Compassionate use of unauthorized drugs: Legal regulations and ethical challenges

https://doi.org/10.1016/j.ejim.2019.04.008Get rights and content

Highlights

  • Compassionate use is use of unauthorized drugs outside of clinical trials.

  • Many countries have introduced legal regulations concerning compassionate use.

  • Compassionate use is associated with a number of ethical challenges.

  • Ethical review of compassionate use is quite controversial.

  • Some ethics codes contain guidelines regarding compassionate use.

Abstract

Compassionate use (also referred to as expanded access) is therapeutic use of unauthorized drugs outside of clinical trials. The objective of this review is to discuss practical aspects of the current legal regulations concerning compassionate use that have been introduced in the European Union, the USA (both the Food and Drug Administration regulations and Right-to-try laws), Canada and Australia. We also present main ethical challenges associated with use of unauthorized drugs such as possible difficulties with obtaining informed consent and fair patient selection. Moreover, we discuss guidelines, especially those contained in the Declaration of Helsinki, which may aid doctors in the ethical conduct of compassionate treatments.

Introduction

In clinical practice there are certain situations when all authorized drugs have proven ineffective or cannot be used. In such cases, the only treatment option may be unauthorized drugs, especially investigational drugs under clinical development. In general, the access of patients to these drugs is restricted due to concerns over their safety and efficacy. Therefore, until recently, patients could receive these drugs mostly after enrolling in a clinical trial. However, in some cases it is possible to use an unauthorized drug outside of clinical trials. Such treatment is most often termed compassionate use or expanded access [1]. While in the USA the Food and Drug Administration (FDA) prefers the term expanded access [2], according to the terminology adopted in the European Union (EU) regulations, therapeutic use of unauthorized drugs in programs involving groups of patients is referred to as compassionate use [3]. Unlike clinical trials, the primary objective of compassionate use is not to investigate a drug's efficacy and/or safety, but to obtain direct therapeutic benefit in a given patient [4].

Over the years, compassionate use has evolved to become a very complex enterprise involving a number of different stakeholders including drug manufacturers, regulatory agencies, physicians, patients and patient advocacy groups [5,6]. Current compassionate use programs may involve large number of patients, sometimes exceeding thousand [7,8]. Compassionate use has been applied in a variety of different medical specialties including but not limited to oncology, hematology, infectious diseases, gastroenterology, transplantology and ophthalmology [9]. According to the FDA's data, the number of requests for compassionate use has increased twofold from 2005 through 2014 (most recent data covering the years 2015–2018 have not yet been published) [9]. Growing interest in compassionate use is a result of several factors including the development of new drugs for serious unmet medical needs, high activity of patient advocacy groups and wider availability of data about new treatments in the Internet [6].

The main objective of this paper is to discuss practical aspects of legal regulations concerning compassionate use that have been introduced in the EU, the USA, Canada and Australia, as well as to present main ethical challenges associated with therapeutic use of investigational drugs.

This review is based on articles selected from Medline through PubMed (years 2014–2019, search terms ‘compassionate use’ and ‘expanded access’; where appropriate, references from these articles were also included).

Section snippets

European union

In the EU the legal framework for compassionate use was introduced by Article 83 (1) of Regulation (EC) No 726/2004 of the European Parliament and of the Council (Table 1); in principle, Regulations of the European Parliament and of the Council are mandatory for all Member States. However, this article formulates only two general requirements for compassionate use: 1) a chronically or seriously debilitating disease, or a life threatening disease of patients who cannot be treated satisfactorily

Compassionate use: ethical considerations

There is a number of important ethical problems related to therapeutic use of unauthorized drugs. These include: (1) Risks and potential benefits associated with the treatment; (2) Fair patient selection; (3) Informed consent, (4) Social responsibility of doctors, (5) Ethical review of compassionate use requests, and (6) Ethical guidelines pertaining to the use of unauthorized treatments.

Conclusions

The EU, the USA, Canada and Australia have introduced legal regulations which enable doctors to use unauthorized drugs (in practice these are most often investigational drugs undergoing clinical trials); in addition, in the USA and Australia treatment with investigational medical devices is permitted. While there are some differences between regulations adopted in individual countries, in principle compassionate treatment can be performed in patients with serious including life-threatening

Acknowledgements

None.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations of interest

None.

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