Pharmaceutical Medicine

, Volume 33, Issue 2, pp 89–98 | Cite as

Providing Patients with Critical or Life-Threatening Illnesses Access to Experimental Drug Therapy: A Guide to Clinical Trials and the US FDA Expanded Access Program

  • Marjorie A. SpeersEmail author
Review Article


This review article considers two alternative options to standard treatment for desperately ill patients when standard treatments are no longer working: clinical trials and the Food and Drug Administration’s (FDA’s) expanded access program. The article describes the history of drug regulation in the United States, pointing out that the clinical research process to demonstrate safety and efficacy has lengthened the time to market approval. The author describes the advantages and disadvantages of clinical trials and of expanded access primarily for patients, with a discussion of the FDA’s expanded access program, including descriptions of single patient, intermediate-size patient populations and widespread treatment uses. The advantages of the FDA’s expanded access program over the new federal right-to-try law are also discussed. Alternative clinical designs are introduced into consideration as a way to improve the clinical trial process, reduce the time to market approval and perhaps interest more patients in enrolling in trials.


Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of interest

Marjorie Speers declares that she has no potential conflicts of interest that might be relevant to the contents of this manuscript.


  1. 1.
    The history of Food and Drug Administration Agency. Accessed 26 Dec 2018.
  2. 2.
    World Health Organization. Clinical trials. Accessed 26 Dec 2018.
  3. 3.
    US Food and Drug Administration. Code of federal regulations Title 21 Subpart I. Accessed 26 Dec 2018.
  4. 4.
    Fountzilas E, Rabih S, Tsimberidoua AM. Expanded access to investigational drugs: balancing patients safety with potential therapeutic benefits. Expert Opin Invest Drugs. 2018;27(2):155–62.CrossRefGoogle Scholar
  5. 5.
    Rosenblatt M, Kuhlik B. Principles and challenges in access to experimental medicines. JAMA. 2015;313(20):2023–4.CrossRefGoogle Scholar
  6. 6.
    Food and Drug Administration. 2015–2016 FDA global participation in clinical trials report. 2017. Accessed 26 Dec 2018.
  7. 7.
    Carey M, Boyes A, Smits R, Bryant J, Waller A, Olver I. Access to clinical trials among oncology patients: results of a cross sectional survey. BMC Cancer. 2017;17:653–61.CrossRefGoogle Scholar
  8. 8.
    Unger JM, Hershman DL, Albain KS, Moinpour CM, Petersen JA, Burg K, Crowley JJ. Patient income level and cancer clinical trial participation. Clin Oncol. 2013;31(5):536–42.CrossRefGoogle Scholar
  9. 9.
    Weckstein DJ, Thomas CA, Emery IF, Shea BF, Fleury A, White ME, Chase E, Robinson C, Frazier S, Pilar C. Assessment of perceived cost to the patient and other barriers to clinical trial participation. J Oncol Pract. 2011;7(5):330–3.CrossRefGoogle Scholar
  10. 10.
    Unger JM, Cook E, Tai E, Bleyer A. Role of clinical trial participation in cancer research: barriers, evidence, and strategies. Am Soc Clin Oncol Educ Book. 2016;35:185–98.CrossRefGoogle Scholar
  11. 11.
    Rinde M. Patient shortage for cancer trials grow. OncologyLive. 2018;19(9). Accessed 26 Dec 2018.
  12. 12.
    Jarow JP, Lemery S, Bugin K, Khozin S, Moscicki R. Expand access of investigational drugs; the experience of the Center for Drug Evaluation and Research over a 10-year period. Ther Innov Regul Sci. 2016;50(6):705–9.Google Scholar
  13. 13.
    Food and Drug Administration. Expanded access INDs and protocols 2009 – 2017. Accessed 26 Dec 2018.
  14. 14.
    Caplan AL, Ray A. The ethical challenges of compassionate use. JAMA. 2016;315(10):979–80.CrossRefGoogle Scholar
  15. 15.
