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FDA Guidance for Industry - Chronic Hepatitis B Virus Infection:
Developing Drugs for Treatment
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Efficacy Endpoints
New finite duration therapies could be evaluated in clinical trials using any of the following efficacy endpoints:
• Sustained suppression (6 months or longer) of HBV DNA (less than LLOQ, TD, or TND) off-treatment after a finite duration of therapy
• Sustained suppression (6 months or longer) of HBV DNA (less than LLOQ, TD, or TND) off-treatment with HBsAg loss (less than 0.05 international unit/milliliter (IU/mL)) with or without HBsAb seroconversion after a finite duration of therapy
At present, utility of reduction in HBsAg from baseline (without complete clearance) for assessing response to CHB therapies is unclear because of inconsistent correlations between qHBsAg and clinical response (Hu et al. 2018; Thompson et al. 2010; Chan et al. 2011).
A limited number of secondary endpoints (e.g., HBeAg loss, anti-HBe seroconversion in HBeAg positive patients, ALT normalization) should be considered for testing using appropriate statistical methods for multiplicity. Biochemical serum markers such as ALT values vary between laboratories, and lack of normalization of ALT may often be confounded by the presence of other chronic liver diseases such as nonalcoholic fatty liver disease.
Other important endpoints: Assessing progression of liver disease
Except for patients with advanced or decompensated cirrhosis, a statistically rigorous evaluation of endpoints of liver progression can be challenging because these events occur infrequently until late in the course of CHB. However, treatment effects on these endpoints provide useful clinical information, and trials evaluating them could be used to support an expanded indication or patient population and could be summarized in appropriate sections of the label.
Some of the parameters or clinical outcomes that sponsors can consider include the following:
• Change in Model for End Stage Liver Disease scores
• Change in Child-Turcotte-Pugh scores
• Progression to liver failure requiring transplantation or resulting in death
• Occurrence of HCC
Treatment-related regression of fibrosis or cirrhosis, as assessed by liver biopsy or noninvasive methods, may be appropriate for display in the label. However, sponsors should discuss with the Division plans for labeling and performance characteristics of the noninvasive modality when protocols evaluating these endpoints are being designed.
Patient-Reported Outcome Measures
Sponsors who are considering incorporating patient-reported outcome measures23 as endpoints in clinical trials to measure treatment benefit should discuss patient-reported outcome instruments with the Agency during the clinical development process.
Virally suppressed on NrtIs
To evaluate the primary efficacy outcome of sustained HBV DNA suppression off-treatment with HBsAg loss in subjects with active disease (HBeAg-positive or HBeAg-negative CHB) who are virally suppressed on NrtIs, sponsors can consider an add-on superiority trial against placebo with a current NrtI treatment regimen as the background therapy. The co-primary efficacy endpoints14 of HBsAg loss and sustained HBV DNA suppression should be assessed at the 6-month posttreatment time point with additional follow-up to monitor for durability of response (i.e., sustained HBV DNA suppression and HBsAg loss) off-treatment. In general, off-treatment refers to discontinuation of all therapies (i.e., investigational agent and background NrtI regimen). To demonstrate sustained response off-treatment, sponsors should systematically assess the duration of a treatment consolidation period, defined as the duration of continued treatment needed after achieving HBsAg loss, during late phase trials. This may vary based on the mechanism of action and half-life of the specific investigational drug.
Sponsors should use the following criteria for stopping NrtI therapy at the end of the investigational treatment period when evaluating a finite duration therapy: (1) applied equally across treatment arms, as applicable; (2) well-defined in the protocol; and (3) stringent, such as HBsAg loss or substantial HBsAg decline or marked reduction in other important biomarkers identified in phase 2 trials. It is expected that few subjects would meet such criteria on the placebo arm. The criteria for stopping NrtI therapy should be based on clinical evidence that also reflects current practice guidelines recommended by the authoritative scientific bodies to ensure that the discontinuation of NrtI therapy does not pose undue safety risk to the trial participants. Sponsors should discuss with the FDA the use of biomarkers as a trigger for treatment interruption in advance of trial initiation.
Alternatively, an outcome of sustained HBV DNA suppression off-treatment without HBsAg clearance can be evaluated after a finite treatment duration using a superiority trial design comparing the investigational drug plus an NrtI with an NrtI alone.
