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EASL 2013: Compassionate Access to New Hepatitis C Drugs Is an 'Emergency' for European Patients

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 EASL 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 organized by the European Liver Patients Association.

[Produced in collaboration with Aidsmap.com]

Daniele Prati, speaking on behalf of the European Association for the Study of the Liver (EASL), said that EASL welcomed compassionate access programs 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 (ELPA). Gardini fought to obtain boceprevir (Victrelis) after being excluded from clinical trials and a compassionate use program 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 2 to 3 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 programs 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 centers.

Pre-licensing access for a large number of patients -- "expanded access" -- without the collection of effectiveness data.

Compassionate use programs for antiretroviral drugs for HIV treatment began in the mid-1990s. They made new agents available to people who had run out of active medications 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 programs.

In France, these early access programs were formalized into a system called Autorisation Temporaire d’Utilisation (ATU) in 1994. A pharmaceutical company is able to submit a proposed program 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 programs 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 ELPA told the symposium.

Until now, the European compassionate release mechanism has only been used for 2 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 program…the more trial-like a compassionate use program is, the better."

"After the success of CUPIC, I would recommend to systematically combine compassionate access and investigation," agreed Daniel Dhumeaux, chair of France’s national hepatitis master plan.

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 (Incivek or Incivo) or boceprevir through the scheme. People with F3 (advanced) fibrosis or cirrhosis who had failed a previous course of treatment were eligible to receive the drugs.

A compassionate access program 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 (formerly GS-7977) and ribavirin available for people awaiting liver transplants, and for people who have developed recurrence of hepatitis C and severe liver disease after a 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 program 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. Prati, speaking on behalf of EASL, said that "compassionate access programs should not be used as a solution to delays in deciding reimbursement criteria."

Liver Transplant Patients and Cirrhotics: Priorities or High Risk?

Pharmaceutical 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.

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. He suggested that compassionate access to new HCV drugs would be best organized through specialized centers 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," Berg 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 Activists Group for HIV/AIDS Treatments (GAT).

Treating patients with cirrhosis and those on the waiting list has the potential to avoid the need for liver transplantation, said Tracy Swan, director of the Hepatitis/HIV Project 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, Gardini pointed out. (Patients with higher hepatic venous gradients are at greater risk of decompensation.)

Yet data from the French ATU program and from Austrian liver centers show the high risk of serious adverse events in patients with cirrhosis, said Prati. 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," Mendão said.

Another population who need compassionate access are people with HV and HCV coinfection. "People with HIV and hepatitis C coinfection are likely to form a disproportionate part of the population needing new drugs because of faster progression of liver disease," said Mendão, who is living with both HIV and hepatitis C.

Gardini urged that compassionate access programs 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.

5/3/13

Sources

48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract.

European Medicines Agency compassionate use: questions and answers. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500069898.pdf.