Advertisement
Mayo Clinic Proceedings Home

Registered Randomized Trials Comparing Generic and Brand-Name Drugs: A Survey

      Abstract

      Objectives

      To evaluate the research agenda of registered randomized trials comparing generic and brand-name drugs in terms of who sponsors them, whether they are published promptly, and whether they find favorable results.

      Methods

      We included randomized trials comparing the safety or efficacy of brand-name vs generic medications that were registered in ClinicalTrials.gov or other registries from January 1, 2000, through July 31, 2015. To identify published articles or results generated from such trials, we searched PubMed, Scopus, Google, and registry databases. Data were compared across sponsorship categories (“inbred” if the compared drugs were owned by the same company or its partners/subsidiaries, “competitive” if the compared drugs were owned by competing companies, and “apparently nonprofit”), and time to publication was evaluated with Cox analysis.

      Results

      We found 207 registered protocols reporting on 186 completed trials. Among those trials, 37 had published their results and another 56 had posted results in registries, for a total of 93 trials with available results. Four years after trial completion, results were available for 64 of 138 trials (46.4%), with substantial differences by sponsor: 70.8% (34 of 48), 28.1% (18 of 64), and 46.2% (12 of 26) of the inbred, competitive, and nonprofit trials, respectively. In multivariate modeling, inbred trials had a 1.73-fold risk of having results available compared with competitive trials (P=.04). Almost all trials reported favorable results, with the exception of 4 (4.3% of the 93 trials with results).

      Conclusion

      Despite the importance of generic drugs, relatively few registered randomized trials have compared the health effects of generic vs brand-name medicines, and there is an associated unsatisfactory publication rate and almost ubiquitous favorable results. The overall literature on the topic is at high risk of bias, possibly in favor of generic drugs. Higher nonprofit funding and stronger pressure to register trials and publish results are needed.

      Abbreviations and Acronyms:

