Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit–risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy–effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy–effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.
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Danish Medicines Agency. Conclusions and recommendations from the Pharmaceutical Forum. Danish Medicines Agency [online], (2010).
Luce, B. R. et al. EBM, HTA, and CER: clearing the confusion. Millbank Q. 88, 256–276 (2010).
European Medicines Agency. European Medicines Agency recommends measures to manage contamination of heparin-containing medicines. European Medicines Agency [online], (2008).
European Medicines Agency. Studies assessed by the EMEA indicate no increased risk of developing cancer for patients who have taken Viracept contaminated with ethyl mesilate. European Medicines Agency [online]. (2008).
Dal Pan, G. J., Blackburn, S. & Karwoski, C. in Textbook of Pharmacoepidemiology (eds Strom, B. L. & Kimmel, S. E.) (John Wiley & Sons, New Jersey), (in the press).
Pocock, S. J. & Lubsen, J. More on subgroup analyses in clinical trials. N. Engl. J. Med. 358, 2076 (2008).
Ingelman-Sundberg, M. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J. Intern. Med. 250, 186–200 (2001).
Roses, A. D. Pharmacogenetics in drug discovery and development: a translational perspective. Nature Rev. Drug Discov. 7, 807–817 (2008).
Pharoa, P. D. & Hollingworth, W. Cost effectiveness of lowering cholesterol concentration with statins in patients with and without pre-existing coronary heart disease: life table method applied to health authority population. BMJ 312, 1443–1448 (1996).
Poole, S. G. & Dooley, M. J. Off-label prescribing in oncology. Support Care Cancer 12, 302–305 (2004).
Hsien, L. et al. Off-label drug use among hospitalised children: identifying areas with the highest need for research. Pharm. World Sci. 30, 497–502 (2008).
[No authors listed.] Guidance for off-label use of drugs. Lancet Neurol. 7, 285 (2008).
Schosser, R. Risk/benefit evaluation of drugs: the role of the pharmaceutical industry in Germany. Eur. Surg. Res. 34, 203–207 (2008).
Friedman, M. A. et al. The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA 281, 1728–1734 (1999).
[No authors listed.] How a statin might destroy a drug company. Lancet 361, 793 (2003).
European Medicines Agency. EPAR Avandia. European Medicines Agency [online], (2009).
Forslund, T. et al. Usage, risk and benefit of weight-loss drugs in primary care. Journal of Obesity [online], (2010).
Center for Medical Technology Policy. Effectiveness Guidance Document: Pragmatic Phase 3 Pharmaceutical Trials. Release Date: September 14, 2010. Center for Medical Technology Policy [online], (2010).
Petak, I. et al. Integrating molecular diagnostics into anticancer drug discovery. Nature Rev. Drug Discov. 9, 523–535 (2010).
Heerdink, E. R., Urquhart, J. & Leufkens, H. G. Changes in prescribed doses after market introduction. Pharmacoepidemiol. Drug Saf. 11, 447–453 (2002).
Cross, J. et al. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980–1999. Pharmacoepidemiol. Drug Saf. 11, 439–446 (2002).
Trusheim, M. R. et al. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nature Rev. Drug Discov. 6, 287–293 (2007).
European Medicines Agency. Herceptin EPAR. European Medicines Agency [online], (Last updated 19 May 2011).
Barron, J. J., Cziraky, M. J., Weisman, T. & Hicks, D. G. HER2 testing and subsequent trastuzumab treatment for breast cancer in a managed care environment. Oncologist 14, 760–768 (2009).
European Medicines Agency. EPAR Ziagen. European Medicines Agency [online], (Last updated 18 Apr 2011).
Stocco, G., Crews, K. R. & Evans, W. E. Genetic polymorphism of inosine-triphosphate- pyrophosphatase influences mercaptopurine metabolism and toxicity during treatment of acute lymphoblastic leukemia individualized for thiopurine-S-methyl-transferase status. Expert Opin. Drug Saf. 9, 23–37 (2010).
Zaza, G., Granata, S., Sallustio, F., Grandaliano, G. & Schena, F. P. Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients. Clin. Exp. Immunol. 159, 268–280 (2010).
ICH Expert Working Group. International Conference on Harmonisation Guideline E5(R1): Ethnic Factors in the Acceptability of Foreign Clinical Data. ICH Harmonisation For Better Health [online], (1998).
