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Expanded Access to Drugs: What Does It Mean?

Medicines that are not yet authorized by regulatory agencies, such as the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA), may be made available to patients through clinical trials. However, certain patients might be ineligible for such trials due to specific conditions. Individuals facing a severe illness or condition, having exhausted available treatment options, and being unable to join a clinical trial are classified as having unmet medical needs. These patients could potentially qualify for access to drugs still in development, even if they are not enrolled in the clinical study. Expanded access is a program that offers, under strict conditions, a treatment option to patients by making available unauthorized medicines or products in development.

Expanded access, also called “compassionate use”, is an approach where patients gain access to investigational products (drugs, biologics, and medical devices used to diagnose, monitor, and treat serious conditions) for which there are no comparable or satisfactory therapy options available (Jarow et al., 2017). The program only applies to medicines that are predicted to be helpful for patients with life-threatening, long-term, or seriously debilitating illnesses that cannot be treated with currently authorized medicines (Krendyukov, 2020). The FDA institutionalized expanded access in 1987 in the context of the acquired immunodeficiency syndrome (AIDS) epidemic as an effort to provide more treatment options for these patients (Darrow et al., 2015). In the European Union (EU), although EMA had recommendations on compassionate use in 2007, the individual EU member states have traditionally regulated their own national expanded access (EMA, 2007). The requirement is that the medicine should be undergoing clinical rials or have entered the marketing-authorization application process in the respective regulatory agency of the country.


Figure 1: Protest of an AIDS activist group in the 80’s that helped speed up the process of finding an effective treatment for AIDS (Aizenman, 2019).

There are many different terms used to describe the process of accessing drugs before their approval in a specific country. For unapproved medicines, many countries or even the drug manufacturer have terminologies for describing pre-approval mechanisms or programs that can be referred to as “compassionate use program” (CUP), “expanded access program” (EAP), “named patient supply” (NPS), “special access” (SA), or similar terms (Aliu et al., 2021). The pharmaceutical industry, as well as patients and physicians, have to face the challenge of inconsistent terminology around the world. An unapproved drug is often referred to as an “investigational medicinal product” (IMP), which means a medicine being studied in a clinical trial and that has not yet been approved by regulatory authorities (i.e., FDA, EMA).


Conditions for Expanded Access to Treatment

According to the FDA, the main standards for a patient to be eligible for the expanded access program are the following:

  1. The patient has a condition or disease that is serious or immediately life-threatening.

  2. The patient cannot be enrolled in a clinical trial (eligibility may be based on your age, gender, type and stage of a disease, overall health, treatment history, and other conditions).

  3. Currently, there are no comparable or satisfactory alternatives to diagnose, monitor, or treat the disease or condition.

  4. The potential patient benefit of the treatment justifies the potential risks.

  5. Providing the investigational medical product will not interfere with investigational trials that could support medical product development or marketing approval.


Figure 2: Eligibility criteria for expanded access (Hiteks, n.d.).

In the process of expanded access to drugs, several key players have distinct roles to facilitate access to investigational drugs for patients who may not qualify for clinical trials but have a serious or life-threatening condition. Here are the main players and their responsibilities:


Patient: in order to determine whether expanded access is the only option, the patient should first consult a licensed physician to investigate alternative approved treatment options and available clinical trials.

Physician: it is the physician's responsibility to oversee patient treatment and contact the company (industry), to file paperwork with the FDA and Institutional Review Board (IRB), and to report on patient progress.

Company (Industry): the company must agree to provide the investigational medical product and support the patient's licensed physician and the FDA in providing the information necessary for the expanded access request or submitting the requests to the FDA.

Institutional Review Board (IRB): the IRB guarantees that appropriate actions are taken to protect the rights and welfare of individuals participating as subjects in a research study. The IRB is responsible for reviewing, approving, and conducting periodic reviews of any biomedical research involving human subjects. It comprises any board, committee, or other group formally designated by an institution.

FDA: it is the FDA's responsibility to review the expanded access request and decide whether it may proceed.


It is important to point out that expanded access differs from emergency use authorization. Emergency use authorizations are medical countermeasures used to combat biological or chemical threats (e.g., radioactive materials, infectious diseases) and are issued by the regulatory agencies during public health emergencies to facilitate access to any essential medical products, including drugs, diagnostic tests, or others, when there are no other options available (Rizk et al., 2021). The most recent example of emergency use authorization was during the pandemic of Coronavirus Disease 2019 (COVID-19). The regulatory agencies FDA and EMA have granted emergency use authorization for two mRNA-based vaccines developed by BioNTech/Pfizer and Moderna in response to the rapid and continuous spread of the deadly virus around the globe (Fortner & Schumacher, 2021). In situations like the COVID-19 pandemic, the regulatory agencies have to evaluate the options promptly using the evidence available and carefully assess the potential benefits and risks (Rizk et al., 2021). Regulatory agencies respond to emergency situations using rigorous strategies to render effective therapies to patients and review their decisions when appropriate for public health. In some cases, however, when applying for an expanded access program, it is necessary to require an ‘emergency use’ when there is not sufficient time to obtain FDA and IRB approval prior to starting the treatment with an unapproved (investigational) drug or device.