      RCT (randomized controlled trial)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Dunne S.
        • Shannon B.
        • Dunne C.
        • Cullen W.
        A review of the differences and similarities between generic drugs and their originator counterparts, including economic benefits associated with usage of generic medicines, using Ireland as a case study.
        BMC Pharmacol Toxicol. 2013; 14: 1
        • Dentali F.
        • Donadini M.P.
        • Clark N.
        • et al.
        • Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium
        Brand name versus generic warfarin: a systematic review of the literature.
        Pharmacotherapy. 2011; 31: 386-393
        • Kesselheim A.S.
        • Misono A.S.
        • Lee J.L.
        • et al.
        Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis.
        JAMA. 2008; 300: 2514-2526
        • Caldeira D.
        • Fernandes R.M.
        • Costa J.
        • David C.
        • Sampaio C.
        • Ferreira J.J.
        Branded versus generic clopidogrel in cardiovascular diseases: a systematic review.
        J Cardiovasc Pharmacol. 2013; 61: 277-282
        • Manzoli L.
        • Flacco M.E.
        • Boccia S.
        • et al.
        Generic versus brand-name drugs used in cardiovascular diseases.
        Eur J Epidemiol. 2016; 31: 351-368
        • Kesselheim A.S.
        • Stedman M.R.
        • Bubrick E.J.
        • et al.
        Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis.
        Drugs. 2010; 70: 605-621
        • Talati R.
        • Scholle J.M.
        • Phung O.P.
        • et al.
        Efficacy and safety of innovator versus generic drugs in patients with epilepsy: a systematic review.
        Pharmacotherapy. 2012; 32: 314-322
        • Ioannidis J.P.
        • Manzoli L.
        • De Vito C.
        • D'Addario M.
        • Villari P.
        Publication delay of randomized trials on 2009 influenza A (H1N1) vaccination.
        PLoS One. 2011; 6: e28346
        • Manzoli L.
        • Flacco M.E.
        • D'Addario M.
        • et al.
        Non-publication and delayed publication of randomized trials on vaccines: survey.
        BMJ. 2014; 348: g3058
        • Turner E.H.
        • Matthews A.M.
        • Linardatos E.
        • Tell R.A.
        • Rosenthal R.
        Selective publication of antidepressant trials and its influence on apparent efficacy.
        N Engl J Med. 2008; 358: 252-260
        • Kesselheim A.S.
        • Mello M.M.
        Confidentiality laws and secrecy in medical research: improving public access to data on drug safety.
        Health Aff (Millwood). 2007; 26: 483-491
        • Chan A.W.
        • Song F.
        • Vickers A.
        • et al.
        Increasing value and reducing waste: addressing inaccessible research.
        Lancet. 2014; 383: 257-266
        • Ross J.S.
        • Mulvey G.K.
        • Hines E.M.
        • Nissen S.E.
        • Krumholz H.M.
        Trial publication after registration in ClinicalTrials.gov: a cross-sectional analysis.
        PLoS Med. 2009; 6: e1000144
        • Jones C.W.
        • Handler L.
        • Crowell K.E.
        • Keil L.G.
        • Weaver M.A.
        • Platts-Mills T.F.
        Non-publication of large randomized clinical trials: cross sectional analysis.
        BMJ. 2013; 347: f6104
        • Saito H.
        • Gill C.J.
        How frequently do the results from completed US clinical trials enter the public domain? a statistical analysis of the ClinicalTrials.gov database.
        PLoS One. 2014; 9: e101826
        • Schmucker C.
        • Schell L.K.
        • Portalupi S.
        • et al.
        • OPEN consortium
        Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries.
        PLoS One. 2014; 9: e114023
        • Anderson M.L.
        • Chiswell K.
        • Peterson E.D.
        • Tasneem A.
        • Topping J.
        • Califf R.M.
        Compliance with results reporting at ClinicalTrials.gov.
        N Engl J Med. 2015; 372: 1031-1039
        • Law M.R.
        • Kawasumi Y.
        • Morgan S.G.
        Despite law, fewer than one in eight completed studies of drugs and biologics are reported on time on ClinicalTrials.gov.
        Health Aff (Millwood). 2011; 30: 2338-2345
        • Prayle A.P.
        • Hurley M.N.
        • Smyth A.R.
        Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study.
        BMJ. 2012; 344: d7373
        • Flacco M.E.
        • Manzoli L.
        • Boccia S.
        • et al.
        Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor.
        J Clin Epidemiol. 2015; 68: 811-820
        • Scherer M.
        • Trelle S.
        Opinions on registering trial details: a survey of academic researchers.
        BMC Health Serv Res. 2008; 8: 18
        • Alsheikh-Ali A.A.
        • Qureshi W.
        • Al-Mallah M.H.
        • Ioannidis J.P.
        Public availability of published research data in high-impact journals.
        PLoS One. 2011; 6: e24357
      1. Food and Drug Administration Amendments Act §801, 42 USC §282(j) (2007).

        • Carswell J.M.
        • Gordon J.H.
        • Popovsky E.
        • Hale A.
        • Brown R.S.
        Generic and brand-name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism.
        J Clin Endocrinol Metab. 2013; 98: 610-617
        • Bourgeois F.T.
        • Murthy S.
        • Mandl K.D.
        Outcome reporting among drug trials registered in ClinicalTrials.gov.
        Ann Intern Med. 2010; 153: 158-166
      2. Pfizer Inc. Clinical case study series: disclosure of clinical trials information. Pfizer Inc website. https://www.pfizer.com/files/research/research_clinical_trials/Disclosure_ClinicalTrialsInformation_030209.pdf. Accessed September 2, 2015.

