Is it ethical to enroll a patient in a hepatitis C virus clinical trial when current standard of care is highly effective and safe?

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Abbreviations

DAA

direct‐acting antiviral agent

HCV

hepatitis C virus

SVR

sustained virological response

Hepatitis C virus (HCV) is estimated to affect approximately 3.4 to 4.4 million people nationwide.1 Within recent years, there has been a rapid evolution in the existing therapeutic options for the treatment of HCV. Previously, the standard of care for HCV relied on the use of peginterferon alpha and ribavirin, which are associated with significant toxicities, including fatigue, neuropsychiatric symptoms, and adverse hematological effects.2 Such toxicities made compliance with the regimen difficult for many patients and impossible for some. Within the past decade, the option of enrollment in clinical trials offered a potential reprieve from the cost and adverse effects of interferon‐based therapies and access to direct‐acting antiviral agents (DAAs). As a result of these trials, we now know that the emergence of DAAs has led to fewer adverse effects, higher efficacy, and increased ease of administration. The clinical success of DAAs as the current standard of care raises ethical concerns surrounding the enrollment of patients into clinical trials, which administer alternative therapies with less data to support their safety and efficacy.

Treatment of HCV should be considered in all patients with evidence of chronic infection over a 6‐month period, except for those with life expectancy less than 1 year because of non‐liver‐related comorbid conditions. The goal of therapy is to achieve a sustained virological response (SVR) with several of the new treatment regimens achieving SVRs exceeding 90%.3

If there is a caveat with these therapies, it is their significant cost. Approved agents such as sofosbuvir, sofosbuvir/ledipasvir, simeprevir, daclatasvir, or paritaprevir/ritonavir/ombitasvir/dasabuvir range in cost from US $60,000 to more than US $100,000 per treatment course. Even with expected downward pressure on price from new agents such as grazoprevir/elbasvir, the cost of treatment is likely to remain a substantial financial burden.4

It is recognized that for many clinical investigators and potential patient‐subjects, a primary attraction to enrollment in any clinical trial is often the financial benefit—obtaining a potentially efficacious treatment without incurring the cost of therapy. When interferon remained a cornerstone of HCV therapy, an additional lure to enroll in clinical trials rather than receive the standard of care was often the chance to avoid the litany of interferon's side effects. However, with the elimination of interferon from most therapeutic regimens, these reasons have waned in importance while cost has likely risen as an integral factor in the decision to enroll in clinical trials.

This raises an important ethical issue whether cost in itself is an appropriate justification in referring patients to clinical trials, as opposed to receiving the highly efficacious standard of care. On one side, this seems to be ethical because patients with access to therapies limited by financial means may not otherwise receive therapy at all. Furthermore, this may be a mutually beneficial exchange between the pharmaceutical company and the patient: The pharmaceutical company gains the clinical data from the patient's enrollment and the patient obtains free therapy. The therapy may be even equally or potentially more efficacious as the current standard of care, providing further possible benefit for the patient. In addition, providers can profit financially from enrollment if a pre‐existing relationship with the pharmaceutical company exists, although this presents its own set of ethical issues.

Despite the benefits of new existing therapies, there are limited data on the use of these therapies in the setting of certain clinical settings, such as severe renal impairment, after liver transplantation, and decompensated cirrhosis.5 In these situations, it is often clinically advantageous for the patient to enroll in clinical trials.

Conversely, enrollment in clinical trials can be viewed as a form of coercion in this vulnerable subset of patients, pushing them to take experimental medications with an efficacy that has yet to be proved and face unforeseen adverse effects. Enrollment in clinical trials may be more of a sole remaining option rather than a discrete choice made by the patient, which questions the presence of true equipoise in these clinical situations. However, it is important to acknowledge that many clinical trial medications may actually possess comparable efficacies and similar side effect profiles to the current standard of care, which may narrow the gap between these two schools of thought.

Although no studies have addressed factors in clinical trial enrollment specifically in HCV, several studies have examined these factors in patients with cancer and other chronic diseases. Factors that have been identified as barriers to enrollment include concerns regarding adverse effects of the trial drug, the possibility of receiving treatment that has not been adequately tested, too many pre‐existing comorbidities, potential drug interactions, additional testing, duration of trial, or barriers to timely follow‐up.6 Factors that positively affect enrollment include altruism, hope for a cure for oneself, or physician encouragement, which are important for HCV providers to consider during discussions with patients regarding clinical trials.7, 8

Given the present implications of cost of therapy, continued enrollment in clinical trials is ethical if industry sponsors support well‐designed trials with true equipoise, which include a control arm that incorporates the current DAA‐based standard of care. Physician‐investigators must also create a climate that allows full informed consent, including appropriate disclosures about relevant conflicts of interests or relationships with sponsors. However, active research into patient and physician decision making in the enrollment in clinical trials should be extended to the HCV literature.