Trend WatchPerspective

FDA Issues Recommendations for Development of DAAs for HCV

The FDA's Center for Drug Evaluation and Research issued a draft of recommendations for industry use on the development of direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection.

The draft guidance, which was last issued in October 2013, represents the current thinking of the FDA regarding overall development of DAAs, phase 2 and 3 clinical trial design and clarifies DAA use among specific patient populations. The goal of the guidance is to help guide industry sponsors through the pre-investigational new drug application, new drug application and postmarketing stages, according to the FDA.

This guidance includes revisions and recommendations since 2013, taking into consideration that multiple DAA agents that are safe, effective and interferon-free have been approved by the FDA. Some of the most significant revisions and recommendations are highlighted below.

General Drug Development 

  • A drug’s antiviral activity should be evaluated at different concentrations of human serum and extrapolation to a 100% human serum-adjusted EC50 value. The assessment of antiviral activity against replication models using HCV components from multiple clinical isolates is also recommended, due to the varying strains of antiviral activity within each subtype.
  • Animal models are not required to show anti-HCV activity.
  • For combination antiviral activity assessments, sponsors are recommended to provide combination index values when two drugs are combined at or near their individual EC50 value. Studies should also include controls for cytotoxicity and antagonism, according to the report.
  • Resistance to a DAA should be measured in cell culture models.

“The resistance barrier for an HCV DAA depends on many factors, and usually is defined as it relates to other drugs that are approved or in development,” the FDA said in the guidance.

Phase 1/2 clinical trials

According to the FDA, phase 1 trials should be conducted to assess the safety, pharmacokinetics and antiviral activity of the DAA. Phase 2 trials are conducted to create an optimal dose and treatment duration regarding antiviral activity and safety found in phase 1 trials. The FDA guidance recommends the following data are needed for support of DAAs in phase 2 trials:

  • Mechanism of action for each drug in the combination;
  • Resistance and cross-resistance patterns for each drug in the combination;
  • Combination antiviral activity data from cell culture studies;
  • Anti-HCV activity data from the clinical trials, including short-term monotherapy trials or dose-finding trials in combination with other antivirals;
  • Phase 1 human safety data for each drug;
  • Dose selection rationale that considers overlapping toxicities with individual components; and
  • Drug-to-drug interaction data if the metabolism profiles suggest an interaction potentially between drugs within the combination regimen.

“A primary objective of a phase 2 program should be demonstration of proof-of-concept of efficacy for DAA-containing regimens that are planned for study in phase 3. … Therefore, off-treatment responses such as SVR at posttreatment weeks 4 and 12 should be available before progression to phase 3,” the FDA said in the guidance.

The FDA recommends the following phase 1 and 2 trial designs for DAAs for HCV:

  • A single- or multiple-ascending dose trial in healthy adult patients for phase 1a or first-in-human clinical trial. Single-dose and short-duration multiple dose pharmacokinetic trials can also be conducted in patients with HCV.
  • A repeat-dose, randomized, dose-ranging, monotherapy clinical trial with intensive HCV RNA, safety and pharmacokinetic data is recommended for phase 1b or proof-of-concept trial. The FDA recommends treatment-naive patients with minimal fibrosis and no significant comorbidities are included.
  • In a phase 1b trial, DAA monotherapy duration depends on multiple factors, including pharmacokinetics, resistance barrier, study population, among others.
  • Phase 2 clinical trials should include randomized comparisons of several DAA combinations at various doses and treatment durations. SVR12 is the recommended primary endpoint and patients should be followed through 24 weeks posttreatment.

Patient populations for inclusion

The FDA recommends a patient population to be as broad as appropriate for the characteristics of the DAA. However, development can be targeted to specific genotypes or to regimens that are optimized for specific subtypes.

“We recommend including patients diagnosed with compensated cirrhosis in phase 2 and phase 3 trials. Also, we encourage the study of DAA HCV antivirals in patients with the greatest need to new drugs, such as patients with bleeding disorders, transplant patients, patients with advanced chronic kidney disease, patients with decompensated cirrhosis and patients who have previously failed DAA-based treatment,” the FDA said in the guidance. 

