Ebola and ethics: is it acceptable to use medicines that have not been tested or registered?

Whether or not it is acceptable to use medicines that have not been tested or registered is a debate that has been raging for decades. But the WHO now appears to be worried about the supplies needed to make a significant effect on the outbreak. Mitya Underwood reports

Liberian foreign affairs minister Augustine Ngafuan carries boxes of an experimental Ebola-fighting drug, ZMapp, on a Delta Airlines flight from New York’s JFK airport to Monrovia. Three doses of the experimental drug were first sent to Liberia last month to be given to Dr Kent Brantly and Nancy Writebol, top right and below, American missionaries who had contracted the disease while working with patients in Liberia. John Moore / Getty ImagesShow less

On August 13, a Delta Airlines aircraft carrying precious cargo left JFK International Airport bound for the Liberian capital Monrovia.

Packed into cardboard boxes and marked as “extremely fragile material”, were 12 doses of an experimental drug that could provide the solution to the current Ebola haemorrhagic fever outbreak in West Africa.

The drug has shown promising results in experiments on Rhesus monkeys but has never been tested on people and is not approved by any regulatory authorities. There is no way of knowing exactly what the consequences of administering it to a human being would be.

The question of whether it is ethically acceptable to use medicines that have not been tested or registered is not a new one. It existed in the 1970s and ‘80s when the HIV/Aids epidemic was erupting and it is currently being discussed in the UK Parliament.

But there is no time for lengthy debates in West Africa, so last week the decision was made by some of the world’s most respected health officials.

The meeting of the 12 experts put the potential fate of thousands into the hands of just a few.

They were made to answer two key questions; is it ethical to use unregistered interventions with unknown side effects as a treatment or prevention? And if so, who gets priority to the doses?

The panel brought together to provide the answers included Dr Jeremy Farrar, director of the Wellcome Trust and a Professor of tropical medicine at the University of Oxford; Professor Peter Smith, Professor of tropical epidemiology at the London School of Tropical Medicine Hygiene and Dr Marion Danis, head of section on ethics and health policy at the National Institutes of Health in the United States.

“In the particular circumstances of this outbreak, and provided certain conditions are met, the panel reached consensus that it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects, as potential treatment of prevention,” said the World Health Organisation in a statement released after the meeting.

The first experimental drug to be used, ZMapp, is marketed by the American firm Mapp Biopharmaceutical Inc. It was first identified as a drug candidate in January this year so there is very little stock available.

In a statement on its website, Mapp Bio said all available supplies were exhausted but that it was working with appropriate government agencies to increase production as quickly as possible.

Three doses were first sent to Liberia in July and were given to Dr Kent Brantly and Nancy Writebol, both American missionaries who had contracted the disease while working with infected patients. This created a debate about who was given priority to what hopefully is a life-saving medicine. Both are now recovering in hospital in Atlanta.

The Canadian government is also donating experimental medicines to the WHO in the form of between 800 and 1,000 doses of the vaccine VSV-EBOV.

The Public Health Agency of Canada said that, like ZMapp, the vaccine had never been tested on humans but had “shown promise in animal research”.

“Canada feels this experimental vaccine is a global resource, so in response we are sharing it with the international community, while keeping a small supply in Canada,” said Rona Ambrose, the minister of health.

Not all offerings of experimental and untested medicines have been accepted. The Nigerian health minister Onyebuchi Chukwu said an experimental drug Nanosilver, offered by a Nigerian doctor on August 14, did not meet requirements for use and would not be used to treat any of the country’s Ebola cases. Nanosilver is nanometre-sized silver particles suspended in water, similar to colloidal water. Critics of experimental medicine say it opens up opportunities for quackery.

The same day as the offer was refused, the Food and Drug Administration released a statement warning of fraudulent Ebola treatment products sold online and reminding people that there was no “approved vaccines, drugs or investigational products specifically for Ebola available for purchase on the internet”.

While the news of the experimental vaccine and treatment has undoubtedly created some unrealistic expectations, the alternative of waiting for an effective medicine to pass through years of clinical trials seems impossible given the rate at which the disease is killing those infected.

There has been more than 2,100 reported cases, and 1,100 deaths.