    Pfizer. Compassionate use and expanded access. Accessed 26 Dec 2018.
  16. 16.
    Holbein MEB, Berglund JP, Weatherwax K, Gerber DE, Adamo JE. Access to investigational drugs: FDA expanded access programs or “right-to-try” legislation? Clin Transl Sci. 2015;8(5):526–32.CrossRefGoogle Scholar
  17. 17.
    Schwartz JL. Real-world evidence, public participation, and the FDA. Hasting Ctr Rep. 2017;47(6):7–8.CrossRefGoogle Scholar
  18. 18.
    21 USC 1 to 5. 1906 § 34 Stat. 768, Chapter 3915 (Pure Food and Drugs Act).Google Scholar
  19. 19.
    21 USC § 355. PLN-, 76 Stat. 780 (safety amendments).Google Scholar
  20. 20.
    21 USC Chapter 9 § 301 et seq 52 Stat. 1040 1962 (safety and efficacy amendments).Google Scholar
  21. 21.
    Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011;122:1–6.CrossRefGoogle Scholar
  22. 22.
    Kaitin KI, DiMasi JA. Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009. Clin Pharmacol Ther. 2011;89(2):183–91.CrossRefGoogle Scholar
  23. 23.
    Food and Drug Administration. Step 3: clinical research. Accessed 26 Dec 2018.
  24. 24.
    Van Norman G. Drugs, devices, and the FDA: part 1: an overview of approval processes for drugs. J Am Coll Cardiol Basic Trans Science. 2016;1:170–9.Google Scholar
  25. 25.
    Amorosa V, Tebas P. Is it time to rethink the expanded-access programs for HIV infection? J Infect Dis. 2007;196(7):974–7.CrossRefGoogle Scholar
  26. 26.
    Young F, Norris J, Levitt J, Nightingale J. The FDA’s new procedures for the use of investigational drugs in treatment. JAMA. 1988;259:2267–70.CrossRefGoogle Scholar
  27. 27.
    US Food and Drug Administration. 21 CFR 812. 62 FR 48947. Accessed 26 Dec 2018.
  28. 28.
    21 USC 321, 331, 351, 352, 353,355 360bbb,371; 42 USC 262. Subpart I—expanded access to investigational drugs for treatment use. Last updated April 1, 2018. Accessed 26 Dec 2018.
  29. 29.
    US Government Accounting Office. Investigational new drugs FDA has taken steps to improve the expanded access program but should further clarify how adverse events data are used. July 2017. Accessed 26 Dec 2018.
  30. 30.
    US Food and Drug Administration. Expanded access to investigational drugs for treatment use—questions and answers guidance for industry. 2016. Accessed 26 Dec 2018.
  31. 31.
    US Food and Drug Administration. Expanded access to investigational drugs for treatment use—questions and answers guidance for industry. 2017. Accessed 26 Dec 2018.
  32. 32.
    21st Century Cures Act, HR 34, 114th Cong, 2015. Accessed 26 Dec 2018.
  33. 33.
    US Government Publishing Office. 42 code of federal regulations part 11.28 What constitutes clinical trial registration information? Accessed 27 Feb 2019.
  34. 34.
    US National Library of Medicine, National Institutes of Health. Accessed 26 Dec 2018.
  35. 35.
    Reagan Udall Foundation for the Food and Drug Administration. Accessed 26 Dec 2018.
  36. 36.
    Patient Protection and Affordable Care Act, 111-147 Public Law, 2010. Accessed 26 Dec 2018.
  37. 37.
    Simon R. Biomarker based clinical trial design. Stat Biopharm Res. 2018;10(3):185–95.CrossRefGoogle Scholar
  38. 38.
    Bhatt DL, Mehta C. Adaptive designs for clinical trials. N Engl J Med. 2016;375:65–74.CrossRefGoogle Scholar
  39. 39.
    Tze LL, Lavori PW. Innovative clinical trials designs: toward a 21st-century health care system. Stat Biosci. 2011;3(2):145–68.CrossRefGoogle Scholar
  40. 40.
    Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, Holmes J, Mander AP, Odondi L, Sydes MR, Villar SS, Wason JMS, Weir CJ, Wheeler GM, Yap C, Jaki T. Adaptive designs in clinical trials: why use them, and how to run and report them. Neurotherapeutics. 2015;12:376–83.CrossRefGoogle Scholar
  41. 41.
    Sato A, Shimura M, Gosho M. Practical characteristics of adaptive design in phase 2 and 3 clinical trials. J Clin Pharm Ther. 2018;43(2):170–80.CrossRefGoogle Scholar
