European governments must move quickly to ensure that compassionate use arrangements are put into place to allow access to new hepatitis C drugs for people with cirrhosis, advocates and doctors said at the 48th International Liver Congress (EASL 2013) in Amsterdam last week.
However, clear differences in opinion emerged between patients and doctors regarding who should make decisions about acceptable levels of risk to patients during a symposium on compassionate use organised by the European Liver Patients Association.
Dr Daniele Prati, speaking on behalf of the European Association for the Study of the Liver (EASL), said that EASL welcomed compassionate access programmes for people with hepatitis C who would otherwise experience progression of disease, such as decompensated cirrhosis, provided that the risk-benefit ratio is positive.
But patient advocates speaking at the symposium asserted that patients should have the right to make informed choices about the risks and benefits of new drugs – even where information is lacking.
“We don’t know why we can’t take these risks, it is our lives”, said Ivan Gardini, Vice-President of the European Liver Patients Association. Mr Gardini fought to obtain boceprevir after being excluded from clinical trials and a compassionate use programme in 2011, due to a very high platelet count. He had been diagnosed with cholestatic and aggressive hepatitis C recurrence following a liver transplant in 2009, and had a life expectancy of two to three years. Following a course of triple therapy he remains HCV-free, 36 weeks after completing treatment, but says he is too cautious to declare himself cured – yet.
What is compassionate access?
Compassionate access programmes provide medicines to people with an urgent unmet need for treatment, prior to marketing approval. In practice they may take the following forms:
- Individual named patient access in urgent cases.
- A cohort study with eligibility criteria, which collects safety and efficacy data, usually run through participating liver centres.
- Pre-licensing access for a large number of patients – “expanded access” – without the collection of effectiveness data.
Compassionate use programmes for antiretroviral drugs for HIV treatment began in the mid-1990s. They made new agents available to people who had run out of active drugs due to drug resistance. In some cases over 10,000 people in the United States and Europe received a new drug through one of the early access programmes.
In France, these early access programmes were formalised into a system called Autorisation Temporaire d’Utilisation (ATU) in 1994. A pharmaceutical company is able to submit a proposed programme for approval and negotiates a price for the medicine, which is made available either on an individual basis or as part of a cohort study. Over 1000 medicines have been made available on this basis.
Arrangements vary across the European Union. Article 83 of the 2004 regulations governing the work of the European Medicines Agency gives the agency’s Committee for Human Medicinal Products the power to review compassionate release programmes and approve the eligibility criteria. It is then up to member countries to approve these schemes, but not all countries have legal mechanisms to allow compassionate use of unlicensed medicines. In Bulgaria, for example, regulations are still being drafted to permit compassionate use schemes, Stanimir Hasurdjiev of the European Liver Patients Association told the symposium.
Until now the European compassionate release mechanism has only been used for two influenza drugs, oseltamivir and intravenous zanamivir. Philip Josephson of the European Medicines Agency told the symposium that the agency has no power to force a company to make a product available on a compassionate use basis. He went on: “It would be very interesting if the Article 83 procedure could be used for a hepatitis C programme…the more trial-like a compassionate use programme is, the better.”
“After the success of CUPIC I would recommend to systematically combine compassionate access and investigation,” agreed Professor Daniel Dhumeaux, chair of France’s national hepatitis masterplan.
Hepatitis C compassionate access schemes
Two hepatitis C direct-acting antivirals have already been made available through ATU in France in the CUPIC cohort study. This scheme is collecting safety and efficacy data on more than 600 people who received telaprevir (Incivo) or boceprevir (Victrelis) through the scheme. People with F3 fibrosis or cirrhosis who had failed a previous course of treatment were eligible to receive the drugs.
A compassionate access programme also provided telaprevir prior to reimbursement approval to over 600 patients with cirrhosis or F3 fibrosis in 16 European countries. French regulators are currently reviewing plans for an ATU that would make sofosbuvir and ribavirin available for people awaiting liver transplant, and for people who have developed recurrence of hepatitis C and severe liver disease after a liver transplant.
In some countries compassionate access schemes have been the only way to get access to new hepatitis C drugs. In Italy for example, the telaprevir compassionate use programme was the only way of obtaining the drug for 15 months after European marketing approval. Patients in Belgium, Ireland, the Netherlands, Spain and the United Kingdom were also kept waiting by reimbursement authorities. Dr Daniele Prati, speaking on behalf of EASL, said that “compassionate access programmes should not be used as a solution to delays in deciding reimbursement criteria.”
Liver transplant patients and cirrhotics: priorities or high risk for compassionate access?
Companies are in discussion with advocates about other access arrangements, but many advocates fear that the lack of data on the use of new hepatitis C drugs in people with cirrhosis and in those who have received liver transplants will prove a barrier to access.
Professor Thomas Berg, head of the Division of Hepatology at the University Hospital, Leipzig, warned that some hepatitis C drugs have shown unexpected serious toxicities, resulting in deaths in several studies. Professor Berg suggested that compassionate access to new HCV drugs would be best organised through specialised centres that have the capacity to manage serious adverse events and to monitor patients carefully.
“Physicians may not be well trained in the use of HCV drugs. Physicians also need to have long-term experience of managing the relevant patient population,” he said.
Physicians are also concerned about the lack of drug interaction data, particularly in patients taking immunosuppressive drugs after liver transplantation. Some are also concerned about the risk of serious side-effects if the drugs are used in people with decompensated cirrhosis who are on the waiting list for a liver transplant.
“I think it is unethical at this moment not to do a study in people on the transplant waiting list,” said Luis Mendão of the Portuguese activist group GAT. Treating patients with cirrhosis and those on the waiting list has the potential to avoid the need for liver transplantation, said Tracy Swan, Hepatitis/HIV Project Director of the Treatment Action Group.
The rate of progression from compensated to decompensated cirrhosis is high – approximately 5-7% of people with compensated cirrhosis will progress to decompensation each year, Ivan Gardini pointed out. (Patients with higher hepatic venous gradients are at greater risk of decompensation).
Yet data from the French ATU programme and from Austrian liver centres show the high risk of serious adverse events in patients with cirrhosis, said Prof. Pratis. Patients with highest risk of decompensation were also at the highest risk for severe infections during triple therapy, Austrian researchers found.
Drug-drug interactions remain a particular concern in people with cirrhosis. Unlike in HIV, where companies had no option but to study drugs in the sickest patients first, hepatitis C drugs are being tested first in trials that either exclude cirrhotics or recruit small numbers. This makes it difficult to draw conclusions about safety and drug-drug interactions.
“Drug-drug interactions should not be an exclusion criteria for cirrhotics,” said Luis Mendão.
The other population who need compassionate access are people with HV and HCV co-infection.
“People with HIV and hepatitis C co-infection are likely to form a disproportionate part of the population needing new drugs because of faster progression of liver disease,” said Luis Mendão, who is living with HIV and hepatitis C.
Ivan Gardini urged that compassionate access programmes should exclude as few patients as possible, and that patients rather than doctors should make the final decision about the degree of risk they are prepared to accept. “We need doctors to have the courage to try something that they don’t know,” he said.
European Medicines Agency compassionate use: questions and answers