The Ethics of Compassionate Use

Only 20 to 40 percent of patients presenting at current cancer clinical trials are eligible for participation. Experimental drugs offer potentially life-saving cures for patients who aren’t responding well to currently available medications. For those whose conditions won’t wait for new drugs to reach the market, the trials their physicians recommend may be literal lifelines.

For those 60 to 80 percent of people, however, it’s impossible to access these life-changing trials. Secondary conditions, developmental disorders or family histories could lead to researchers turning patients away from the trial out of concern over confounding variables. Furthermore, patients who are unable to access study sites due to mobility, location, time or money are unlikely to even attempt to enrol for studies.

How, then, can patients legally access experimental drugs before they’re on the market? With support from their physicians, they may be able to try something called compassionate use, or the Early Access to Medicines Scheme (EAMS). This allows them to try the drug being researched without being directly involved in the trial itself.

While involvement in this process could be lifesaving, there are many barriers toward patients taking advantage of it. The guidelines around putting a patient forward for compassionate use are not always clear, and many physicians are unwilling to seek access to experimental drugs.

We explore the legal and ethical implications of compassionate use, and offer a basic guide to making requests for pre-approval access and potentially saving lives.

What are the legal implications of compassionate use?

Compassionate drug use is legal, but limited, taking into account the fact that unlicensed drugs can’t be guaranteed safe or efficient. In the USA, law dictates that compassionate use be permitted in only the following ways:

When a drug is in Phase III Clinical trials or later, pharmaceutical companies can offer expanded access programs (EAPs) to those who don’t meet trial eligibility requirements. At this point, researchers can be fairly certain of the drug’s efficacy and safety, and the FDA regulates and approves EAPs.

If a patient doesn’t qualify for a standard EAP, physicians can apply on their behalf for single patient access. In these cases, the drug company, FDA and the doctor’s own institution must all be in agreement before the drug can be administered.

In the UK, the EAMS is run and regulated by the Medicines and Healthcare Products Regulatory Agency (MHRA). Only drugs that have gone through Phase I and Phase II trials are applicable, and pharmaceutical companies must apply to the MHRA for a Promising Innovative Medicine designation before it can be considered for the scheme.

The MHRA will then assess the drug and assign it a positive scientific opinion, meaning that doctors can prescribe it to patients who are ineligible for clinical trials. They will produce a Public Assessment Report (PAR) to help physicians and patients decide which, if any, experimental drug is right for the case at hand.

How do patients access pre-approval drugs?

In the USA, the process begins with a doctor and patient working together to identify an experimental drug they want to try. The doctor will then contact the company developing the drug and request unlicensed use.

If the pharmaceutical company agrees to release the drug on a single access basis, the doctor will then complete a form for the FDA, outlining the treatment plan including doses and monitoring.

The FDA will review the application in under 4 days, or in under 24 hours in emergency situations, offering changes to the treatment plan if necessary, and giving their consent. The Government Accountability Office has found that over 99% of the requests are approved.

In the final stage, doctors must request permission from the hospital or institution they represent to use the unlicensed drug. These institutions each have an Investigative Review Board, which reviews the ethics of such proposals and grants the final level of permission.

In the UK, too, the process starts with patients discussing their options with their physicians, sifting through available PARs to see if any EAMS-applicable medicines will fit the patient’s requirements.

As all drugs involved have already been given general MHRA permission for use in the scheme, the only significant permission left to attain is informed consent from the patient. Patients will be provided with clear information about the drug, its risks and benefits according to Phase I and Phase II trials, and instructions for use before signing their consent.

Some pharmaceutical companies will also request access to data about the patient's condition and general health while they’re using the medicine. Patients will also be asked to consent to this.

What are the challenges?

It’s unlikely that doctors have a comprehensive knowledge of all the drugs in development, and they will therefore have difficulty selecting an ideal option for their patients - particularly in the case of the USA’s single access procedures. This makes it crucial for doctors, patients and advocacy groups to work together to research and raise awareness of drugs in development and their applicability for different conditions.

Another significant challenge is doctors’ unwillingness to recommend a patient for compassionate use schemes. The risks are significant at this unlicensed stage, and regardless of the patient’s informed consent, any adverse effects could negatively impact the physician’s career. Furthermore, physicians may not feel like they have enough information about the process or the drugs on offer to take a gamble.

This is looking to change with recent regulation, however: a recent US law has made it necessary for doctors to publicise their pre-approval access policies and request processes on their websites as soon as a drug enters Phase II of clinical trials.

Fortunately, a law passed last year requires that drug companies make public their pre-approval access policies and information about how to make requests once any of their drugs in development enter the Phase 2 clinical trial stage. Companies are increasingly complying with this requirement by posting this information on their websites.

Meanwhile, in the UK the ready availability of PARs means that doctors can find MHRA-approved documentation on any drugs earmarked for EAMS.

US physicians may also face issues when it comes to approval from IRBs in their own institutions. Not all private hospitals have active IRBs, meaning that the doctor may be unable to find an authority to sign off the final stage of the application.

Some private IRBs charge a fee for their review, which patients may be unable to afford. Healthcare charity The WCG Foundation is attempting to alleviate this issue by coordinating free and fast reviews for patients who would otherwise miss out on compassionate use.

What does the future look like?

While there’s still a long way to go in terms of making patients and physicians aware of the compassionate use options available, a number of recent innovations have us heading in the right direction: the FDA released a new simple and streamlined form for physician applications, and the Reagan-Udall Foundation has pioneered an online navigator for finding relevant information posted by pharmaceutical companies.

To support these innovations and ensure that as many patients as possible can benefit from them, we need compassionate use processes to be included in physicians’ training, ensuring that doctors have the knowledge and the confidence to help patients find options outside of clinical trials.

However, that’s not to detract from the clinical trial system in itself. Instead of searching for options to help patients who are unable to access clinical trials, we could be spending our time and resources widening eligibility criteria and improving trial accessibility in order to include as many patients as possible in clinical research, and in doing so creating more externally valid results.

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