The Food and Drug Administration’s Antiviral Drugs Advisory Committee met on October 19 and 20 to discuss issues regarding the development and approval of new drugs to treat hepatitis C. A number of investigational drugs – particularly hepatitis C protease and polymerase inhibitors – are far along in development, making the meeting a timely one. Questions examined by the Committee related focused on four broad areas:
1. Identification of appropriate control arms (in clinical trials, people receiving the investigational drug are compared to those in the ‘control arm’, who typically receive the standard of care – pegylated interferon and ribavirin – plus placebo)
2. Populations for study (including whether to include people with all hepatitis C genotypes, people with advanced liver disease, and people co-infected with HIV; the importance of studies in people who have never been previously treated for hepatitis C vs. in people who have prior treatment experience but did not clear the virus; racial/ethnic diversity in study participants; the need for data on new drugs in children and in liver transplant recipients)
3. Endpoints (the measurement of treatment success – for hepatitis C, typically a sustained virologic response [SVR], defined as undetectable viral load six months after the end of treatment; other possible endpoints include normalization of liver enzyme values such as ALTs, and reduction in liver inflammation as measured by biopsy)
4. Long-term follow-up (whether people with an SVR after treatment remain undetectable several years later, and whether successful treatment results in improvements in the liver and reductions in complications of liver disease [such as decompensated cirrhosis and liver cancer])
Jules Levin of NATAP presented a community perspective (online here, or here for PowerPoint file), emphasizing the importance of research new drugs in people co-infected with HIV prior to approval, and the desirability of study designs that allow participants to receive two investigational agents, due to concerns about drug resistance (resistance to new hepatitis C protease and polymerase inhibitors can emerge quickly and compromise treatment success). The Advisory Committee also included two community members and long-time advocates, Tracy Swan of Treatment Action Group and Bob Munk of AIDS InfoNet.
Documents from the meeting, including slides and transcripts, are available online here.
Highlights from the meeting, and other research issues, follow below.
Some key recommendations that came out of the discussion:
- The Committee called for preliminary data on safety & efficacy in HIV/HCV co-infected patients and cirrhotics available by the time each new drug is submitted for FDA approval. Historically, research in co-infected people has not occurred until well after hepatitis C treatments have reached the market.
- The Committee encouraged but did not require data/studies on transplant recipients at time of approval, and urged that safety & dosing research in pediatrics (children) be initiated prior to approval.
- The committee wanted adequate data on African Americans as part of the submission package – a significant step, due to the underenrollment of African Americans in the major studies used for the approval of pegylated interferons, and community concerns about the recent exclusion of African Americans from the first stage of a Schering-Plough protease inhibitor study.
- The committee endorsed the concept of studies including multiple experimental agents – for instance, a study where participants would receive both an investigational protease inhibitor and an investigational polymerase inhibitor.
- The committee was interested in long-term follow-up, beyond the 24-week SVR endpoint, but did not reach consensus on duration, though 5 years was mentioned.
- The committee did not reach consensus on whether to require research in people who had not responded to prior treatment (vs. only studying people who had never been treated for hepatitis C), though virtually all companies are studying their drugs in both populations.
These recommendations are largely good news for the hepatitis C community. However, Advisory Committee recommendations are not binding on the FDA or on companies developing new drugs, and further advocacy will be necessary to ensure that research meaningfully address and include key groups - particularly people co-infected with HIV and African Americans - in a timely manner.
However, the Advisory Committee meeting did not exhaust all issues of interest to the community. What follows are some reflections on a community-centered approach to the research of new hepatitis C drugs.
Comments on HCV trial design issues
The search for new medications to treat hepatitis C has yielded a wealth of new compounds in or approaching clinical trials, accompanied by a range of scientific and regulatory challenges. Several once-promising investigational agents have already failed to demonstrate adequate antiviral activity or acceptable safety in early phases of development. Moreover, many of the current crop of drugs in phase II and III studies have faced setbacks or produced disappointing results this year. Nevertheless, we have many reasons for optimism, and the state of the field makes this a timely moment for reflection.
The goal of the drug development and approval process is to establish the efficacy and safety of new drugs in a manner that balances timeliness and expediency (making new drugs available as quickly as possible) with thoroughness (obtaining as clear a profile of new drugs’ safety and efficacy as possible). Within this framework, I would propose two principles to guide our thinking about clinical trial design issues in hepatitis C drug development:
1. HCV drug development programs should aim to maximize the amount of clinically-relevant information available to guide treatment decisions when a new drug reaches the market.