  42. 42.
    Chow SC. Adaptive clinical trial design. Annu Rev Med. 2014;65:405–15.CrossRefGoogle Scholar
  43. 43.
    Lansberg MG, Bhat NS, Yeatts SD, Palesch YY, Broderick JP, Albers GW, Lai TL, Lavori PW. Power of an adaptive trial design for endovascular stroke studies: simulations using IMS (interventional management of stroke) III Data. Stroke. 2016;47(12):2931–7.CrossRefGoogle Scholar
  44. 44.
    Bothwell LE, Kesselheim AS. The real-world ethics of adaptive-design clinical trials. Hastings Cent Rep. 2017;47(6):27–37.CrossRefGoogle Scholar
  45. 45.
    Elman SA, Ware JH, Gottlieb AB, Merola JF. Adaptive clinical trial design: an overview and potential applications in dermatology. J Invest Dermatol. 2016;136(7):1325–9.CrossRefGoogle Scholar
  46. 46.
    Spencer AV, Harbron C, Mander A, Wason J, Peers I. An adaptive design for updating the threshold value of a continuous biomarker. Stat Med. 2016;35(27):4909–23.CrossRefGoogle Scholar
  47. 47.
    Korn EL, Freidlin B. Adaptive clinical trials: advantages and disadvantages of various adaptive design elements. J Natl Cancer Inst. 2017;109(6):djx13.CrossRefGoogle Scholar
  48. 48.
    Chiuzan C, Garrett-Mayer E, Nishimura M. An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials. Stat Biopharm Res. 2018;10(3):185–95.CrossRefGoogle Scholar
  49. 49.
    Renfro LA, Sargent DJ. Basket trials, umbrella trials, and other master protocols: a review and examples. Ann Oncol. 2017;28(3):34–43.Google Scholar
  50. 50.
    Renfro LA, Mandrekar DJ. Targeted therapies in oncology: perspectives on trial designs and practical considerations. Clin Inv. 2015;5(2):117–9.Google Scholar
  51. 51.
    Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. NEJM. 2017;377:62–70.CrossRefGoogle Scholar
  52. 52.
    Gerber DE, Oxnard GR, Govindan R. ALCHEMIST: bringing genomic discovery and targeted therapies to early-stage lung cancer. Clin Pharmacol Ther. 2015;97:447–50.CrossRefGoogle Scholar
  53. 53.
    Slosberg ED, Kang BP, Peguero J, Taylor M, Berry DA, Braiteh F, Spira A, Meric-Bernstam F, Stein S, Piha-Paul SA, Salvado A. Signature program: a platform of basket trials. Oncotarget. 2018;9(30):21383–95.CrossRefGoogle Scholar
  54. 54.
    National Cancer Institute. NCI-COG Pediatric MATCH. Accessed 26 Dec 2018.
  55. 55.
    Janiaud P, Serghiou S, Iannidis JPA. New clinical trial designs in the era of precision medicine: an overview of definitions, strengths, weaknesses, and current use in oncology. Cancer Treat Rev. 2019;73:20–30.CrossRefGoogle Scholar
  56. 56.
    Office of the Federal Register. Adaptive designs for clinical trials of drugs and biologics; draft guidance for industry; availability. 2018. Accessed 26 Dec 2018.
  57. 57.
    Hoerger M. Right-to-try laws and individual patient “compassionate use” of experimental oncology medications: a call for improved provider-patient communication. Death Stud. 2016;40(2):113–20.CrossRefGoogle Scholar
  58. 58.
    Van Norman, GA. Expanding patient access to investigational drugs. Single patient investigational new drug and “right to try”. J Am Coll Cardiol Basic Trans Science. 2018;3(2):280–293.Google Scholar
  59. 59.
    Jarow JP, Lurie P, Ikenberry SC, Lemery S. Overview of FDA’s expanded access program for investigational drugs. Ther Innov Regul Sci. 2017;51(2):177–9.Google Scholar
  60. 60.
    US Food and Drug Administration. Single patient expanded access: what you need to know. Assessed 27 Feb 2019.
  61. 61.
    US Food and Drug Administration. Subpart I: expanded access to investigational drugs for treatment use. Sec. 312.315 Intermediate-size patient populations. Accessed 27 Feb 2019.
  62. 62.
    US Food and Drug Administration. Subpart I: expanded access to investigational drugs for treatment use. Sec. 312.320 Treatment IND or treatment protocol. Accessed 27 Feb 2019.
