Clinical, Translational and Implementation Science: Part 3 – The PRIORITIZE Study

On Oct. 8, 2015, a research team led by David Nelson, M.D., a professor of medicine and director of the UF Clinical and Translational Science Institute, learned it has been approved for a $15.5 million research funding award by the Patient-Centered Outcomes Research Institute, or PCORI, to study the effectiveness of three medications used to treat hepatitis C. Other lead sites for the study, assembled by Dr. Nelson, include the Johns Hopkins University, the University of North Carolina and the University of Michigan. The story of “The PRIORITIZE Study: A Pragmatic, Randomized Study of Oral Regimens for Hepatitis C: Transforming Decision-Making for Patients, Providers and Stakeholders,” is the third and last part in our OTSP series on clinical, translational and implementation science at UF.

The PRIORITIZE study builds on considerable work spearheaded by Dr. Nelson over many years. In 2011, he and Dr. Michael W. Fried at the University of North Carolina at Chapel Hill created the international Hepatitis C Therapeutic Registry and Research Network, or HCV-TARGET, to evaluate the safety and efficacy of newly emerging direct-acting antivirals for HCV treatment. The HCV-TARGET model is rooted in the infrastructure and collaborative network developed through the National Institutes of Health’s Clinical and Translational Science Award program. To date, more than 45 HCV-TARGET sites have enrolled more than 7,000 patients to participate in two phases of its longitudinal observational cohort study, which has attracted more than $30 million in support from multiple pharmaceutical companies.

In 2013, HCV-TARGET partnered with the FDA to share national data on how newly approved treatments for hepatitis C are used and managed in routine practice. The FDA can use the data to monitor and act on differences in safety from what was reported during Phase III trials or expand label indications. HCV-TARGET data has already been instrumental in identifying new safety signals (cardiovascular risk in patients taking the anti-hepatitis C drug, sofosbuvir) and expanding drug labels. As the clinical coordinating center and national biorepository for HCV-TARGET, UF Health became a backbone of global research that provides real-world data on the safety, management and comparative effectiveness of hepatitis C therapies. In 2015, Dr. Nelson was invited to participate in the World Health Organization’s guidelines development group focused on the treatment of hepatitis C, and HCV-TARGET data are being used to inform updated recommendations for the use of direct-acting antivirals.

A key milestone in the emerging field of direct-acting antiviral drug development were two Phase 3, randomized trials showing very high efficacy of sofosbuvir (brand name Sovaldi), which has revolutionized the treatment of patients with hepatitis C. Compared with previous treatments, sofosbuvir-based regimens provided the opportunity for the first ever all-oral treatment regimen, a much higher cure rate, fewer side effects and a two- to four-fold reduced duration of therapy. On April 10, 2014, Dr. Nelson, who was the senior author on the publication reporting the results of these trials (NEJM 2013;368:1867-77), was awarded the Clinical Research Forum’s Top 10 Clinical Research Achievements of 2013, which he accepted “on behalf of the many researchers, clinicians and patients who took part in these clinical trials.”

Hepatitis C is a complex liver disease caused by the hepatitis C virus, or HCV, first discovered in 1989. HCV is a major clinical and public health problem, infecting about 140,000 million to 180,000 million — 2 percent to 3 percent of the world’s population — and about 3 million to 4 million people in the United States. The first phase of infection lasts for a few weeks, but if untreated the virus may persist. About 80 percent of acutely infected HCV patients progress to chronic infection. Of these, 20 percent develop cirrhosis within 25 years, with 25 percent of cirrhosis patients developing hepatocellular carcinoma and/or decompensated liver disease. Hepatitis C virus is the primary cause of liver cancer and liver transplantation in the United States. An analysis presented by Centers for Disease Control and Prevention researchers at this month’s Infectious Disease Week forum found that from 2003-2013, deaths with hepatitis C recorded on death certificates increased from 11,051 in 2003 to 19,368 in 2013, while deaths associated with all 59 other notifiable infectious conditions decreased from 24,434 in 2003 to 18,002 in 2013.

