Recent events in West Africa have raised many issues with regards to the use of experimental drugs in humans and the ethical issues attached to this. And yet we regularly see drugs used ‘off-license’ in situations where there are either limited therapeutic options or all other avenues of care have been exhausted, which led me to question the differences between the two.

The Ebola outbreak in West Africa has ravaged the nations of Liberia, Sierra Leone and Guinea resulting in almost 7,000 deaths at this point. The disease is passed via blood and body fluids of infected patients however can be picked up from infected surfaces or from deceased patient, breast milk and semen for several weeks following recovery. Patients with the disease are at high risk of death, from 25-90% (50% on average) however there is no known cure for the disease which carries symptoms of fever, vomiting, diarrhea and a rash, followed by internal and external bleeding which is most often the cause of death.

Although there are several drugs in development with the aim of treating Ebola, not one of them has been used in a randomized controlled trial (RCT); however, several of them have been employed to treat patients suffering from the virus in an attempt to save their lives. ZMapp, being developed by Leaf Pharmaceuticals, is an experimental drug composed of 3 monoclonal antibodies, which has only been tested on Rhesus monkeys, however the 100% success rate of this drug within the trial has led it to be used experimentally in humans during the 2014 Ebola outbreak. TKM-Ebola, in development by Tekmira Pharmaceutical Corp., is a combination of Small Interfering RNA’s. It entered a Phase I clinical trial in January 2014 however the trial was halted by the FDA in July 2014, and then in August 2014 underwent a status change to ‘partial hold’ allowing the drug to be used under ‘expanded access’ to allow availability to patients infected with Ebola in Africa. But what of the ethics involved here? ZMapp successfully treated 18 monkeys and has now been used in 7 humans. Should it be used at all? Or to view it from a different angle, should there be a mass-manufacturing program put into place such that all sufferers are able to access the medication even though there is no strong clinical trial evidence? Currently ZMapp stocks have run out. There is none left. Should this be allowed to happen?

At the same time many drugs are used off-license to treat patients who have failed to respond to conventional, approved therapies.

The FDA differentiates between Expanded Access or Compassionate Use and Investigational or Off-Label Use. In both these circumstances drugs are used either without substantial clinical evidence in clinical trials, or with an approved license but not within a specific therapeutic indication. The former frequently allows patients into clinical trials who did not meet initial entry criteria giving new treatment opportunities, which would otherwise not be available. The latter give clinicians the flexibility to use licensed drugs to treat patients at either a higher dose of therapy than is licensed or to use it to treat conditions, which are outside the current indications. One of the most common uses of off-label prescribing is within cancer treatment. Many cancer therapies are standardized, but within patients who have rare or resistant forms of cancer other options need to be considered. In this therapy area most often the aim is not cure, but progression-free survival, quality of life and limiting toxicity and side effects. To not use these drugs outside the current licensed areas would mean that many hundreds of cancer patients would lose their battle against the horrid disease much sooner.

Pregnancy is another scenario where, because of the risk to the developing fetus, pregnant females are rarely used in clinical trials and therefore drug licenses in pregnancy are few and far between. Although APIs are tested and ranked for teratogenicity this isn’t necessarily an indication of effect in-utero. In many cases there is often a risks vs. benefit consideration and drugs such as anti-thrombotic agents are used routinely in pregnant women who have either a history of thrombosis or are at elevated risk, even though the license doesn’t exist.

Although therapeutic license regulation is highly controlled by awarding agencies, the fact that once a product is marketed means that it may well be used out of license for similar or related disease conditions. Meanwhile drugs that are in Phase I, II and III of development are unavailable outside clinical trial, apart from exceptional circumstance such as the Ebola crisis. But yet the fact that they are both used to treat conditions for which they don’t have substantial clinical evidence from RCT’s will always be questionable from an ethical point of view. Further food for thought comes along when considering the implications of a seemingly effective drug in development not being made available to the wider population when it is clearly efficacious but the long-term effects may not have been recorded. Does the industry have a responsibility to manufacture adequate quantities of the active ingredient in order to fulfill the global need—ZMapp hasn’t been used in one African patient. And should a clinician who sees an unmet need, be at liberty to use their expertise to try and treat a patient regardless of license?

Although there is no easy answer to these questions the industry and professional bodies need to consider these issues. Indeed in August 2014 the World Health Organization (WHO) issued a statement of “Ethical Considerations for the use of Unregistered Interventions for Ebola virus disease (EVD)” supporting the use of the two currently available drugs under specific ethical criteria. Hopefully, it will be decades before we see the global need that has occurred over recent months for unlicensed medicines, and hopefully at that point many of the conditions that currently don’t have effective treatments will be reduced. In the interim there will always be the discussion of off-label and minimal evidence use and the ethical implications of treatment vs. non-treatment. Clarity and unknown implications of treatment or abstinence must be of utmost importance at all times but the outcomes can never be predicted. It’s a difficult place to stand in the clinicians’ shoes.