Figure 3: Decision-making for expanded access to treatment (VCU, n.d.).

What to Consider When Applying for the Expanded Access Program

The decision regarding the use of an investigational medical product should be a cooperative process between the patient and a licensed physician. The discussion between them should involve some essential factors, such as the nature of the illness, the specific stage of the illness, and any other concurrent health conditions the patient may be facing. In simple terms, the severity of the patient's condition and the current available therapies must be considered. If the patient has a serious or immediately life-threatening illness or condition and there is no other approved treatment available on the market to treat its condition, the first option to consider is the patient’s enrollment in a clinical trial. All clinical trials around the globe can be accessed through the website https://clinicaltrials.gov/. The patient may qualify for a clinical trial to treat a disease or condition. For example, age, gender, type of condition, and stage of the disease may be decisive for the patient’s eligibility in a particular clinical study. By participating in a clinical trial, patients help to increase the chances that a medical product will be useful for other patients with the same disease or condition. If the patient is not eligible for a clinical trial, then an expanded access program may be an option. In this scenario, it is crucial to obtain comprehensive knowledge about the investigational medical product, for example, its potential benefits for treating the condition and the possible risks and side effects of the treatment. There is also an important consideration to make when using investigational medical products: costs related to the product and the medical services it requires. The costs related to investigational medical products are usually not covered by third-party payers, such as health insurance companies. There may also be costs associated with IRB review, which are the responsibility of the patient (FDA, 2022).


Challenges Associated with Expanded Access Programs

Expanded access programs can offer hope to individuals who have exhausted other treatment options. These programs have grown in popularity around the globe due to several factors, including the development of new drugs to meet serious unmet medical needs, the increasing activity of patient advocacy groups, and the wide availability of information about new treatments on the Internet (Caplan et al., 2018). However, there are several important ethical challenges related to therapeutic use of unauthorized drugs that should be discussed. For example, expanded access programs can increase exposure of patients to investigational products that may not ultimately be approved (Borysowski & Gorski, 2019). It is known that many investigational drugs fail in clinical studies often due to inadequate safety and/or efficacy. Furthermore, in initial studies the safety profile and therapeutic dosage guidelines may not be fully established (Darrow et al., 2015). Therefore, it is often difficult to predict the potential risks and benefits related to the use of this investigational drug, and this needs to be done with great caution. When considering a patient for an expanded access program, the physician should be highly qualified for this position. Not only the medical aspects should be taken into account, but also the complex ethical dilemmas inherently linked to the use of unapproved medicines. Therefore, the physician should not only possess high professional qualifications, but also have some ethical training to deal with the complexity involving expanded access.


Figure 4: Patient approach in clinical research (Florence, n.d.).

Expanded access programs may also have an impact on the recruitment and conduct of clinical trials. Due to the burdens associated with clinical trials (e.g. performing tests essential to collect the data about the effects of the investigational drug) and the possibility of being assigned to a control group, patients are likely to prefer compassionate treatment over clinical trials (Borysowski & Gorski, 2019). This is one of the reasons that only patients who cannot be enrolled in a clinical trial can be considered for an expanded access program. Furthermore, for a medicine to be approved for widespread use, it must complete clinical trials under rigorous regulations, which serve as the gold standard for evaluating the safety and efficacy of medicines. If expanded access is used on a large scale, this would challenge current medicine regulatory systems, which guarantee the production of safe and effective medicines for the population (Borysowski & Gorski, 2019). Therefore, compassionate treatment should only be undertaken with caution and in exceptional cases. Another aspect to consider is that expanded access programs always focus on patient treatment, and data collection is a secondary objective. Thus, information generated may not provide the same level of quality and interpretability as data generated by clinical trials (Darrow et al., 2015).

Another concern is regarding the potential socioeconomic disparities in access to experimental treatments through expanded access programs. Insurers may refuse to intervene and manufacturers may not cover the costs associated with treatment. As a result, patients with fewer resources may have disadvantages or may not even apply for these programs (Darrow et al., 2015). The ethical aspects of expanded access need to strike a balance between the urgent needs of patients facing life-threatening conditions and the ethical principles that underpin responsible medical practice centered not only on the patient but also on society.


Conclusion

An expanded access program is an approach that allows patients with serious or life-threatening conditions to access experimental medicines or therapies that have not yet been approved by regulatory agencies. These programs were designed around the world to provide treatment options for patients who have exhausted all available standard therapies and do not qualify for clinical trials. Expanded access programs can be a last resort for patients who urgently need access to treatments for very specific conditions. Therefore, these programs require careful regulatory oversight to ensure patient safety and that ethical standards are followed. Access to these programs has increased in recent years, and it is extremely important that discussions related to regulation and ethics are constantly debated.