"The public needs to understand that these medical products are under investigation," warned the WHO in a statement. "Evidence of their effectiveness is suggestive, but not based on solid scientific data from clinic trials. Safety is also unknown, raising the possibility of adverse side effects, when administered to humans. For most, administration is difficult and demanding."

Even if it is deemed ethically acceptable to use experimental drugs, WHO continued, supplies will be too small to have a significant impact on the outbreak.

“They have not yet been tested in humans and are not approved by regulatory authorities, beyond use for compassionate care,” it said.

The idea of “compassionate care” relates specifically to a US policy that is also known as the “expanded access” programme and allows for the wider use of new drugs that are not yet approved by the FDA, or at least not approved for use on a particular ailment.

Known as investigational drugs, the FDA has stated that sufficient evidence of safety and efficacy to support its use would “ordinarily consist” of data from phase three of clinical trials, or “compelling data” from completed phase two trials.

There are four main phases of clinical trials for new or change-of-use medicines. The first involves a small group of people used to assess the dosage, side effects and its safety.

The second and third involve larger groups of people, and the fourth comes after the treatment has ben marketed and looks at the drug’s effect on certain demographics and longer-term side effects.

It takes years for medicines to be researched, developed and tested, and the costs can run into the millions or even billions of dollars. Pharmaceutical companies are unlikely to test a drug that is not expected to pass all tests and clinical trials. It also needs to be profitable once it hits the market, either by selling vast quantities or selling at high prices, or, ideally, both.

But this is where the potential problems with the medicine pipeline start.

With something like the Ebola virus, which infected less than 2,500 people between 1976 and 2012 according to WHO figures, the opportunity for profit is low and therefore pharmaceutical companies have not considered it a priority.

But high costs or a lack of approved medicines, as is the current case with Ebola, is what creates the need for experimental and unapproved drugs.

The 2013 film Dallas Buyers Club starring Matthew McConaughy, was based on the real life story of Ron Woodroff who imported and sold unapproved medicines to fellow Aids patients in Texas in the 1980s. He was using experimental medicines instead of waiting years for breakthroughs in research. Some credit him with saving hundreds of lives of people who lived long enough for new medicines to be approved.

Even when a disease or epidemic requires vast quantities of medicines, such as HIV/Aids, if the research and development was expensive, the price of the drug will be high.

It is thought that millions of people in African countries died from Aids-related complications in the 1990s because they could not afford access to the appropriate medicines.

The Antiretroviral drugs (ARVs) were patented by large pharmaceutical companies who did not allow other firms to make cheaper genetic versions.

According to a 2005 article by Michael Reich and Priya Bery, printed in book The Aids Pandemic: Impact on Science and Society, the standard treatment in developed countries cost up to US$21,000 per person per year. In developing countries only a “small number” of HIV patients received treatment, paid for by private insurance or limited government companies.

“The past decade has witnessed a surge of international pressure to lower the prices fro Aids medicines in developing countries,” said the 2005 article.

In 2000, UNAIDS joined forces with other international agencies and pharmaceutical companies to create the Accelerating Access Initiative to bring down the costs of HIV/Aids medicines and increase affordability in developing countries.

Despite the successful efforts, figures from 2003 still revealed that only about two per cent of those in Sub-Saharan Africa with HIV/Aids had access to treatment.

The debates of access to treatment and experimental medicines are not limited to the developing world or certain illnesses.

A bill recently presented to the UK Government for consultation aims to encourage medical innovation by doctors when conventional treatments are not working.

The Medical Innovation Bill, introduced by Lord Maurice Saatchi, would remove the risk of a doctor being accused of negligence when "he or she moves away from existing and established standards within the profession".

A June briefing note explains that if the bill was enacted, a doctor could use a treatment that “has not been tested in clinical trials and is not the subject of any published medical research in relation to heart disease” to treat a patient with a heart condition if a number of conditions were met, including the patient giving up the right to sue if things went wrong.

In a foreword to the briefing, Lord Saatchi said: “This Bill will stop quacks more effectively than the law does at present; but it will give doctors who want to innovate the ability to innovate responsibly, with clarity and certainty that the law will support them.”

It will essentially provide the country’s doctors with the same protection as has been given to doctors currently administering untested and unregistered medicines to Ebola patients in West Africa.