Efficacy considerations

Efficacy of the DAA should be established in patients with and without cirrhosis, with compensated and decompensated liver disease, with HCV genotypes 1, 2, 3, 4, 5, and 6 if susceptible and patients who are treatment-naive and -experienced to DAAs.

According to the guidance, a sponsor can submit a new drug application for approval of a drug in a single population. This application should include at least two well-controlled clinical trials in the proposed population of patients. Sponsors can also choose to pursue approval for different patient populations and its new drug application must include one well-controlled phase 3 trial in each patient population with supporting data from phase 2 trials.

Safety considerations

The FDA recommends initial marketing applications for DAAs for patients with chronic HCV without decompensated cirrhosis have a safety database of 1,000 to 1,500 patients who have been exposed to the proposed dose and duration of treatment. Further safety studies may need to be conducted if safety issues emerge during drug development. 

Data from randomized, controlled and comparative clinical trials are recommended by the FDA to determine the safety of the DAA. 

Phase 3 clinical trials

The FDA recommends the following phase 3 designs for DAAs for HCV:

  • At least one of the pivotal efficacy trials is designed as a randomized trial with an active-control arm.
  • The active comparator in the controlled trial should be an antiviral that is also recommended for the treatment of chronic HCV based on clinical evidence from current practice.
  • The FDA recommends sponsors discuss with them the choice of the active control and choice of study patient population prior to initiation of the trial, due to the fact a single-arm trial using a historical control could be more appropriate.
  • For treatment-naive and non-DAA treatment-experienced patients, a randomized, active-controlled noninferiority or superiority trial design is recommended over a single-arm design.
  • The active comparator should be an antiviral drug recommended for chronic HCV based on evidence from current practice.
  • If a single-arm trial is being considered due to no feasibility of other trials, the FDA recommends an immediate vs. deferred placebo-controlled trial design in patients who are not considered in need of immediate treatment. As an alternative to the immediate vs. delayed treatment design, a dose or treatment duration comparison trial could be used.

Specific patient populations

  • Patients with advanced chronic kidney disease, decompensated cirrhosis, hepatic impairment and pre or posttransplant patients have unmet medical needs and are encouraged to be discussed in early development of clinical trials to determine appropriate timing for initiation. 
  • Patients with HIV-1 and HCV coinfection should be included in clinical trials with HCV mono-infected patients or in a separate trial altogether to determine proper treatment duration and safety. For these patients, new drug applications should include: drug interaction data with commonly used HIV drugs and safety data, such as HIV RNA, to assess the loss of HIV efficacy and changes in CD4 cell counts, according to the guidance.
  • New drug applications are strongly recommended to include the treatment of HCV and DAAs among patients with decompensated cirrhosis and pre- and posttransplant patients. Required data include: drug interaction data with commonly used immunosuppressive drugs and safety data of all patients who received the DAA for the recommended treatment duration.
  • The FDA encourages sponsors to discuss a pediatric formulation and clinical development plan early, following requirements of the Pediatric Research Equity Act (PREA). The PREA requires sponsors to submit pediatric study plans no later than 60 days after an end-of-phase 2 meeting or other time agreed upon between the sponsor and FDA. The PREA also requires pediatric assessments of certain drugs be conducted using a formulation of the drug that is appropriate for the age group being studied.
  • Therefore, the FDA recommends pediatric formulation development begin as early as possible to create the proper pediatric formulations of HCV drugs.
  • The FDA recommends sponsors focus pediatric development on their best available regimen that is highly effective based on data from adult trials.
  • The guidance states that patients with advanced chronic kidney disease will most likely require treatment with interferon- and ribavirin-free combination of DAA regimens to achieve optimal SVR. Active-controlled trials are recommended when feasible. However, a placebo-controlled group can be used as well.

