Hepatitis C Drug Head-To-Head Comparative Studies Debated At PCORI Workshop

There appeared to be support for the idea that if head-to-head studies are funded, they should focus on “high risk populations,” such as intravenous drug users.

The many challenges to conducting head-to-head comparative effectiveness studies of the new all-oral hepatitis C drugs were debated at a stakeholder workshop convened by the Patient-Centered Outcomes Research Institute Oct. 17.

The workshop was held to help generate consensus on what types of comparative effectiveness studies in hepatitis C treatment should be funded by PCORI. Input gathered at the day-long session will be analyzed by the PCORI Scientific Oversight Committee, which will then discuss possible funding topics with the PCORI board. The board will make a final decision on funding.

PCORI Chief Science Officer Bryan Luce suggested at the workshop that the process will move ahead “we hope and expect in the near future” but no specific timeline was announced. To date, PCORI has funded relatively few head-to-head studies on drugs, though it has expressed an interest in expanding its activities in that area (Also see "PCORI To Solicit More Head-To-Head Comparative Studies" - Pink Sheet, 25 Nov, 2013.).

PCORI Senior Advisor Harold Sox commented at the conclusion of the workshop that there appeared to be support for the idea that if head-to-head studies were funded, they should focus on “high-risk populations,” such as patients with active or past abuse of intravenous drugs or alcohol, risky sexual behaviors and those in prison.

However, some stakeholders questioned the need for head-to-head studies at all, particularly randomized clinical trials. One approach under consideration is a comparison of Gilead Sciences Inc.’sHarvoni (sofosbuvir/ledipasvir) with AbbVie Inc.’s upcoming triple combination drug, expected to be approved by late December.

Discussion of head-to-head trials was led by Camilla Graham, assistant professor of medicine with the National Viral Hepatitis Roundtable, who presented ideas generated in a breakout session held earlier during the day. Participants in the breakout session on head-to-head trials also included CMS Technical Advisor Linda Gousis, FDA Medical Officer Poonam Mishram, Veterans Health Administration HIV, HCV and Public Health Pathogens Programs Director David Ross, UnitedHealth Group Chief Medical Officer Richard Migliori and American Gastroenterological Institute Instructor of Medicine Joseph Lim.

“In order to make meaningful comparisons, you’re going to have to have a monstrously huge trial,” Merck’s Eliav Barr said.

Graham began with the premise that head-to-head studies should focus on issues and patients not included in the registration trials funded by pharmaceutical companies. She explained, “There have been groups that have been systematically excluded from our pharmaceutical company-sponsored clinical trials. We are all responsible for taking care of these patients but we have very little data about the right thing to do. All of us would encourage PCORI to focus on those patient populations.”

For example, “if you’re working with a difficult to reach population of people who inject drugs,” she said, “you can demonstrate that a particular regimen that has a couple of more pills than another can still maintain high quality of life, high adherence and good long-term outcomes or that it actually can’t. That’s really important to know and there’s no other mechanism right now for us to get those data.”

In terms of the drugs to be studied, she said her group would “strongly advocate” an adaptive trial design that would allow the comparisons to incorporate new drugs as they reach the market. The research “needs to reflect the real life choices patients and providers and payers are making right now. Today we have one choice and in a year we’re going to have different choices. So if this trial can’t adapt … it will be immediately obsolete,” Graham said.

She acknowledged, however, that studies should not duplicate others that are already planned or underway. During the workshop, Merck & Co. Inc. Research Labs VP Infectious Diseases Eliav Barr pointed out that various drug companies are already conducting studies in high-risk patients and cautioned that PCORI should make sure it chooses to study what “has not yet been studied.”

“I agree we don’t need to waste money if other people are spending it answering the same questions,” Graham said.

Barr said Merck recently began a study of its experimental hepatitis C treatment in I.V. drug users. The company is developing an oral, once-daily, fixed-dose treatment combining its grazoprevir (MK-5172) and elbasvir (MK-8742). The combination has been granted breakthrough review status by FDA, and an NDA filing is pending. Gilead and AbbVie are also planning or conducting studies of hepatitis C treatments in high-risk patients.

Access, Not Relative Effectiveness, Is the Issue

Stakeholders warned that a head-to-head randomized clinical trial would be prohibitively expensive and probably not worth the cost.

Merck’s Barr argued that “in order to make meaningful comparisons, you’re going to have to have a monstrously huge trial.” Because sustained virologic response (SVR) rates are quite high and fairly comparable between the new hepatitis C drugs, “you’re talking about ginormous studies, if you’re also trying to address notions of small patient populations, discrete sets of individuals and the like,” he asserted.

Workshop participant Sanjeev Arora, University of New Mexico, also raised the question of whether “we want to make such a large investment on something which is really a non-issue for a clinician because, as a clinician, my main issue is not the distinction between” the AbbVie and Gilead treatments. “Both are amazing drugs. … The real problem is that we have great drugs but patients don’t get their hands on them for one reason or another,” he said.

Graham noted that participants in her breakout session expressed interest in tapping a large database, such as the patient registry known as HCV Target, to conduct an observational study.

“Many of us kept coming back to [the idea that] Target would be, or something like Target would be, a really great way to answer many of these questions. So I think we are all on the same page,” she said.

The HCV Target registry is being developed by an international consortium of hepatitis C virus (HCV) investigators, with collaboration from FDA, who have established a common research database and are conducting a longitudinal observational study to answer questions about treatment with direct acting antiviral agents.

It is led jointly by researchers at the University of Florida and the University of North Carolina at Chapel Hill. The project is being supported by funding from Merck, AbbVie, Gilead, Janssen Pharmaceutical Cos.,Bristol-Myers Squibb Co., GlaxoSmithKline PLC, Kadmon Corp. LLC and Vertex Pharmaceuticals Inc.

Treating Early vs. Late-Stage Disease

Many stakeholders agreed that PCORI should address whether hepatitis C patients are injured by delaying treatment because some payers, such as Medicaid agencies, are limiting coverage to later-stage patients for budget reasons.

Graham acknowledged there was a lot of disagreement about whether “you could have an ethical trial that randomizes people … into a delayed arm versus those that are immediately treated.” She suggested that discussions with patient-oriented community groups may be needed to further explore the issue.

One challenge with such an analysis is that PCORI wants to fund studies of shorter duration than may be needed to identify differences in outcomes between patients who are treated at earlier stages versus those treated later. PCORI is interested in studies that last three to five years, and it might take a decade or more to generate a definitive answer.

However, some stakeholders maintained that even a short-term study might uncover advantages to treating and curing early-stage patients, such as the ability to return to work, increased productivity and assurance that they would not be in danger of infecting others. Others argued that such a study is not justified because payers are withholding coverage for early-stage patients based on economics and not a lack of data showing a benefit.

Summarizing trends in the workshop’s four breakout discussions – which also included “patient populations/timing of treatment,” care delivery and screening/diagnostic tests – Johns Hopkins Evidence-based Practice Center Director Eric Brass said, “What struck me is all four groups gravitated toward the importance of addressing the issues in high-risk populations.”

He added, “Where the greatest controversy has arisen – and it particularly came up in the head-to-head comparison group – is what do we do in those patients at an early stage? What is ethical to do and how important is it to invest in studies that will address the issues that have arisen because of existing health policies that put clinicians in a difficult position and certainly raise concerns with patients and their advocates?”