Following the release of Sovaldi, other oral agents were approved for use without being compared with current standard-of-care treatment. This created a gap in knowledge that has impacted patient and clinician decisions. As Dr. Nelson comments: “There is not a single study in the world that has compared any of these oral therapies against each other. These drugs are already in use and have significant differences, but patients and doctors typically have no choice, as the insurance company usually chooses based on price. So we need to understand their safety and effectiveness and how they’re working in diverse populations. The main goal of PRIORITIZE will be to compare the recently approved oral medications to determine if one of them is more effective than the others in curing hepatitis C.” Nelson and his colleagues will also learn more about the drugs’ side effects and whether they work equally well in real-world conditions when used by a diverse group of patients that includes minorities and people with other medical conditions.

The PRIORITIZE study is led by an inclusive and representative team — with patients and patient organizations at its core — united by a shared commitment to improve outcomes and access to care for all patients with hepatitis C. To ensure the trial addresses outcomes of interest to HCV patients and their caregivers, the PRIORITIZE team conducted 45 patient interviews and formed a nine-member Patient Engagement Group to inform selection of the patient-centered outcomes that will be evaluated in the trial. Further, the study team includes a committee of eight patient advocacy and education organizations that were extensively engaged in development of the PRIORITIZE proposal and will be key partners in the dissemination and implementation of findings.

PCORI sought research proposals because the hepatitis C oral medications had only been tested in carefully selected patient populations, leaving patients with no comparative evidence about the drugs’ effectiveness. The PRIORITIZE study will compare Gilead Sciences’ Harvoni (the successor to Sovaldi), the Viekira Pak produced by AbbVie and a forthcoming combination tablet from Merck & Co. About 3,750 patients at approximately 36 sites nationwide will be randomly assigned one of the medications. During the trial, UF Health will coordinate many of the study’s logistical and clinical aspects while researchers at the University of North Carolina at Chapel Hill will be responsible for data analysis. Researchers at Johns Hopkins and the University of Michigan will contribute specialized scientific expertise in the areas of comparative effectiveness methodology and liver disease progression, respectively.

To obtain data on the comparative results using the different drugs under real-world conditions with diverse populations having co-morbid conditions, PCORI sought to use a clinical research methodology called a “pragmatic clinical trial,” or PCT. In a classic randomized clinical trial, or RCT, investigators determine the efficacy of an intervention under ideal conditions. Participants are often a highly selected and homogenous group exhibiting good compliance, and are usually recruited in secondary or tertiary care sites. They are more likely to remain in the study, typically have only the target condition, and are subject to strict dosing schedules and monitoring. RCTs are deliberately designed to give the maximum chance of showing an effect, if one is present. In contrast, PCTs seek to determine the effectiveness of an intervention in a real-world setting to inform clinical decision-making. Researchers designing pragmatic trials take particular care to ensure that the study population is as similar as possible to the population on which the intervention is meant to be used (external validity), reflecting the normal range of diversity in disease severity, comorbidities, age, sex and social and ethnic groups seen in everyday clinical practice. Pragmatic trials also ensure that the sorts of interventions tested can be plausibly rolled out in clinical practice and that the outcomes used to assess effectiveness are valid and easily understood by a range of users, including clinicians, patients, policymakers and health commissioners.

Thus, RCTs typically try to answer the question “can this treatment work under ideal conditions?” They usually precede pragmatic trials, which then ask “we now know it can work, but how well does it work in real-world clinical practice?” In this sense, the PRIORITIZE trial is the PCT that follows the RCTs of Sovaldi and other drugs. However, the PRIORITIZE study is actually a blend of randomized and pragmatic methods. It will consist of a two-stage study design that will allow for a randomized, pragmatic study of currently available medications (Harvoni and Viekira Pak), and a subsequent randomized, pragmatic evaluation of a third regimen (Merck) expected to enter the market in early 2016. What makes this study different from an RCT is that, once randomized to a particular drug, participants will receive the standard clinical care that is delivered in their respective center for the treatment of HCV; the clinical management, visit schedule, and safety-and-efficacy lab evaluation schedule are not defined by the protocol. Moreover, all data related to that standard clinical care will be abstracted from submitted medical records (clinic notes, telephone notes, safety and efficacy labs) by a specially trained group of chart data abstractors. Along these lines, the collection of patient reported outcomes by research-type surveys is atypical in standard clinical care; therefore, to preserve the usual clinical conditions, such outcome data will be obtained through the use of technology and devices outside of clinical interactions, such as web-based surveys.