Dose selection and efficacy endpoints

The FDA recommends sponsors develop a mechanistic model of concentration-viral kinetics and concentration safety using all available exposure, viral kinetic and safety data from previous clinical trials to predict the most active, tolerable and safe doses for phase 2 trials.

The recommended primary endpoint for approval in clinical trials is SVR12. In addition, viral RNA clearance should be measured using an FDA-approved sensitive and specific HCV RNA assay. Any use of unapproved assays need to be discussed with the FDA. Secondary endpoints should include virologic failure rate to help optimize proper dose and treatment duration, SVR4 and SVR24 rates, end-of-treatment response rate and rate of drug resistance emergence in patients who experience virologic failure.

The guidance is currently a draft and is open for comment and suggestions within 60 days of its original release. A spokesperson at the CDER told HCV Next, “Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. The public may comment on the draft guidance by visiting www.regulations.gov.”

For more information:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery

The FDA's Center for Drug Evaluation and Research issued a draft of recommendations for industry use on the development of direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection.

The draft guidance, which was last issued in October 2013, represents the current thinking of the FDA regarding overall development of DAAs, phase 2 and 3 clinical trial design and clarifies DAA use among specific patient populations. The goal of the guidance is to help guide industry sponsors through the pre-investigational new drug application, new drug application and postmarketing stages, according to the FDA.

This guidance includes revisions and recommendations since 2013, taking into consideration that multiple DAA agents that are safe, effective and interferon-free have been approved by the FDA. Some of the most significant revisions and recommendations are highlighted below.

General Drug Development 

  • A drug’s antiviral activity should be evaluated at different concentrations of human serum and extrapolation to a 100% human serum-adjusted EC50 value. The assessment of antiviral activity against replication models using HCV components from multiple clinical isolates is also recommended, due to the varying strains of antiviral activity within each subtype.
  • Animal models are not required to show anti-HCV activity.
  • For combination antiviral activity assessments, sponsors are recommended to provide combination index values when two drugs are combined at or near their individual EC50 value. Studies should also include controls for cytotoxicity and antagonism, according to the report.
  • Resistance to a DAA should be measured in cell culture models.

“The resistance barrier for an HCV DAA depends on many factors, and usually is defined as it relates to other drugs that are approved or in development,” the FDA said in the guidance.

Phase 1/2 clinical trials

According to the FDA, phase 1 trials should be conducted to assess the safety, pharmacokinetics and antiviral activity of the DAA. Phase 2 trials are conducted to create an optimal dose and treatment duration regarding antiviral activity and safety found in phase 1 trials. The FDA guidance recommends the following data are needed for support of DAAs in phase 2 trials:

  • Mechanism of action for each drug in the combination;
  • Resistance and cross-resistance patterns for each drug in the combination;
  • Combination antiviral activity data from cell culture studies;
  • Anti-HCV activity data from the clinical trials, including short-term monotherapy trials or dose-finding trials in combination with other antivirals;
  • Phase 1 human safety data for each drug;
  • Dose selection rationale that considers overlapping toxicities with individual components; and
  • Drug-to-drug interaction data if the metabolism profiles suggest an interaction potentially between drugs within the combination regimen.

“A primary objective of a phase 2 program should be demonstration of proof-of-concept of efficacy for DAA-containing regimens that are planned for study in phase 3. … Therefore, off-treatment responses such as SVR at posttreatment weeks 4 and 12 should be available before progression to phase 3,” the FDA said in the guidance.

The FDA recommends the following phase 1 and 2 trial designs for DAAs for HCV:

  • A single- or multiple-ascending dose trial in healthy adult patients for phase 1a or first-in-human clinical trial. Single-dose and short-duration multiple dose pharmacokinetic trials can also be conducted in patients with HCV.
  • A repeat-dose, randomized, dose-ranging, monotherapy clinical trial with intensive HCV RNA, safety and pharmacokinetic data is recommended for phase 1b or proof-of-concept trial. The FDA recommends treatment-naive patients with minimal fibrosis and no significant comorbidities are included.
  • In a phase 1b trial, DAA monotherapy duration depends on multiple factors, including pharmacokinetics, resistance barrier, study population, among others.
  • Phase 2 clinical trials should include randomized comparisons of several DAA combinations at various doses and treatment durations. SVR12 is the recommended primary endpoint and patients should be followed through 24 weeks posttreatment.