HBV is an enveloped DNA virus belonging to the Hepadnavirus family. The highly stable covalently closed circular viral DNA (cccDNA) functions as a nonreplicative minichromosome and persists throughout the lifespan of infected hepatocytes. The cccDNA is not eliminated by currently approved therapies that include drugs from the nucleoside/nucleotide reverse transcriptase inhibitor (NrtI) class, and pegylated interferon.
Chronic HBV (CHB) infection results in progressive liver disease ranging from asymptomatic to severe disease with complications including cirrhosis, liver failure, and the development of hepatocellular carcinoma (HCC). In untreated adults with CHB, the cumulative 5-year incidence of cirrhosis is 8 to 20 percent; and among those with cirrhosis, the 5-year cumulative risk of hepatic decompensation is 20 percent, and risk of HCC is 2 to 5 percent (Terrault et al. 2016). An effective vaccine and antiviral therapies are approved for the prevention of HBV infection and treatment of CHB, respectively.
Currently available therapies achieve sustained suppression of HBV DNA while on treatment, but rates of HBV surface antigen (HBsAg) loss with or without seroconversion to anti-HBsAg (HBsAb) remain low. Sustained HBV DNA suppression is associated with serum alanine aminotransferase (ALT) normalization and improvement in liver histology including regression of hepatic fibrosis and cirrhosis (Chang et al. 2010; Marcellin et al. 2013; Buti et al. 2015). Effective antiviral therapy for CHB reduces disease-related complications, such as hepatic decompensation and liver failure, and decreases risk of HCC (Lok et al. 2016; Papatheodoridis et al. 2017). Clearance of HBsAg is associated with reduced risk of hepatic decompensation and improved survival (Terrault et al. 2016). HBsAg loss is considered the best predictor of sustained remission off-treatment (Terrault et al. 2016). New finite duration therapies target treatment regimens that can achieve sustained suppression of HBV DNA off-treatment with HBsAg loss (with or without HBsAb seroconversion) with low risk of virologic relapse (as defined by HBV DNA) and minimal risk of liver disease progression after the treatment is stopped (Lok et al. 2017).
2. Drug Development Population
Therapies should be developed for use in a wide range of patients with CHB, including pediatric populations.
Early phase clinical trials should focus on the adult population without cirrhosis. Initial trials can be conducted in HBV e antigen positive (HBeAg-positive) or HBV e antigen negative (HBeAg-negative) patients with active disease who are treatment-naïve, or those who were previously treated but currently viremic, off-treatment. Trials can also be conducted in HBeAg-positive or HBeAg-negative patients who are virally suppressed on NrtIs. In addition to endpoints discussed in section III. B., sponsors can evaluate exploratory endpoints in early phase trials to gather data to inform and support the choice of appropriate endpoints in late phase trials, particularly those evaluating treatments of finite durations. Some of these exploratory endpoints may include the following:
• Change in quantitative HBsAg (qHBsAg) concentration at various time points on treatment
• Quantitative HBeAg levels
• Quantitative HBV RNA levels
• Quantitative HBV core-related antigen (HBcrAg) levels
• cccDNA quantification
• Quantitative HBsAg levels from integrated HBV genome fragments
• Quantitative HBsAg-anti-HBs immune complex levels
Also depending on the drug's mechanism of action, liver biopsy findings can be used in certain proof-of-concept studies to further understand the effect of the drug on the cccDNA reservoir and/or to help better understand potential surrogate markers of antiviral activity.
CHB is a global disease, and clinical trials are often conducted in multiple countries. FDA will accept a well-designed and well-conducted foreign clinical study not conducted under an IND as support for an IND or application for marketing approval if the trial was conducted in accordance with good clinical practice and if the FDA is able to validate the data from the trial through an onsite inspection if the Agency deems it necessary.11 When sponsors rely on foreign data, these should be supported with information about predominant HBV genotypes and subtypes in the region or regions (Schweitzer et al. 2015). Development programs should include a sufficient number of U.S. patients to ensure prevalent genotypes in the U.S. population are represented. FDA strongly encourages sponsors to provide a plan to address inclusion of clinically relevant subpopulations with regard to age, gender, race, and ethnicity in the clinical trials to support an NDA or BLA, no later than the end-of-phase 2 meeting.12

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