        • Karassa F.B.
        • Ioannidis J.P.
        Clinical trials: a transparent future for clinical trial reporting.
        Nat Rev Rheumatol. 2015; 11: 324-326
        • Ross J.S.
        • Tse T.
        • Zarin D.A.
        • Xu H.
        • Zhou L.
        • Krumholz H.M.
        Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis.
        BMJ. 2012; 344: d7292
        • Hopewell S.
        • Loudon K.
        • Clarke M.J.
        • Oxman A.D.
        • Dickersin K.
        Publication bias in clinical trials due to statistical significance or direction of trial results.
        Cochrane Database Syst Rev. 2009; : MR000006
        • Bekelman J.E.
        • Li Y.
        • Gross C.P.
        Scope and impact of financial conflicts of interest in biomedical research: a systematic review.
        JAMA. 2003; 289: 454-465
        • Bero L.
        • Oostvogel F.
        • Bacchetti P.
        • Lee K.
        Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others.
        PLoS Med. 2007; 4: e184
        • Young N.S.
        • Ioannidis J.P.
        • Al-Ubaydli O.
        Why current publication practices may distort science.
        PLoS Med. 2008; 5: e201
        • Gallelli L.
        • Palleria C.
        • De Vuono A.
        • et al.
        Safety and efficacy of generic drugs with respect to brand formulation.
        J Pharmacol Pharmacother. 2013; 4: S110-S114
        • Alasbali T.
        • Smith M.
        • Geffen N.
        • et al.
        Discrepancy between results and abstract conclusions in industry- vs nonindustry-funded studies comparing topical prostaglandins.
        Am J Ophthalmol. 2009; 147: 33-38.e2
        • Perlis R.H.
        • Perlis C.S.
        • Wu Y.
        • Hwang C.
        • Joseph M.
        • Nierenberg A.A.
        Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry.
        Am J Psychiatry. 2005; 162: 1957-1960
        • Tulikangas P.K.
        • Ayers A.
        • O'Sullivan D.M.
        A meta-analysis comparing trials of antimuscarinic medications funded by industry or not.
        BJU Int. 2006; 98: 377-380
        • Lundh A.
        • Sismondo S.
        • Lexchin J.
        • Busuioc O.A.
        • Bero L.
        Industry sponsorship and research outcome.
        Cochrane Database Syst Rev. 2012; 12: MR000033
        • Als-Nielsen B.
        • Chen W.
        • Gluud C.
        • Kjaergard L.L.
        Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events?.
        JAMA. 2003; 290: 921-928
        • Lexchin J.
        • Bero L.A.
        • Djulbegovic B.
        • Clark O.
        Pharmaceutical industry sponsorship and research outcome and quality: systematic review.
        BMJ. 2003; 326: 1167-1170
        • Djulbegovic B.
        • Lacevic M.
        • Cantor A.
        • et al.
        The uncertainty principle and industry-sponsored research.
        Lancet. 2000; 356: 635-638
        • Djulbegovic B.
        • Kumar A.
        • Miladinovic B.
        • et al.
        Treatment success in cancer: industry compared to publicly sponsored randomized controlled trials.
        PLoS One. 2013; 8: e58711
        • Gøtzsche P.C.
        Lessons from and cautions about noninferiority and equivalence randomized trials.
        JAMA. 2006; 295 ([editorial]): 1172-1174
        • Chokshi D.A.
        • Avorn J.
        • Kesselheim A.S.
        Designing comparative effectiveness research on prescription drugs: lessons from the clinical trial literature.
        Health Aff (Millwood). 2010; 29: 1842-1848
        • Gerlinger C.
        • Schmelter T.
        Determining the non-inferiority margin for patient reported outcomes.
        Pharm Stat. 2011; 10: 410-413
        • Meredith P.
        Bioequivalence and other unresolved issues in generic drug substitution.
        Clin Ther. 2003; 25: 2875-2890
        • Dighe S.V.
        A review of the safety of generic drugs.
        Transplant Proc. 1999; 31: 23S-24S
        • Zuluaga A.F.
        • Agudelo M.
        • Cardeño J.J.
        • Rodriguez C.A.
        • Vesga O.
        Determination of therapeutic equivalence of generic products of gentamicin in the neutropenic mouse thigh infection model.
        PLoS One. 2010; 5: e10744
        • Hess J.
        • Litalien S.
        Battle for the market: branded drug companies' secret weapons that generic drug makers must know.
        J Generic Med. 2005; 3: 20-29
      3. US Food and Drug Administration. ANDA (generic) drugs approvals. Food and Drug Administration website. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/. Updated May 9, 2016. Accessed September 15, 2015.