Bibliographical References

Aliu, P., Sarp, S., & Fitzsimmons, P. (2021). Increasing Use of Compassionate Use/Managed Access Channels to Obtain Medicines for Use in COVID-19. Clinical Pharmacology & Therapeutics, 110(1), 26-28. https://doi.org/10.1002/cpt.2140


Borysowski, J., & Gorski, A. (2019). Compassionate use of unauthorized drugs: Legal regulations and ethical challenges. European Journal of Internal Medicine, 65, 12-16. https://doi.org/10.1016/j.ejim.2019.04.008


Caplan, A. L., Teagarden, J. R., Kearns, L., Bateman-House, A. S., Mitchell, E., Arawi, T., . . . Gardner, S. L. (2018). Fair, just and compassionate: A pilot for making allocation decisions for patients requesting experimental drugs outside of clinical trials. Journal of Medical Ethics, 44(11), 761-767. https://doi.org/10.1136/medethics-2016-103917


Darrow, J. J., Sarpatwari, A., Avorn, J., & Kesselheim, A. S. (2015). Practical, legal, and ethical issues in expanded access to investigational drugs. The New England Journal of Medicine, 372(3), 279-286. https://doi.org/10.1056/NEJMhle1409465


European Medicines Agency. (2007) Committee for Medicinal Products for Human Use (CHMP). Guideline on Compassionate Use of Medicinal Products, Pursuant to Article 83 tf Regulation (Ec) No 726/2004. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-compassionate-use-medicinal-products-pursuant-article-83-regulation-ec-no-726/2004_en.pdf


Food and Drug Administration. (2022) Expanded Access. https://www.fda.gov/news-events/public-health-focus/expanded-access


Food and Drug Administration. (2022) Expanded Access | Information for Patients. https://www.fda.gov/news-events/expanded-access/expanded-access-information-patients


Eyal, N., & Lipsitch, M. (2020). Opinion: It's ethical to test promising coronavirus vaccines against less-promising ones. Proceedings of the National Academy of Sciences of the USA, 117(32), 18898-18901. https://doi.org/10.1073/pnas.2014154117


Fortner, A., & Schumacher, D. (2021). First COVID-19 Vaccines Receiving the US FDA and EMA Emergency Use Authorization. Discoveries (Craiova), 9(1), e122. https://doi.org/10.15190/d.2021.1


Jarow, J. P., Lurie, P., Ikenberry, S. C., & Lemery, S. (2017). Overview of FDA's Expanded Access Program for Investigational Drugs. Therapeutic Innovation & Regulatory Science, 51(2), 177-179. https://doi.org/10.1177/2168479017694850


Krendyukov, A. (2020). Early Access Provision for Innovative Medicinal Products in Oncology: Challenges and Opportunities. Frontiers in Oncology, 10, 1604. https://doi.org/10.3389/fonc.2020.01604


Rizk, J. G., Forthal, D. N., Kalantar-Zadeh, K., Mehra, M. R., Lavie, C. J., Rizk, Y., . . . Lewin, J. C. (2021). Expanded Access Programs, compassionate drug use, and Emergency Use Authorizations during the COVID-19 pandemic. Drug Discovery Today, 26(2), 593-603. https://doi.org/10.1016/j.drudis.2020.11.025



Visual Sources

Cover Image: Eyal, N., & Lipsitch, M. (2020). Opinion: It's ethical to test promising coronavirus vaccines against less-promising ones. Proceedings of the National Academy of Sciences USA, 117(32), 18898-18901. [Image]. Retrieved November 29, 2023. https://doi.org/10.1073/pnas.2014154117


Figure 1: Aizenman N., Health News from NPR. (2019). How To Demand A Medical Breakthrough: Lessons From The AIDS Fight [Image]. Retrieved November 29, 2023. https://www.npr.org/sections/health-shots/2019/02/09/689924838/how-to-demand-a-medical-breakthrough-lessons-from-the-aids-fight


Figure 2: Hiteks Solutions. (n.d). PSimplifying Paperwork and Increasing Patient Access to Oncology Compassionate Use Therapeutics [Image]. Retrieved December 2, 2023. https://hiteks.com/simplifying-paperwork-and-increasing-patient-access-to-oncology-compassionate-use-therapeutics/


Figure 3: Virginia Commonwealth University (VCU), Office of the Vice President for Research and Innovation. (n.d.). Compassionate, expanded access and emergency use of drugs/devices [Image]. Retrieved November 29, 2023. https://research.vcu.edu/human-research/regulatory-affairs/comp-emerg-use/


Figure 4: Florence. (n.d.). What Is a Patient-Centric Approach in Clinical Trials [Image]. Retrieved November 29, 2023. https://florencehc.com/blog-post/what-is-a-patient-centric-approach-in-clinical-trials/



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Juliana Priscila Vago

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