2. HCV clinical trials should aim to maximize therapeutic benefits to all trial participants.
In the following discussion, I hope to demonstrate that the application of these principles is consistent with the goal of drug development and the interests of various stakeholders. My discussion will focus primarily on the development of new drugs directly targeting HCV, including protease and polymerase inhibitors.
1. Maximizing clinically-relevant information
The amount of information available upon a new drug’s approval is inevitably partial and limited, and reflects the shifting balance of timeliness and thoroughness negotiated between regulatory officials, pharmaceutical companies, and other stakeholders in any given historical moment. For HCV drug development, the following parameters are of particular interest:
• Optimal dose, optimal duration of treatment, and the predictive value of early viral kinetics
• Relative safety and efficacy in specific populations (e.g., African Americans, HIV co-infection, cirrhotics, etc.)
• Impact of drug-drug interactions, resistance, and adherence on treatment outcomes
The consequences of any gaps in this information at the time a new drug reaches the market can be considerable for not only people with hepatitis C and clinicians, but also for pharmaceutical companies and other stakeholders. For example, Peg-Intron received marketing approval from the FDA based on pivotal trials that failed to resolve critical questions about appropriate dosing of Peg-Intron and ribavirin, and appropriate duration of treatment for genotype 2 and 3. As a result, the FDA required post-marketing studies – the WIN-R and IDEAL trials – involving thousands of participants. Similarly, post-marketing commitments for Pegasys included a pediatric study, a comparison of treatment outcomes between African Americans and Caucasians, an exploration of shortening treatment for genotype 2 and 3 to 16 weeks, and an investigation of higher doses of Pegasys and ribavirin for genotype 1 patients with high viral load weighing greater than 85 kg.
Of particular concern, the registrational trials for both Peg-Intron and Pegasys enrolled inadequate numbers of African Americans to characterize the relative success of treatment in this group, making calculations on the relative risks and benefits of treatment impossible for this population. Similarly, no information on treatment in people co-infected with HIV was available at the times these drugs were approved – nor were such studies stipulated in the post-marketing commitments for either company.
More broadly, the approval of these drugs ushered in a range of questions – some only recently or partially resolved -- about whether SVR rates could be improved by increasing doses and/or duration of therapy, particularly for people with genotype 1 and/or high viral load. Conversely, additional research has suggested that at least a subset of people with genotype 2 or 3 may not require a full 24 weeks of treatment, and that rapid virologic responses measure after 4 weeks on therapy can effectively guide decisions about treatment duration.
Consequently, a substantial body of evidence and experience suggests that a considerable amount of people have been either overtreated or undertreated, due to the limitations in available information at the times of approval for Peg-Intron and Pegasys. Overtreatment incurs greater, potentially unnecessary, exposure to considerable side effects and toxicities; undertreatment entails missed opportunities for achieving an SVR.
Drugs currently in development may not fully avoid these pitfalls; some refinements in dosing and treatment duration will inevitably occur after these drugs reach the market. However, the lessons of Peg-Intron and Pegasys – along with advances in the understanding of viral kinetics – can guide future clinical trial design.
The lesson from recent research indicates that genotype alone is no longer sufficient to optimize treatment duration. Baseline viral load and early viral kinetics can guide decisions about treatment duration and should be factored in to phase II and III trial design. As new drugs increase the antiviral potency of treatment regimens, we can begin to envision shorter durations of treatment; even with currently approved therapies, we have evidence that at least a subset of patients achieve SVRs after as few as 12 weeks of therapy. Conversely, subgroups less responsive to pegylated interferon/ribavirin therapy may require higher doses of investigational agents or longer durations of therapy to achieve equal benefits. Exploratory studies of viral kinetics in select populations can inform phase III trial designs that factor in these considerations.