Falagas, M. E. & Karageorgopoulos, D. E. Adjustment of dosing of antimicrobial agents for bodyweight in adults. Lancet 375, 248–251 (2010).
Kirsch, I. et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 5, 260–268 (2008).
van Staa, T.-P., Leufkens, H. G., Zhang, B. & Smeeth, L. A comparison of cost effectiveness using data from randomized trials or actual clinical practice: selective Cox-2 inhibitors as an example. PLoS Med. 6, e1000194 (2009).
Greenblatt, D. J. Analysis of drug interactions involving fruit beverages and organic anion-transporting polypeptides. J. Clin. Pharmacol. 49, 1403–1407 (2009).
Bailey, D. G. Fruit juice inhibition of uptake transport: a new type of food–drug interaction. Br. J. Clin. Pharmacol. 70, 645–655 (2010).
Klaasen, R., Wijbrandts, C. A., Gerlag, D. M. & Tak, P. P. Body mass index and clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum. 63, 359–364 (2011).
US Government Accountability Office: Report to the Ranking Member, Committee on Finance, US Senate. Prescription drugs: FDA's oversight of the promotion of drugs for off-label uses; July 2008. US Government Accountability Office [online], (2008).
Radley, D.C., Finkelstein, S.N. & Stafford, R. S. Off-label prescribing among office-based physicians. Arch. Intern. Med. 166, 1021–1026 (2006).
Jonville-Béra, A. P., Béra, F. & Autret-Lecaq, E. Are incorrectly used drugs more frequently involved in adverse drug reactions? A retrospective study. Eur. J. Clin. Pharmacol. 61, 231–236 (2005).
Cereza, G., Pedros, C., Garcia, N. & Laporte, J. R. Topiramate in non-approved indications and acute myopia or angle-closure glaucoma. Br. J. Clin. Pharmacol. 60, 578–579 (2005).
Kohn, L. T., Corrigan, J. M., & Donaldson, M. S. (eds) To Err is Human: Building a Safer Health System (National Academy Press, Washington DC, 2000).
Bonaccorso, S. & Sturchio, J. L. Perspectives from the pharmaceutical industry. BMJ 327, 863–864 (2003).
WHO. Adherence to long-term therapies: evidence for action. World Health Organization [online], (2003).
Urquhart, J. The odds of the three nons when an aptly prescribed medicine isn't working: non-compliance, non-absorption, non-response. Br. J. Clin. Pharmacol. 54, 212–220 (2002).
Horwitz, R. I. et al. Treatment adherence and risk of death after a myocardial infarction. Lancet 336, 542–545 (1990).
Cramer, J. A, Benedict, Á, Muszbek, N., Keskinaslan, A. & Khan, Z. M. The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review. Int. J. Clin. Pract. 62, 76–87 (2008).
Vrijens, B., Gross, R. & Urquhart, J. The odds that clinically unrecognised poor or partial adherence confuses population pharmacokinetic/pharmacodynamic analyses. Basic Clin. Pharmacol. Toxicol. 96, 225–227 (2005).
Urquhart, J. Getting a handle on why good drugs sometimes don't work. J. R. Coll. Physicians Edinb. 34, 95–98 (2004).
Centers for Disease Control and Prevention. Achievements in Public Health, 1900–1999 Family Planning. MMWR Morb. Mortal. Wkly. Rep. 48, 1073–1080 (1999).
Vrijens, B. et al. Modellling the association between adherence and viral load in HIV-infected patients. Stat. Med. 24, 2719–2731 (2005).
Vrijens, B. & Urquhart, J. Patient adherence to prescribed antimicrobial drug dosing regimens. J. Antimicrob. Chemother. 55, 616–627 (2005).
Olfson, M., West, J. C., Wilk, J. E. & Marcus, S. Factors affecting the effectiveness of clinical decisions in treating schizophrenia. in Proc. of the American Psychiatric Assoc. 156th Annual Meeting (17–22 May 2003; San Francisco, California, USA; Abstract S28C).
Vrijens, B., Vincze, G., Kristanto, P., Urquhart, J. & Burnier, M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 336, 1114–1117 (2008).
Vincent, O. et al. Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J. Clin. Oncol. 28, 2423–2429 (2010).
Saevarsdottir, S. et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors. Arthtitis Rheum. 63. 26–36 (2011).
