichler H, Kristensen FB, Lee DK, Lim JCW, et al. Accelerated Access to Innovative Medicines for Patients in Need. 2014;96(5):559–71.
(4)  Prasad V, Kim C, Burotto M, Vandross A. The Strength of Association Between Surrogate End Points and Survival in Oncology. JAMA Internal Medicine. 2015;175(8):1389.
(5)  Haslam A, Hey S, Gill J, Prasad V. A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology. European Journal of Cancer. 2019;106:196-211.
(6)  Shimp WS, Smartstate CLB. Interpretation of surrogate endpoints in the era of the 21st Century Cures Act. 2016;6286 (December):1–4. Available from:
(7)  Heneghan C, Goldacre B, Mahtani KR. Why clinical trial outcomes fail to translate into benefits for patients. 2017;1–7.
(8)  Heneghan C, Mahtani K, Goldacre B, Godlee F, Macdonald H, Jarvies D. Evidence based medicine manifesto for better healthcare. BMJ. 2017;:j2973.
(9)  All Trials. Available from:
(10)  Ladanie A, Speich B, Briel M, Sclafani F, Bucher H, Agarwal A et al. Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies. Journal of Clinical Epidemiology. 2019.
(11)  Goring S, Taylor A, Müller K, et al. Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review. BMJ Open 2019;9:e024895. doi:10.1136/ bmjopen-2018-024895
(12)  Davis C, Naci H, Gurpinar E, Poplavska E, Pinto A, Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ. 2017;:j4530.
(13)  Downing NS, Aminawung JA, Shah ND, Krumholz HM, Ross JS. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA – J Am Med Assoc. 2014. JAMA. 2014 January 22; 311(4): 368–377. doi:10.1001/jama.2013.282034.
(14)  Mostaghim S, Gagne J, Kesselheim A. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. BMJ. 2017;358:j3837.

Conflict of interest statement: None to declare

Biography: Tatiane Ribeiro is a 2019 Building Capacity Bursary awardee, currently investigating evidence quality of new anticancer drugs on a Master’s degree at the University of Sao Paulo (USP) Medical School, Department of Preventive Medicine (Sao Paulo-Brazil). She is a Clinical Pharmacist and Health Technology Assessment consultant interested in oncology, real-world evidence, meta-epidemiology, HEOR, critical appraisal tools and shared decision making.


2017 Highlights