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FDA showcases clinical trial design, regulations for HCV

Treatments for hepatitis C virus infection have improved over the past few years and in a new report published in Hepatology, researchers from the Food and Drug Administration detailed several scientific approaches and regulatory mechanisms used that have had an impact on direct-acting antiviral development and subsequent approvals.

“The FDA’s approach to evaluation of recent hepatitis C drugs underscores the agency’s flexibility in considering innovative or alternative trial designs for drugs that have demonstrated highly promising outcomes in early phase development,” Poonam Mishra, MD, MPH, deputy director for safety, division of antiviral products/office of antimicrobial products, FDA center for drug evaluation and research, told Healio.com/Hepatology. “Expedited approaches can be used without compromising efficacy standards for drugs that demonstrate breakthrough therapy potential.”

The report was published in an effort to “increase transparency” to various stakeholders (eg, healthcare providers) about the FDA’s scientific approaches and regulatory processes that support drug development and marketing approval of DAAs for the treatment of HCV. The authors outlined specific approaches the FDA used for HCV drug development and approvals.

SVR as a “validated” surrogate

Sustained virologic response, a virologic surrogate known as SVR, has been used for countless studies to determine successful therapy in clinical trials. Obtaining clinical outcomes can be challenging, according to the researchers, so SVR was named an objective endpoint that signifies clearance of HCV and has been labeled a “virological cure,” according to the report.

“Based on numerous observational cohorts showing strong correlations between SVR and multiple clinically important outcomes, such as development of hepatocellular carcinoma, end-stage liver complications and mortality, the FDA considers SVR a ‘validated’ surrogate efficacy endpoint in [chronic hepatitis C] clinical trials,” the researchers wrote.

12-week time point

SVR at 12 weeks as a primary endpoint was developed after researchers from the FDA analyzed pooled data from multiple clinical trials of pegylated-interferon-based regimens for 12 and 24 weeks. The report states that researchers and scientists noticed recurrence earlier than 24 weeks post-treatment, so researchers wanted to find an acceptable endpoint at which patients could be considered cured. From the research, the FDA noticed a high rate of concordance between SVR12 and SVR24, and deemed SVR12 sufficient.

“SVR12 signifies a durable virologic response and is now used as the primary efficacy endpoint in all HCV registrational trials,” the researchers wrote. “This allows for earlier approvals of highly effective and well-tolerated therapies, facilitating access to those in need.”

Use of historical controls

Currently, the FDA recommends phase 3 trial designs and HCV drug development programs to include placebo-controlled and historical-controlled trials with and without comparison of treatment duration or the addition of ribavirin to a regimen, according to the report.

The primary purpose of a placebo-controlled design is to collect safety data. However, it also shows the efficacy of the regimen being investigated, as it is compared to placebo or no treatment at all.

The report states that the use of historical controls for evaluating HCV therapies was appropriate for drug development based on four points: investigators and patients did not endorse active controlled trials due to poorly tolerated interferon-based regimens, which was a safety concern for participants; interferon is not well-tolerated by a majority of patients; treatment effects of investigational regimens were known to be greater than placebo, so choosing an active-controlled or historical control trial was based on a clinician’s perspective; and SVR is an objective endpoint, consistent in trials with interferon-based regimens.

“Non-inferiority margin choices were based on clinical judgment regarding how much loss in SVR was acceptable for a regimen that has the advantages of not including interferon, had a shorter duration or potentially a better tolerability profile,” the researchers wrote.

Expanding treatment to subpopulations

The report stated that criticism has evolved over time regarding patients in phase 3 clinical studies not representing real-world patients, and that women, elderly and ethnic subgroups are being under-represented. However, the FDA maintains that exact regimens for specific patient subgroups can be determined in a post-marketing trial.

“Our approvals have shown robust efficacy, but tailoring an optimal regimen for all patient populations with various genotypes as a pre-market strategy may unnecessarily delay access to lifesaving treatments; identifying shorter treatment regimens or providing data on other populations such as patients undergoing transplantation could be addressed in the post-marketing setting,” the researchers wrote.

The researchers further wrote: “Regulatory bodies have a public health responsibility of making sure that safe and effective drugs are available to [the] public in a timely manner. A fine balance needs to be struck between providing sufficient data for drug development and labeling and providing patient access to therapies as soon as possible. A valid evidence-based approach was used in our approach to the approval of therapies to treat hepatitis C.” – by Melinda Stevens

Disclosures: The researchers report no relevant financial disclosures.