  63. 63.
    US Food and Drug Administration. Expanded access INDs and protocols 2009-2017. Accessed 26 Dec 2018.
  64. 64.
    Jarow JP, Lemery S. Expanded access of investigational drugs: the experience of the Center of Drug Evaluation and Research over a 10-year period. Ther Innov Regul Sci. 2016;50(6):705–9.Google Scholar
  65. 65.
    Caplan AL, Bateman-House A. Should patients in need be given access to experimental drugs? Expert Opin Pharmacother. 2015;16(9):1275–9.CrossRefGoogle Scholar
  66. 66.
    Bunnik EM, Aarts N, van de Vathorst S. The changing landscape of expanded access to investigational drugs for patients with unmet medical needs: ethical implications. J Pharm Policy Pract. 2017;10:10.CrossRefGoogle Scholar
  67. 67.
    Jerome RN, Edwards TL, Boswell HC, Bernard GR, Harris PA, Pulley JM. Recommendations to facilitate expanded access to investigational therapies for seriously ill patients. Acad Med. 2016;91(3):305–9.CrossRefGoogle Scholar
  68. 68.
    Norman GA. Expanding patient access to investigational drugs. Single patient investigational new drug and the “right to try”. JACC:Basic Transl Sci. 2018;3(2);280–93.Google Scholar
  69. 69.
    Puthumana J, Miller J, Kim J, Ross JS. Availability of investigational medicines through the US Food and Drug Administration’s expanded access and compassionate use programs. JAMA Network Open. 2018;1(2):e180283.CrossRefGoogle Scholar
  70. 70.
    Clinical Research Pathways. For drugs and biologics: intermediate-size patient populations and widespread treatment. Accessed 26 Dec 2018.
  71. 71.
    Goldwater Institute. Right to try model legislation. Accessed 26 Dec 2018.
  72. 72.
    Begg CB, Kim K, Neaton JD. “Right to try” laws. Clin Trials. 2014;11(5):519–20.CrossRefGoogle Scholar
  73. 73.
    Wendler T, Mongiello F, McLinn J, Bellina MS. HR5247: Trickett Wendler, Frank Mongiello, Joran McLinn, and Matthew Bellina Right to Try Act of 2018. Accessed 26 Dec 2018.
  74. 74.
    Lynch HF, Zettler P, Sarpatwari A. Promoting patient interest in implementing the federal right to try act. JAMA. 2018;320(9):869–70.CrossRefGoogle Scholar
  75. 75.
    Bateman-House A, Robertson CT. The federal right to try act of 2017 – a wrong turn for access to investigational drugs and the path forward. JAMA Int Med. 2018;178:321–2.CrossRefGoogle Scholar
  76. 76.
    Blair Holbein ME, Weatherwax KJ, Gravelin M, Hutchinson R, Mashour GA. Right now, in the right way: US Food and Drug Administration’s expanded access program and patient rights. J Clin Trans Science. 2018;2:115–7.CrossRefGoogle Scholar
  77. 77.
    Joffe S, Lynch HR. Federal right-to-try legislation—threatening the FDA’s public health mission. NEJM. 2018;378:695–7.CrossRefGoogle Scholar
  78. 78.
    Keown A. Glioblastoma patient given right to try experimental drug in California. 2019. Accessed 18 Mar 2019.
  79. 79.
    Cour E. Only one patient will get access to this experimental ALS therapy before it's approved. 2018. Accessed 18 Mar 2019.
  80. 80.
    US Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D., on new efforts to strengthen FDA’s expanded access program. Accessed on 26 Dec 2018.
  81. 81.
    Hwang TJ, Darrow JJ, Kesselheim AS. The FDA’s expedited programs and clinical development times for novel therapeutics, 2012-2016. JAMA. 2017;318(21):2137–8.CrossRefGoogle Scholar
  82. 82.
    US Food and Drug Administration. Expanded access program report May 2018. Accessed 26 Dec 2018.
  83. 83.
    Jarow JP, Lemery S, Bugin K, Lowy N. Ten-year experience for the center for drug evaluation and research, part 2: FDA’s role in ensuring patient safety. Ther Innov Regul Sci. 2017;51(2):246–9.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Clinical Research PathwaysAtlantaUSA

Personalised recommendations