Harter, J. G. & Peck, C. C. Chronobiology: suggestions for integrating it into drug development. Ann. N. Y. Acad. Sci. 618, 563–571 (1991).
Rothwell, P. M. Factors that can affect the external validity of randomised controlled trials. PLoS Clin. Trials 1, e9 (2006).
Thorpe, K. E. et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. CMAJ 180, e47–e57 (2009).
Temple, R. Enrichment of clinical study populations. Clin. Pharmacol. Ther. 88, 774–778 (2010).
Goldstein, J. Why Medicare Pays so Much For Cancer Drugs. European Medicines Agency. Wall Street Journal [online], (2009).
Barbui, C. & Garattini, S. Regulatory policies on medicines for psychiatric disorders: is Europe on target? Br. J. Psychiatry 190, 91–93 (2007).
Woosley, R. L. & Rice, G. A new system for moving drugs to market. Issues Sci. Technol. XXI, 63–68 (2005).
Eichler, H. G., Pignatti, F., Flamion, B., Leufkens, H. & Breckenridge, A. Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma. Nature Rev. Drug Discov. 7, 818–826 (2008).
[No authors listed.] Road map to 2015. European Medicines Agency [online], (2010).
Maxwell, S., Eichler, H. G., Bucsics, A., Haefeli, W. E. & Gustafsson, L.L. on behalf of the e-SPC consortium. e-SPC — delivering drug information in the 21st century: developing new approaches to deliver drug information to prescribers. Br. J. Clin. Pharmacol. 6 Apr 2011 (doi:10.1111/j.1365–21252011.03981.x.).
Urquhart, J. Patient noncompliance with drug regimens: measurement, clinical correlates, economic impact. Eur. Heart J. 17 (Suppl. A), 8–15 (1996).
Leufkens, H. G. & Urquhart, J. Variability in patterns of drug usage. J. Pharm. Pharmacol. 46 (Suppl. 1), 433–437 (1994).
McQuay, H. J. & Moore, R. A. Using numerical results from systematic reviews in clinical practice. Ann. Intern. Med. 126, 712–720 (1997).
Woodcock, J. Assessing the clinical utility of diagnostics used in drug therapy. Clin. Pharmacol. Ther. 88, 765–773 (2010).
Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).
Donnelly, L. A. et al. A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study. Pharmacogenet. Genomics 18, 1021–1026 (2008).
Flockhart, D. A. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet. Med. 10, 139–150 (2008).
Ginsburg, G. S. & Voora, D. The long and winding road to warfarin pharmacogenetic testing. J. Am. Coll. Cardiol. 55, 2813–2815 (2010).
Kamali, F. & Wynne, H. Pharmacogenetics of warfarin. Annu. Rev. Med. 61, 63–75 (2010).
Schilsky, R. L. Personalised medicine in oncology. Nature Rev. Drug Discov. 9, 363–366 (2010).
Roses, A. D. Pharmacogenetics in drug discovery and development: a translational perspective. Nature Rev. Drug Discov. 7, 807–817 (2008).
European Medicines Agency. Reflection paper on co-development of pharmacogenomic biomarkers and assays in the context of drug development. European Medicines Agency [online], (2010).
FDA. International Pharmaceutical Regulatory Monitor: US FDA draft guidance explains new drug development tools. FDA News [online], (2010).
European Medicines Agency. Qualification of novel methodologies for drug development: guidance to applicants. European Medicines Agency [online], (2009).
McClellan, M. et al. An accelerated pathway for targeted cancer therapies. Nature Rev. Drug Discov. 10, 79–80 (2011).
[No authors listed.] Rethinking therapeutic cancer vaccines. Nature Rev. Drug Discov. 8, 685–686 (2009).
Hampel, H. et al. Biomarkers for Alzheimer's disease therapeutic trials. Prog. Neurobiol. 2 Dec 2010 (doi:10.1016/j.pneurobio.2010.11.005).
Falissard, B. et al. Relative effectiveness assessment of listed drugs (REAL): a new method for an early comparison of the effectiveness of approved health technologies. Int. J. Technol. Assess Health Care 26, 124–130 (2010).
Birkett, D. et al. Clinical pharmacology in research, teaching and health care: considerations by IUPHAR, the Inter-national Union of Basic and Clinical Pharmacology. Basic Clin. Pharmacol. Toxicol. 107, 531–559 (2010).
