Failure of investigational drugs in late-stage clinical development and publication of trial results

JAMA Internal Medicine

Volumn 176, Issue 12, 2016, Pages 1826-1833

  Hwang, Thomas J ^a   Carpenter, Daniel ^b   Lauffenburger, Julie C ^a   Wang, Bo ^a   Franklin, Jessica M ^a   Kesselheim, Aaron S ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BIOLOGICAL PRODUCT; NEW DRUG;

ARTICLE; CLINICAL DEVELOPMENT PLAN; CLINICAL PRACTICE; DRUG APPROVAL; DRUG EFFICACY; DRUG RESEARCH; DRUG SAFETY; DRUG TREATMENT FAILURE; FOLLOW UP; FOOD AND DRUG ADMINISTRATION; HUMAN; META ANALYSIS; PEER REVIEW; PRIORITY JOURNAL; PUBLICATION; SYSTEMATIC REVIEW; EARLY TERMINATION OF CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL (TOPIC); PUBLISHING; SAFETY; STATISTICS AND NUMERICAL DATA; TREATMENT FAILURE;

CLINICAL TRIALS, PHASE III AS TOPIC; DRUG APPROVAL; DRUGS, INVESTIGATIONAL; EARLY TERMINATION OF CLINICAL TRIALS; HUMANS; PERIODICALS AS TOPIC; PUBLISHING; SAFETY; TREATMENT FAILURE;

EID: 85011311009     PISSN: 21686106     EISSN: None     Source Type: Journal    
DOI: 10.1001/jamainternmed.2016.6008     Document Type: Article

References (45)