        • Naci H.
        • Brugts J.
        • Ades T.
        Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.
        Circ Cardiovasc Qual Outcomes. 2013; 6: 390-399
        • Wisman P.P.
        • Roest M.
        • Asselbergs F.W.
        • et al.
        Platelet-reactivity tests identify patients at risk of secondary cardiovascular events: a systematic review and meta-analysis.
        J Thromb Haemost. 2014; 12: 736-747
        • Kesselheim A.S.
        The backlash against bioequivalence and the interchangeability of brand-name and generic drugs.
        CMAJ. 2011; 183: 1350-1351
        • Dal-Ré R.
        • Bracken M.B.
        • Ioannidis J.P.
        Call to improve transparency of trials of non-regulated interventions.
        BMJ. 2015; 350: h1323
        • Jones C.W.
        • Platts-Mills T.F.
        Quality of registration for clinical trials published in emergency medicine journals.
        Ann Emerg Med. 2012; 60: 458-464.e1
        • McGee R.G.
        • Su M.
        • Kelly P.J.
        • Higgins G.Y.
        • Craig J.C.
        • Webster A.C.
        Trial registration and declaration of registration by authors of randomized controlled trials.
        Transplantation. 2011; 92: 1094-1100
        • Zarin D.A.
        • Ide N.C.
        • Tse T.
        • Harlan W.R.
        • West J.C.
        • Lindberg D.A.
        Issues in the registration of clinical trials.
        JAMA. 2007; 297: 2112-2120
        • van de Wetering F.T.
        • Scholten R.J.
        • Haring T.
        • Clarke M.
        • Hooft L.
        Trial registration numbers are underreported in biomedical publications.
        PLoS One. 2012; 7: e49599
        • Roberts I.
        • Ker K.
        • Edwards P.
        • Beecher D.
        • Manno D.
        • Sydenham E.
        The knowledge system underpinning healthcare is not fit for purpose and must change.
        BMJ. 2015; 350: h2463
        • van der Meersch A.
        • Dechartres A.
        • Ravaud P.
        Quality of reporting of bioequivalence trials comparing generic to brand name drugs: a methodological systematic review.
        PLoS One. 2011; 6: e23611
        • Royle P.
        • Waugh N.
        Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.
        Health Technol Assess. 2003; 7 (iii, ix-x, 1-51)
        • Sampson M.
        • Barrowman N.J.
        • Moher D.
        • et al.
        Should meta-analysts search Embase in addition to Medline?.
        J Clin Epidemiol. 2003; 56: 943-955
        • Hopewell S.
        • Clarke M.
        • Lefebvre C.
        • Scherer R.
        Handsearching versus electronic searching to identify reports of randomized trials.
        Cochrane Database Syst Rev. 2007; : MR000001
        • Halladay C.W.
        • Trikalinos T.A.
        • Schmid I.T.
        • Schmid C.H.
        • Dahabreh I.J.
        Using data sources beyond PubMed has a modest impact on the results of systematic reviews of therapeutic interventions.
        J Clin Epidemiol. 2015; 68: 1076-1084
        • Lathyris D.N.
        • Patsopoulos N.A.
        • Salanti G.
        • Ioannidis J.P.
        Industry sponsorship and selection of comparators in randomized clinical trials.
        Eur J Clin Invest. 2010; 40: 172-182
        • van Lent M.
        • IntHout J.
        • Out H.J.
        Differences between information in registries and articles did not influence publication acceptance.
        J Clin Epidemiol. 2015; 68: 1059-1067