Pocock, S. J., Assmann, S. E., Enos, L. E. & Kasten, L. E. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat. Med. 21, 2917–2930 (2002).
Aarons, L. et al. Role of modelling and simulation in Phase I drug development. Eur. J. Pharm. Sci. 13, 115–122 (2001).
Manolis, E. & Pons, G. Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br. J. Clin. Pharmacol. 68, 493–501 (2009).
[No authors listed.] How to reduce prescribing errors. Lancet 374, 1945 (2009).
[No authors listed.] Evidence-based Practice Centres: synthesizing scientific evidence to improve quality and effectiveness in health care. Agency for Healthcare Research and Quality [online], (2011).
Bahri, P. Public pharmacovigilance communication: a process calling for evidence-based, objective-driven strategies. Drug Saf. 33, 1065–1079 (2010).
Smalley, W. et al. Contraindicated use of cisapride: impact of food and drug administration regulatory action. JAMA 284, 3036–3039 (2000).
John, J. et al. HER2 testing and subsequent trastuzumab treatment for breast cancer in a managed care environment. Oncologist 14, 760–768 (2009).
Gustafsson, L. L. et al. The “Wise List” — a comprehensive concept to select, communicate and achieve recommendations of essential drugs in ambulatory care in Stockholm. Basic Clin. Pharmacol. Toxicol. 108, 224–233 (2011).
Shea, S. & Hripcsak, G. Accelerating the use of electronic health records in physician practices. N. Engl. J. Med. 362, 192–195 (2010).
Sjöborg, B. et al. Design and implementation of a point-of-care computerized system for drug therapy in Stockholm metropolitan health region-bridging the gap between knowledge and practice. Int. J. Med. Inform. 76, 497–506 (2007).
Classen, D. C., Avery, A. J. & Bates, D. W. Evaluation and certification of computerized provider order entry systems. J. Am. Med. Inform. Assoc. 14, 48–55 (2007).
Böttiger, Y. et al. SFINX — a drug–drug interaction database desgined for clinical decision support systems. Eur. J. Clin. Pharmacol. 95, 627–633 (2009).
Wettermark, B. et al. The new Swedish Prescribed Drug Register—opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol. Drug Saf. 16, 726–735 (2007).
Cutler, D. & Everett, W. Thinking outside the pillbox — medication adherence as a priority for health care reform. N. Engl. J. Med. 362, 1553–1555 (2010).
Modi, A. C. & Quittner, A. L. Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way? J. Pediatr. Psychol. 31, 846–858 (2006).
Osterberg, L. G., Urquhart, J. & Blaschke, T. F. Understanding forgiveness: minding and mining the gaps between pharmacokinetics and therapeutics. Clin. Pharmacol. Ther. 88, 457–459 (2010).
Frieden, T. R., Fujiwara, P. I., Washko, R. M. & Hamburg, M. A. Tuberculosis in New York City — turning the tide. N. Engl. J. Med. 333, 229–233 (1995).
Lester, R. T. et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 376, 1838–1845 (2010).
Chi, B. H. & Stringer, J. S. A. Mobile phones to improve HIV treatment adherence. Lancet 376, 1807–1808 (2010).
Ogedegbe, G. Self-titration for treatment of uncomplicated hypertension. Lancet 376, 144–146 (2010).
Singer, E. Message from a pill bottle. Technology Review [online], (2010).
Au-Yeung, K. Y. et al. A networked system for self-management of drug therapy and wellness. ACM Digital Library [online], (2010).
Sokol, M. C., McGuigan, K. A., Verbrugge, R. R. & Epstein, R. S. Impact of medication adherence on hospitalization risk and healthcare cost. Med. Care 43, 521–530 (2005).
Ware, J. H. & Hamel, M. B. Pragmatic trials — guide to better patient care? N. Engl. J. Med. 364, 1685–1687 (2011).
Hughes, B. 2009 FDA drug approvals. Nature Rev. Drug Discov. 9, 89–92 (2010).
Eichler, H. G., Aronsson, B., Abadie, E. & Salmonson, T. New drug approval success rate in Europe in 2009. Nature Rev. Drug Discov. 9, 355–356 (2010).
The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agencies, health technology assessment bodies or other organizations that the authors work for.
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Eichler, HG., Abadie, E., Breckenridge, A. et al. Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response. Nat Rev Drug Discov 10, 495–506 (2011). https://doi.org/10.1038/nrd3501
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