1. Institute of Medicine, Forum on Drug Discovery, Development, and Translation. Transforming Clinical Research in the United States: Challenges and Opportunities.Washington, DC: National Academies Press; 2010.
2. Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-2122.
3. Doody RS, Raman R, FarlowM, et al; Alzheimer's Disease Cooperative Study Steering Committee; Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369(4):341-350.
4. Amiri-Kordestani L, Fojo T. Why do phase III clinical trials in oncology fail so often? J Natl Cancer Inst. 2012;104(8):568-569.
5. Lurie P, Chahal HS, Sigelman DW, Stacy S, Sclar J, Ddamulira B. Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study. BMJ. 2015;350:h2758.
6. Hakala A, Kimmelman J, Carlisle B, Freeman G, Fergusson D. Accessibility of trial reports for drugs stalling in development: A systematic assessment of registered trials. BMJ. 2015;350:h1116.
7. Sacks LV, Shamsuddin HH, Yasinskaya YI, Bouri K, Lanthier ML, Sherman RE. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA. 2014;311(4):378-384.
8. Ross JS, Dzara K, Downing NS. Efficacy and safety concerns are important reasons why the FDA requires multiple reviews before approval of new drugs. Health Aff (Millwood). 2015;34(4):681-688.
9. Hwang TJ, Carpenter D, Kesselheim AS. Target small firms for antibiotic innovation. Science. 2014; 344(6187):967-969.
10. Carpenter D, Zucker EJ, Avorn J. Drug-review deadlines and safety problems. N Engl J Med. 2008;358(13):1354-1361.
11. Lincker H, Ziogas C, Carr M, Porta N, Eichler HG. Regulatory watch: where do new medicines originate from in the EU? Nat Rev Drug Discov. 2014;13(2):92-93.
12. Adams CP, Brantner VV. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006;25(2):420-428.
13. Kesselheim AS, Hwang TJ, Franklin JM. Two decades of new drug development for central nervous system disorders. Nat Rev Drug Discov. 2015;14(12):815-816.
14. Hamburg MA.Why FDA Supports a Flexible Approach to Drug Development. FDA website. http://blogs.fda.gov/fdavoice/index.php/2014/02/why-fda-supports-A-flexible-approach-to-drug-development/ Accessed February 22, 2016.
15. Lanthier M, Miller KL, Nardinelli C,Woodcock J. An improved approach to measuring drug innovation finds steady rates of first-in-class pharmaceuticals, 1987-2011. Health Aff (Millwood). 2013;32(8):1433-1439.
16. Kesselheim AS,Wang B, Franklin JM, Darrow JJ. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ. 2015;351:h4633.
17. Eder J, Sedrani R, Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov. 2014;13(8):577-587.
18. Hwang TJ, Lauffenburger JC, Franklin JM, Kesselheim AS. Temporal trends and factors associated with cardiovascular drug development, 1990 to 2012 [published online August 29, 2016]. J AmColl Cardiol Basic Trans Science. doi:10.1016/j.jacbts.2016.03.012
19. Abola MV, Prasad V. The Use of Superlatives in Cancer Research. JAMA Oncol. 2016;2(1):139-141.
20. Djulbegovic B, Kumar A, Glasziou PP, et al. New treatments compared to established treatments in randomized trials. Cochrane Database Syst Rev. 2012;10:MR000024.
21. O'Day S, Gonzalez R, Lawson D, et al. Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J Clin Oncol. 2009;27(32):5452-5458.
22. O'Day SJ, Eggermont AM, Chiarion-Sileni V, et al. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013;31(9):1211-1218.
23. Kesselheim AS,Myers JA, Avorn J. Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA. 2011;305(22):2320-2326.
24. Mitsumoto J, Dorsey ER, Beck CA, Kieburtz K, Griggs RC. Pivotal studies of orphan drugs approved for neurological diseases. Ann Neurol. 2009;66(2):184-190.
25. Button KS, Ioannidis JP, Mokrysz C, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013; 14(5):365-376.
26. Lee K, Bacchetti P, Sim I. Publication of clinical trials supporting successful new drug applications: A literature analysis. PLoS Med. 2008;5(9):e191.
27. Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med. 2008;5(11):e217.
28. Smithy JW, Downing NS, Ross JS. Publication of pivotal efficacy trials for novel therapeutic agents approved between 2005 and 2011: A cross-sectional study. JAMA Intern Med. 2014;174 (9):1518-1520.
29. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-260.
30. Hart B, Lundh A, Bero L. Effect of reporting bias on meta-analyses of drug trials: reanalysis of meta-analyses. BMJ. 2012;344:d7202.
31. Becker RE, Greig NH. Lost in translation: neuropsychiatric drug development. Sci Transl Med. 2010;2(61):61rv6.
32. van derWorp HB, Howells DW, Sena ES, et al. Can animal models of disease reliably inform human studies? PLoS Med. 2010;7(3):e1000245.
33. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van derWorp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59(3):467-477.
34. Chalmers I. Underreporting research is scientific misconduct. JAMA. 1990;263(10): 1405-1408.
35. Seruga B, Templeton AJ, Badillo FE, Ocana A, Amir E, Tannock IF. Under-reporting of harm in clinical trials. Lancet Oncol. 2016;17(5):e209-e219.
36. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565-1571.
37. Hudson KL, Collins FS. Sharing and reporting the results of clinical trials. JAMA. 2015;313(4): 355-356.
38. Federal Register. National Institutes of Health: Notice of Proposed Rulemaking on Clinical Trials Registration and Results Submission. https://federalregister.gov/a/2014-26197. Accessed August 11, 2016.
39. Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat Rev Drug Discov. 2013;12(8):569.
40. WaringMJ, Arrowsmith J, Leach AR, et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov. 2015;14(7):475-486.
41. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32 (1):40-51.
42. Zuckerman DM, Jury NJ, Silcox CE. 21st Century Cures Act and similar policy efforts: at what cost? BMJ. 2015;351:h6122.
43. Redberg RF. Faster drug approvals are not always better and can be worse. JAMA Intern Med. 2015;175(8):1398.
44. Gonsalves G, Zuckerman D. Commentary: Will 20th century patient safeguards be reversed in the 21st century? BMJ. 2015;350:h1500.
45. Floyd JS, Psaty BM. The potential risks of expedited approval of drugs for acute bacterial infections. JAMA Intern Med. 2014;174(9):1436-1437.