Cost-effectiveness of Interferon-free therapy for Hepatitis C in Germany

Hepatitis C is one of the most common chronic infectious diseases worldwide and in
Germany. The total number of patients infected with hepatitis C virus (HCV) is declining
in Germany, with an estimated 4,980 new infections in 2013 1]. In contrast to the declining number of patients, severe long-term complications
such as decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and ultimately
liver transplants (LT) are estimated to be increasing due to the ageing of the existing
infected population. Of the HCV-infected patients in Germany, 62 % are infected with
HCV genotype 1, which is most difficult to treat 2].

Recently approved direct-acting antiviral agents (DAA) have improved sustained virologic
response (SVR) rates compared to the classic combination therapy of PegInterferon
(IFN) and Ribavirin (RBV; combination with IFN: PR). Despite higher SVR rates close
to 100 %, high treatment costs have stirred a public debate on the pricing of recently
approved DAAs 3], 4].

While triple therapy with first generation protease inhibitors (PI) Boceprevir or
Telaprevir improved SVR rates compared to PR, IFN was still required with both agents.
One of the greatest advantages of new DAAs is the advent of IFN-free treatment regimens.
IFN-free therapies provide dramatically increased SVR rates compared to first-generation
DAAs and avoid IFN’s side effects like depression, anxiety and fatigue, which in many
cases has negative effects on patients’ ability to work 5]. Another advantage of recently approved DAAs are shorter treatment durations, which
can contribute to a better compliance.

As of August 2014, two treatment regimens are recommended for IFN-free therapy of
HCV genotype 1 infection by German Society for Gastroenterology, Digestive and Metabolic
Diseases (DGVS) guidelines 6]:

Sofosbuvir (SOF) and Simeprevir (SMV) combination therapy with or without RBV for
12 weeks

SOF and RBV combination therapy for 24 weeks

Since the approval of DAAs, HCV therapy has played a major economic role in the German
Statutory Health Insurance (SHI) funds. In 2013, the German SHI funds spent € 48.6
mn on Telaprevir and € 19.0 mn on Boceprevir 7].

In 2011, Germany introduced early benefit assessments and rebate negotiations as a
measure of regulating pharmaceutical reimbursement 8]. After approval for the German market, pharmaceutical manufacturers are free to set
a price for one year. Within that one year after approval, all prices of newly approved
drugs need to be negotiated with the German SHI funds. The outcome of the negotiations
is a rebate agreement, which comes into effect one year after approval in Germany
9].

Negotiations for the rebate agreement are based on a 6-month early benefit assessment,
which determines additional benefits of the new therapy compared to an existing alternative
therapy 10]. Early benefit assessments are conducted by German Federal Joint Committee (GBA).
GBA’s assessment in turn relies on a 3-month assessment by German Institute for Quality
and Efficiency in Health Care (IQWIG).

The outcomes of cost-effectiveness analyses with the efficiency frontier approach
are maximum reimbursable prices. Under current German legislation, no cost-effectiveness
analysis is involved in the process of the initial rebate negotiations 11]. However, cost-effectiveness analysis can be requested by either negotiating party
as a base for further negotiations, once a first rebate agreement has been reached,
i.e., the maximum reimbursable price would serve as a base for a new rebate negotiation
between manufacturer and SHI funds. We aim to analyze the cost-effectiveness of DAAs
for IFN-free therapies in this context.

Cost-effectiveness analyses are conducted by IQWIG and they are based on the efficiency
frontier method 12], 13]. IQWIG’s method has previously been criticized because it does not use quality-adjusted
life years (QALYs) as a measure of patient benefits. Contrary to approaches based
on QALYs, German IQWIG requires the definition of specific clinical parameters as
a measure of patient benefits, i.e., the method is not suitable to define a global threshold per QALY gained, as practiced
in England and Wales 14].

Application of IQWIG’s efficiency frontier method requires the assessment of previously
existing therapies. The ratio of previous increases in effectiveness and costs determines
the efficiency frontier. This was heavily criticized by health economists 14], 15]. The results of efficiency frontier analyses depend on the benefits and costs of
previously existing therapies, even though these therapies have never been subject
to health technology assessment and no willingness-to-pay can be derived from the
prices, which could previously be unilaterally determined by manufacturers.

If the ratio of previous gains in benefits and costs has been relatively expensive
(i.e., relatively higher costs per clinical benefit unit), the efficiency frontier approach
leads to higher maximum reimbursable prices for new approvals, too. This might not
be desired from a regulatory perspective. Another problem of application can arise
if multiple efficiency frontiers need to be computed to reflect the relevance of more
than one clinical parameter. Naturally, the results of different efficiency frontiers
may vary, potentially leading to conflicting results. IQWIG suggested to aggregate
specific efficiency frontier results based on patient preferences as found by analytic
hierarchy processes or conjoint analyses 16]–18]. We aim to analyze whether the problems outlined above prevent useful results if
the efficiency frontier method is applied to DAAs for HCV in Germany.