Compassionate use — what it means in practice

Compassionate use refers to patient access to investigational therapies outside of clinical trials when approved treatments have failed, and the survival or alleviation of suffering of a patient is dependent on finding an alternative. While the primary objective of clinical trials is to investigate the efficacy and safety of a drug in the general population, compassionate use, also referred to as ‘expanded access’, seeks to obtain benefit in a specific patient or a group of patients whose options are limited.

The term ‘compassionate use’ goes back to the early stages of the AIDS epidemic when experimental drugs were undergoing clinical trials. Programs allowing access to these experimental drugs came to be known as ‘compassionate use’, because people were dying from this untreatable disease faster than the clinical trials could provide solutions.

Recently the subject of compassionate use came up as a part of my scientific writing career. While my client was very adept on the practical implications and regulatory requirements for compassionate use, some of my medical writing colleagues indicated they had not been involved with this before, and of course correctly noted it would require the right ethics approval. This article will attempt to enlighten the reader on this issue, and present it from the perspective of regulatory bodies and that of the patient.

Over 99% of requests for compassionate use of investigational drugs are approved by regulatory authorities; however more than half of investigational drugs entering pivotal clinical trials fail, primarily due to efficacy and safety

Requests for compassionate use of investigational therapies increased 2-fold from 2005 to 2014, and the numbers have risen significantly since 2015. The rise in requests is mainly due to a greater awareness of promising therapies from the internet. Potential pandemic threats from emerging infectious disease, coupled with the willingness of chronically ill or dying patients to try a novel untested therapy, have contributed to this increase. Patients may even launch social media campaigns to raise awareness of their plight.

A well-publicized example of the power of social media in influencing decisions about compassionate use was for Josh, a seven-year old boy who was critically ill at St Jude’s Hospital in Tennessee, USA, with a life-threatening viral infection. After the failure of approved treatments, his doctor requested access to a drug that was undergoing phase 3 clinical trial. It would be heartless not to see the dilemma facing physicians caring for Josh, who had battled childhood cancers for all but 9 months of his life, only to watch him succumb to a viral infection that could be treated with a medication that had proven efficacy in earlier clinical trials. On the flip-side, the drug company had stopped accepting new requests for compassionate use, deciding to focus their resources on the phase 3 trial required for FDA approval that would, in the long run, be in the best interest of the greatest number of patients. We may ask, why could they not do both? It takes considerable resources and people-time to get the necessary approvals in place to obtain compassionate access to investigational drugs. In the case of Josh, the company denied the second plea by the hospital administration for access, which led to a Facebook post by a relative of Josh trying to identify someone at the company who could be influenced to change their decision. This mushroomed within days into main-stream media coverage and more social media pressure, with the company’s management and board members receiving hundreds of phone calls, emails, and even death threats, pleading for access for Josh. State and national politicians got involved, and discussions began between regulatory authorities and the company on how to permit compassionate access without compromise to the ongoing clinical trial. Five days after the first Facebook post, the company announced they would make the drug available for Josh as part of a small open-label trial.

The outcome was good for Josh who responded well to the treatment. However, there were many unexpected downstream consequences. Where social media led to the release of the drug for an individual, an important question raised was “Do attempts to help individuals in immediate need place at risk the pursuit of evidence-based regulatory approval that will make a product available as quickly as possible to the largest number of affected or soon-to-be affected individuals?” Smaller companies with less resources are more likely to have difficulty addressing such a moral dilemma.

Patient access to experimental treatments presents a very powerful moral and ethical dilemma, and has generated much debate in the scientific community. On the one hand, there is the immediate need of a very ill patient who has not responded to approved therapies, but is aware that an investigational one exists. On the other hand, the process of obtaining regulatory approval for compassionate use rests with the manufacturer, and may delay or divert resources away from the more streamline and efficient process of a well-designed clinical trial that will ultimately benefit a much larger number of patients. There is also the healthcare provider who has a duty to help and not harm patients, and to decide whether any potential for benefit outweighs the likelihood of harm from treatments with insufficient or limited safety data.

Very often regulatory authorities are blamed for non-access to investigational drugs. Since 1999, the US FDA, for example, has approved over 99% of expanded access requests. This has raised further concerns that pressures on regulatory authorities to approve these requests might circumvent science and logic, and create a system of unfairness and inequality. However, compassionate use requests can only occur if the company who owns the therapeutic entity applies for approval with the appropriate regulatory agency. This process often tends to delay the development of the therapeutic entity. If a drug is already in a clinical trial program, the available supply of the drug may already be allocated to the trial, with limited supply available for compassionate use.

Even if the drug has not yet entered phase 1 clinical trials, there is often a high likelihood that it will not be approved. Recent published estimates suggest that among novel therapeutics that entered trials between 1998 and 2008, only 36% were approved by the US FDA. Failures were mainly due to inadequate efficacy (57%), while safety accounted for 17% of failures.

There is also the question of risk versus benefit in the specific patient, and the extent to which those seeking the therapy can truly be ‘informed’ about these risk given their circumstances in order to give informed consent. Patients in the situation where an untested drug is a last resort are often likely to overestimate the potential benefits and underestimate its risks, and efforts to ensure that rational decisions are made, whether by the patient or a close relative, based on a thorough understanding of the risks, can be very problematic.

With regard to the ethics and the medical practitioner, the ‘first do no harm’ principle immediately comes into force. The potential for benefit, however is perhaps the counterpoint to the argument, and weighing this up can be fraught with assumptions and value judgments. Decisions by the medical practitioner should be on a case-by-case basis, and should involve consideration of whatever data is available on the drug, the patient’s prognosis, and unintended mental and emotional consequences of giving hope where none can be assured.

Regulations governing compassionate use require fairly lengthy ethical and legal regulations before this could occur. In the US, access to experimental treatments for emergency use requires approval by the manufacturer, the FDA, and the ethics committee of the institution where the patient is being treated. The manufacturer also has no legal obligation to make the treatment available. The FDA also requires that doctors who offer the investigational therapy must, in general, follow all procedures as if the patient was part of a clinical trial, including reporting of adverse events. In Australia, there are two schemes that enable clinicians to use unauthorised treatments; the Authorized Prescriber Scheme (APS) and the Special Access Scheme (SAS), both regulated by the Therapeutic Goods Administration of Australia. Ethics approval, informed consent of the patient, and a thorough clinical justification is needed for both schemes. 

In 2018 the US signed into law the Right to Try Act, which provided patients with life-threatening conditions an alternative pathway to access investigational drugs that had completed phase 1 clinical trials, without the need for FDA authorisation. This has been criticized for a number of reasons, mainly for unreasonable use of drugs that have not been fully trialled, and also the apparent ‘hands-off’ approach of the FDA that could negatively impact proper regulatory oversight of drug development.

For patients with serious life-threatening disease for whom authorised treatments have failed, compassionate use may be a last resort. There are also the issues of how to allocate limited supplies of an investigational drug in a transparent, ethical, evidence-based and patient-focussed manner. It may be the lucky few who know about investigational drugs, and can rally the forces of social media for their cause, or have the tenacity to navigate the processes involved in obtaining it. There is however, no consensus on how best to handle these ethical and moral dilemmas, and deciding on what is fair access, and whether the individual need should be placed ahead of the ‘greater good’, remains an emotional and legislative minefield.

At SugarApple Communications, our mission is to adhere to the highest ethical standards in the promotion of high quality research. Get in touch today and let’s talk.

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