The absence of comparative effectiveness data in combination with the relative high cost of these drugs has led to restricted access to treatment and payer-mandated use of specific regimens based on negotiated pricing. The limitations to treating patients in the real world are based on two ill-conceived principles: 1) restrictions to the formulary for which drugs are accessible under specific insurance plans and 2) restrictions about which patients can be treated based upon the severity of liver disease or other more arbitrary factors such as history of substance abuse. Despite objections by many, including the Guidelines Panel of the American Association for the Study of Liver Diseases/Infectious Diseases Society of America and The President’s Advisory Council on HIV/AIDS, these restrictions have been imposed, without scientific rationale, solely to minimize cost to payers. Indeed, the preponderance of current evidence suggests that almost all patients with hepatitis C would benefit from treatment, with minimal harms and regardless of severity of liver disease. Furthermore, in clinical practice there appear to be treatments that would be better than others for certain subpopulations with comorbidities, yet by happenstance of socioeconomic status or geography, these medications are beyond the reach for many persons infected with hepatitis C. Thus, the choice of treatment and regimen has been removed from key stakeholders (patients and physicians).

Also, important patient groups have been underrepresented in HCV clinical trials, including black Americans, older adults and persons with active substance use or mental illness, especially those with advanced liver disease. Through active engagement with HCV patient advocacy organizations and HCV patient partners, the PRIORITIZE team learned that the top-ranked priorities to inform decisions about HCV treatment include likelihood of being cured, out-of-pocket costs of therapy, drug side effects and other short- and long-term treatment harms and benefits. The PRIORITIZE pragmatic clinical trial is specifically designed to address these important study outcomes identified by multiple stakeholders. Importantly, the study will provide data on underrepresented populations (black Americans, individuals with multiple comorbidities, low-income groups, older adults (over age 65), individuals with substance use and mental health disorders) and HCV subgroups (genotype 1a vs 1b), so the results of this study will be applicable to most clinical settings. The study will also include a large subgroup analysis of patients with cirrhosis who are underrepresented in clinical trials, typically <15% of trial population but who comprise up to 50% of those who will be considering antiviral therapy. Moreover, those with cirrhosis are potentially more susceptible to short- and long-term harms from the medications and have shown the largest difference in sustained virologic response (i.e., cure) when comparing real-world observational data with Phase III trial results.

Lastly, due to the critical importance of this proposal to U.S. veterans, the PRIORITIZE study plans to enroll up to 1,250 patients receiving care in Veterans Affairs Medical Centers. The VA system is the single largest HCV care provider in the U.S., with a prevalence rate of 5.4 percent (three times that of the general population) and over 170,000 veterans in VA care with confirmed chronic HCV. Veterans who served in the Vietnam War era, those with alcohol or substance use disorders, and those with psychiatric conditions or homelessness are particularly likely to be infected and eligible for the PRIORITIZE trial. The oral regimens being evaluated in the proposed trial are ideal for the treatment of these vulnerable populations due to their low incidence of treatment harms, such as neuropsychiatric side effects.

Thus, the PRIORITIZE study will provide valuable information for all patients considering HCV treatment, including vulnerable subgroups. This study of new oral regimens will answer critical questions regarding: 1) rates of patients being cured and durability of cure, 2) drug side effects and other short- and long-term treatment harms and 3) patient-centered clinical benefits (changes in patient-reported HCV symptoms) and short- and long-term liver disease progression or regression.

I now return to the question posed at the outset of this three-part series on clinical, translational and implementation science at UF: “Is this what unstoppable momentum feels like in research?” Hopefully, by reviewing in some detail the extraordinary series of intertwined research programs that have been funded in recent weeks — the CTSA, PCORnet and PRIORITIZE — you will agree that our progress in clinical, translational and implementation science is accelerating, and can only lead to even more research at UF Health that will improve patient outcomes locally, nationally and globally.

The Power of Together,

David S. Guzick, M.D., Ph.D. UF Senior Vice President for Health Affairs & UF Health President