Drug development guidelines for Hepatitis C virus

Debra Birnkrant, director, Division of Antiviral Products

Dr. Deborah Birnkrant caricatureChronic hepatitis C virus infection is a global public health burden. It is estimated that 170-200 million persons around the world are infected with the hepatitis C virus; it affects about 3 to 5 million people in the United States.

Many people infected with the hepatitis C virus (HCV) are not aware of their condition so they do not seek or receive treatment. Approximately 75 percent of those with HCV infection in the United States were born between 1945 and 1965.
Without treatment, chronic hepatitis C infection can progress to cirrhosis, liver cancer, liver failure, and death. Chronic hepatitis C is currently the most common reason for liver transplants in the U.S.
Guiding the way
To aid in the development of new treatments for chronic hepatitis C, FDA’s Center for Drug Evaluation and Research released revised guidance to assist drug companies in the development of direct-acting antiviral (DAA) drugs.
The original guidance, Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment, was issued in September, 2010. The landscape of chronic hepatitis C treatment has changed since then.
Direct acting antiviral drugs interfere with specific steps in the hepatitis C virus replication cycle through interaction with the virus’s genome, polyprotein, or polyprotein cleavage products.  
Up until 2011, pharmaceutical treatment for chronic hepatitis C infection consisted of taking two drugs, pegylated interferon and ribavirin. Although the revised guidance discusses the development of DAAs with and without interferon, the main focus is on the development of direct-acting antiviral drugs as part of interferon-free regimens.
The guidance also outlines many different trial design options in multiple patient populations and specific populations.
For example, although randomized controlled comparative trials are preferable, in some situations, single-arm trials using a historical control may be appropriate. As outlined in the draft guidance, an immediate-versus-deferred placebo controlled trial design can be used in subjects who are not considered to need immediate treatment. In this design, subjects should be randomized to the DAA-based regimen or placebo for the intended treatment duration. The purpose of the deferred treatment design is to collect comparative safety data. At the end of treatment, subjects randomized to the placebo arm can receive the DAA-based regimen. Alternatively, a dose or treatment duration comparison could be used.
Once interferon-free DAA combination regimens become available, an active-controlled superiority or noninferiority trial design may be feasible and preferred over a single-arm design.
Since direct-acting antiviral drugs for treatment of chronic hepatitis C is a rapidly evolving field, recommendations in this guidance are flexible to accommodate developments in the therapeutic area. To help drug companies with the shifting landscape, we strongly encourage early discussions with us. We can address any questions or concerns regarding scientific advances that may impact their clinical development program.
Breakthrough developments
The development of new therapeutic modalities that are more efficacious, better tolerated, have less associated pill and injection burden, and can be administered with simple treatment and management algorithms are much needed – and the field is progressing towards that goal.
In May, 2011, two direct acting antiviral drugs, boceprevir and telaprevir, were approved which substantially improved efficacy. However, the tolerability of these regimens is a major issue and these drugs need to be taken with pegylated interferon and ribavirin. One of the most difficult things people on hepatitis C therapy have to deal with is the side effects caused by interferon injections and ribavirin pills.
Sofosbuvir was approved in December, 2013 as a component of the first all-oral, interferon-free treatment for chronic hepatitis C patients with genotype 2 and 3 infections. An interferon-freeregimen provides a therapeutic option for patients who are ineligible, intolerant or not willing to take interferon-based treatments. This regimen addresses an unmet need in this patient population.
With interferon-free, all-oral therapies the emergence of resistance mutations is a concern. The attainment of a sustained viral response -- now defined as the absence of detectable HCV RNA (genetic material of the hepatitis C virus) in blood serum three months after completion of treatment -- depends on many factors. When drugs are not used as part of an optimal regimen or for optimal duration, resistance may emerge -- this may impact future treatment options.
We’ll need to evaluate data from long-term follow-up studies including resistance data to monitor for durability of response as well as viral resistance.
Advances in the field of hepatitis C drug development and promising data being presented at scientific meetings are reasons to be optimistic. The approvals of sofosbuvir and simeprevir give physicians the option to treat most of their hepatitis C patients with simpler, shorter duration treatment regimens with improved efficacy and safety profiles.

With sustained viral response rates reaching greater than 90 percent using direct acting antiviral combination regimens, it is anticipated that the majority of chronic hepatitis C patients can be cured of their infection within the foreseeable future.  


Debra B. Birnkrant, M.D. is the director of the Division of Antiviral Products in the Office of Antimicrobial Products, one of six offices of drug evaluation in CDER’s Office of New Drugs. As director, Dr. Birnkrant has been instrumental in accelerating the review and approval of several leading AIDS therapies.

Page Last Updated: 12/11/2014
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