Patients with serious, life-threatening health conditions and who have no available treatment alternatives, often want to know if and how they can receive early access to investigational products, sometimes even before they are approved by the regulatory agencies. “Expanded access programme” (EAP), also referred to as “compassionate use programme” or “managed access programme”, is a potential pathway for such patients to obtain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials.(1) This way, eligible patients can have an access to the medical products whose efficacy and safety is made known through clinical trials, and the natural delay that is involved in the process leading to the regulatory approval and ‘proper’ market access of these medical products does not hamper the patient access to such medical products.
The EAP is an initiative exclusive to the purview of the US Food and Drug Administration (USFDA). The USFDA’s history of enabling access to investigational therapies dates back to the 1970s; however, precise regulations around the same did not establish until 1987.(2) The USFDA later published specific regulations in 2009, further clarifying the expanded access process.(3)
The EAP was conceived to cater to the patients who are suffering from a serious, life-threatening condition with no feasible treatment options available. This means, either there are no approved treatments in their home country, or the approved available treatments have proven ineffective for them, or they are unable to enrol in an active clinical trial. Essentially, there needs to be an unmet clinical need for this programme to be considered. The access to investigational drug through EAP can only be granted by the drug manufacturer (sponsor), i.e., no regulatory body or a third-party provider can facilitate it in the absence of an approval from the sponsor.(4)
There are three categories under EAP, which are as follows: (5)
- Individual patient EAP (both regular and emergency access): when the patient does not have time to gain access via a written permission from the USFDA,(6)
- Intermediate-size patient population EAP, and
- Widespread treatment use EAP under an Investigational New Drug (IND) application: the patient must have a serious or immediately fatal disease and have no suitable alternative therapy; the potential benefit of the IND must justify the potential risks; and access to the IND must not interfere with the drug development process.
The primary difference in the above three categories is the number of participating patients. The individual patient EAP is for a single patient, and is usually the preferred way of providing access in an emergency setting. An intermediate-size patient population EAP has no requirement for number of patients, but it certainly applies for more than one patient and when the IND is not actively being developed for marketing. A widespread treatment use EAP usually applies when the access is to be provided to a large population, often bridging the gap between the end of the clinical trials and marketing approval.(5)
Expanded access for an individual patient depends on the cooperation and expertise of more than just the patient himself. The physician applying for access on behalf of the patient, the drug manufacturer, i.e., the sponsor, the institutional review board (IRB), and the USFDA, all play crucial roles and must work together for the success of the EAP. Expanded access is possible only if and when the drug company (sponsor) agrees to provide the investigational product. The USFDA cannot instruct the sponsor to provide the drug,(7) and the sponsor’s denial to do so may have valid reasons, such as the option for the patient to join an ongoing clinical trial and/or limited drug supply. Moreover, the apprehension about ‘clinical holds’ or unfavorable outcomes in case of any adverse events reported during an EAP is a common concern. However, a review of around 11,000 expanded access requests throughout a 10-year period showed only two clinical holds during drug development programs, the reason being ‘temporary’ adverse events observed in patients receiving expanded access.(8) Therefore, the occurrence of an adverse event is extremely rare during expanded access to adversely impact drug development.(5)
An example for drugs made available through compassionate use program was when a composite of three chimeric monoclonal antibodies against ebolavirus (ZMapp) was administered to six Ebola-infected patients following the disease outbreak in West Africa, pending regulatory approval for the same.(9) This was in line with the World Health Organization’s (WHO’s) statement ethicizing the alternative to provide needy patients with access to investigational drugs that were not yet approved by regulators or even tested on human beings, with the aim of limiting the epidemic to save the lives of patients.(10, 11) The drug had shown 100% survival in animal trials; however, in the EAP, four out of six patients improved and two patients died.(9, 12)
The USFDA facilitates the EAP; however, its success depends on the initiative and cooperation of other involved parties, including drug manufacturers (sponsors) and physicians, along with the USFDA’s review and authorization.(5)
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- Expanded Access. The US Food and Drug Administration. March 2021. Available at: https://www.fda.gov/news-events/public-health-focus/expanded-access
- 21 CFR Parts 312, 314, 511, and 514: New Drug, Antibiotic, and Biologic Drug Product Regulations (IND Rewrite). March 1987, Updated August 2010. Available at: http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm120111.htm
- Federal Register. 2009; 74(155); Available at: https://www.gpo.gov/fdsys/pkg/FR-2009-08-13/pdf/E9-19005.pdf
- Expanded Access Programs. Available at: https://www.wepclinical.com/expanded-access-programs/
- 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):177-179.
- Gaffney A. Regulatory Explainer: FDA’s Expanded Access (Compassionate Use) Program. February 2014. Available at: https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2014/2/regulatory-explainer-fda-s-expanded-access-(compassionate-use)-program
- Expanded Access to Investigational Drugs for Treatment Use—questions and answers. June 2016. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf
- Jarrow J, Lemery S, Bugin K, Khosin S, Moscicki R. Expanded access of investigational drugs: the experience of the Center of Drug Evaluation and Research over a 10-year period. Therapeutic Innovation & Regulatory Science 2016; 50(6):705–709.
- Gallagher J. Ebola: Experimental drug ZMapp is ‘100% effective’ in animal trials: BBC News; 29 August, 2014. Available from: http://www.bbc.com/news/health-28980153
- Geneva: World Health Organization; 2014. World Health Organization. Ethical Considerations for Use of Unregistered Interventions for Ebola Viral Diseases: Report of an Advisory Panel to WHO. Available at: http://www.who.int/mediacentre/news/statement/2014/ebola-ethical-review-summary/en/
- Hantel A, Olopade CO. Drug and vaccine access in the Ebola epidemic: Advising caution in compassionate use. Ann Intern Med. 2015; 162:141–2.
- Patil S. Early access programs: Benefits, challenges, and key considerations for successful implementation. Perspect Clin Res. 2016; 7(1):4-8.