Patient populations for inclusion

The FDA recommends a patient population to be as broad as appropriate for the characteristics of the DAA. However, development can be targeted to specific genotypes or to regimens that are optimized for specific subtypes.

“We recommend including patients diagnosed with compensated cirrhosis in phase 2 and phase 3 trials. Also, we encourage the study of DAA HCV antivirals in patients with the greatest need to new drugs, such as patients with bleeding disorders, transplant patients, patients with advanced chronic kidney disease, patients with decompensated cirrhosis and patients who have previously failed DAA-based treatment,” the FDA said in the guidance. 

Efficacy considerations

Efficacy of the DAA should be established in patients with and without cirrhosis, with compensated and decompensated liver disease, with HCV genotypes 1, 2, 3, 4, 5, and 6 if susceptible and patients who are treatment-naive and -experienced to DAAs.

According to the guidance, a sponsor can submit a new drug application for approval of a drug in a single population. This application should include at least two well-controlled clinical trials in the proposed population of patients. Sponsors can also choose to pursue approval for different patient populations and its new drug application must include one well-controlled phase 3 trial in each patient population with supporting data from phase 2 trials.

Safety considerations

The FDA recommends initial marketing applications for DAAs for patients with chronic HCV without decompensated cirrhosis have a safety database of 1,000 to 1,500 patients who have been exposed to the proposed dose and duration of treatment. Further safety studies may need to be conducted if safety issues emerge during drug development. 

Data from randomized, controlled and comparative clinical trials are recommended by the FDA to determine the safety of the DAA. 

Phase 3 clinical trials

The FDA recommends the following phase 3 designs for DAAs for HCV:

  • At least one of the pivotal efficacy trials is designed as a randomized trial with an active-control arm.
  • The active comparator in the controlled trial should be an antiviral that is also recommended for the treatment of chronic HCV based on clinical evidence from current practice.
  • The FDA recommends sponsors discuss with them the choice of the active control and choice of study patient population prior to initiation of the trial, due to the fact a single-arm trial using a historical control could be more appropriate.
  • For treatment-naive and non-DAA treatment-experienced patients, a randomized, active-controlled noninferiority or superiority trial design is recommended over a single-arm design.
  • The active comparator should be an antiviral drug recommended for chronic HCV based on evidence from current practice.
  • If a single-arm trial is being considered due to no feasibility of other trials, the FDA recommends an immediate vs. deferred placebo-controlled trial design in patients who are not considered in need of immediate treatment. As an alternative to the immediate vs. delayed treatment design, a dose or treatment duration comparison trial could be used.
PAGE BREAK

Specific patient populations

  • Patients with advanced chronic kidney disease, decompensated cirrhosis, hepatic impairment and pre or posttransplant patients have unmet medical needs and are encouraged to be discussed in early development of clinical trials to determine appropriate timing for initiation. 
  • Patients with HIV-1 and HCV coinfection should be included in clinical trials with HCV mono-infected patients or in a separate trial altogether to determine proper treatment duration and safety. For these patients, new drug applications should include: drug interaction data with commonly used HIV drugs and safety data, such as HIV RNA, to assess the loss of HIV efficacy and changes in CD4 cell counts, according to the guidance.
  • New drug applications are strongly recommended to include the treatment of HCV and DAAs among patients with decompensated cirrhosis and pre- and posttransplant patients. Required data include: drug interaction data with commonly used immunosuppressive drugs and safety data of all patients who received the DAA for the recommended treatment duration.
  • The FDA encourages sponsors to discuss a pediatric formulation and clinical development plan early, following requirements of the Pediatric Research Equity Act (PREA). The PREA requires sponsors to submit pediatric study plans no later than 60 days after an end-of-phase 2 meeting or other time agreed upon between the sponsor and FDA. The PREA also requires pediatric assessments of certain drugs be conducted using a formulation of the drug that is appropriate for the age group being studied.
  • Therefore, the FDA recommends pediatric formulation development begin as early as possible to create the proper pediatric formulations of HCV drugs.
  • The FDA recommends sponsors focus pediatric development on their best available regimen that is highly effective based on data from adult trials.
  • The guidance states that patients with advanced chronic kidney disease will most likely require treatment with interferon- and ribavirin-free combination of DAA regimens to achieve optimal SVR. Active-controlled trials are recommended when feasible. However, a placebo-controlled group can be used as well.