For the foreseeable future, the decision to pursue HCV treatment will never be an easy or automatic one. The HCV protease and polymerase inhibitors first to receive approval will likely be added on to pegylated interferon and ribavirin; any initial improvements in treatment efficacy will be offset by the burden of side effects and toxicity that will match and perhaps exceed those associated with current treatment. Thus the uptake of new therapies will rely on the ability of people with hepatitis C and their clinicians to adequately balance potential benefits of treatment with established risks. These calculations require sufficient data in groups with poorer responses to current treatment – especially African Americans, people co-infected with HIV, and cirrhotics. Clinical development programs must be required to include at least preliminary safety and efficacy data in these groups with their initial NDA filings. Similarly, inclusion and exclusion criteria should reflect as closely as possible the variety of people living with hepatitis C. Arbitrary criteria that exclude all ‘substance abusers’ or people with histories of mental illness should be narrowed to reflect only legitimate safety considerations and ability to comply with study requirements.
Finally, the new classes of direct antivirals targeting HCV raise additional questions: What are the risks and consequences of drug resistance? What degree of adherence is required to achieve an SVR? How do these antivirals interact with other drugs commonly used by people with HCV? Again, these questions may not be completely resolved until after a new drug reaches the market. However, the clinical development program can and should provide a number of opportunities and means to provide tentative answers with some degree of confidence. This, of course, requires that analysis of these issues becomes both a central theme in early and on-going planning of clinical trials, and a standard expectation of regulatory officials. Such analyses may benefit from standardization of assessment tools and protocols across agents and classes.
2. Maximizing benefit to all participants
Enrollment in phase II and III HCV clinical trials requires a substantial commitment from potential study participants: studies typically last 48 weeks, with a six-month follow-up period, and require frequent visits, including bloodwork, throughout the study period. These demands are accompanied by substantial uncertainty about the likelihood of personal benefit – specifically, achieving an SVR – alongside considerable risks of side effects – both well-known in the case of pegylated interferon and ribavirin, and largely unknown in the case of investigational agents.
Current phase II and III trial designs virtually ensure that a substantial number of participants will endure all the side effects associated with treatment without achieving an SVR. Phase II trials aimed at establishing ideal doses pose particular problems – lower-dose arms may yield suboptimal antiviral activity (as occurred in the phase II trial for Schering-Plough’s SCH 503034), while higher-dose arms may result in excessive toxicity and poor tolerability (as occurred with Idenix’ phase II study of valopicitabine). Moreover, the failure to establish optimal dosing in phase II based on both safety and efficacy parameters can jeopardize phase III studies (as occurred with Valeant’s Viramidine). The challenge in trial design is thus to increase the likelihood of SVR for participants in all arms, while minimizing exposure to toxicities. Adaptive trial designs and cross-over protocols provide possible strategies to meet this challenge.
Adaptive trial designs can be used to modify allocation to treatment/dosing arms during a study based on initial, interim results using Bayesian statistical inferences. Several proposed models have applicability to phase I/II dose-finding studies to determine optimal trade-offs between efficacy and toxicity. The appeal of these methods for potential study participants is that such trials result in a greater proportion of participants receiving the best possible dose of study drug. In some cases, adaptive trial designs may require lesser total numbers of participants to yield equivalent information.
Cross-over designs can also increase the likelihood of benefit to all study participants while ensuring sufficient collection of safety and efficacy data. Participants randomized to a pegylated interferon/ribavirin/placebo comparator arm could be rolled over into an arm receiving active drug if early viral kinetics (12 week or earlier) show limited likelihood of treatment success. Similarly, participants randomized to an arm receiving a lower dose of the investigational drug could be switched to a higher dose if early virologic response is deemed inadequate. Ideally, modeling of viral kinetics could shorten the relevant assessment to 4 weeks or sooner.
The growing number of new drugs advancing into phase II and III studies offers additional opportunities for maximizing benefits to study participants through inter-company collaboration. In principle, participants who do not achieve an early virologic response to drug A could be rolled over to a protocol that randomly assigns them to either add or switch to drug B. This would require some degree of coordination between companies, and prior assessment of any potential drug interactions between the two investigational agents. However, new polymerase and protease inhibitors expected to reach the market at roughly the same time will likely be used together, and a roll-over protocol would serve to generate some data on these combinations to guide clinical practice.
Finally, investigational protocols should reflect the standard of care in current clinical practice. The medical community – supported by patients and advocates – has reached a clear consensus on the need for aggressive side effect management, including adjunctive treatment, to support people through HCV treatment. Off-label use of hematopoietic growth factors to offset the toxicities of interferon and ribavirin has become mainstream in HCV treatment, and should not be excluded in clinical trials of new agents.