Dose selection and efficacy endpoints

The FDA recommends sponsors develop a mechanistic model of concentration-viral kinetics and concentration safety using all available exposure, viral kinetic and safety data from previous clinical trials to predict the most active, tolerable and safe doses for phase 2 trials.

The recommended primary endpoint for approval in clinical trials is SVR12. In addition, viral RNA clearance should be measured using an FDA-approved sensitive and specific HCV RNA assay. Any use of unapproved assays need to be discussed with the FDA. Secondary endpoints should include virologic failure rate to help optimize proper dose and treatment duration, SVR4 and SVR24 rates, end-of-treatment response rate and rate of drug resistance emergence in patients who experience virologic failure.

The guidance is currently a draft and is open for comment and suggestions within 60 days of its original release. A spokesperson at the CDER told HCV Next, “Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. The public may comment on the draft guidance by visiting www.regulations.gov.”

For more information:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery

    Perspective
    William Carey

    William Carey

    The CDC has determined that hepatitis C accounts for more deaths in the U.S. (19,659 in 2014) than the combined total from 60 other infectious diseases including HIV, tuberculosis and pneumococcal disease. Accordingly, eradication of this infection must be of highest national priority. Development of simple to administer highly effective therapy for all those infected is urgently needed.

    Until 2011, HCV treatment relied on boosting the immune system with interferons. This strategy was cumbersome, lengthy, fraught with side effects and not highly effective. Spurred by the enormous burden of hepatitis C, and aided by clarity about HCV RNA structure and its enzymes, scientists in and outside the pharmaceutical industry have been engaged in a “fight for cure.” Hundreds of compounds that act directly on HCV (direct-acting antiviral agents — DAAs) have been tested and scores are in various stages of development. The field of HCV treatment is changing so rapidly, that the first DAAs — telaprevir and boceprevir, approved in 2011 — are no longer used, supplanted by better DAAs. The therapeutic pipeline continues to be robust.

    Bringing a drug to FDA approval status is an expensive and lengthy process. As the efficacy of DAAs improves, the bar is ever-rising for new entries. It no longer makes sense to compare new agents to placebos or to interferon-based therapy. New agents must demonstrate efficacy at least as good as existing drugs, or expand our ability to treat those with special circumstances, such as HIV-coinfected patients, those with severe renal impairment (including those on dialysis), cirrhotics, post-transplant patients and patients not cured by a full therapeutic duration of existing DAAs.

    Left without guidance, resources might be spent on clinical trials that do not meet contemporary clinical needs. The FDA serves as the gatekeeper. Fortunately, since 2010 the FDA has provided such guidance in a series of updates to its 2010 Guidance: Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment. These provide those conducting clinical trials a framework for study design. The FDA further urges those planning a clinical trial to meet with the FDA well beforehand to assure the highest likelihood of regulatory approval.

    The current guidance document has been issued as a draft with an invitation for stakeholders to comment. Those of us engaged in treatment of HCV-infected patients know that it is within our capability to make HCV a rare disorder. We welcome this draft document and look forward to the continuation of the evolution of HCV therapy.

    • William Carey, MD
    • Senior hepatologist Department of Gastroenterology and Hepatology at Cleveland Clinic Cleveland, Ohio

    Disclosures: Carey reports no relevant financial disclosures.