Research Shorts: Surrogate endpoints using the example of hepatitis C virus

Contributed by Claudia Dobler, MD, PhD

2018 U.S. GRADE Workshop Scholarship Recipient

Surrogate endpoints (for example laboratory or imaging results) are commonly used in clinical trials, as they require less participants and can be done in a shorter period of time compared to trials that use clinically important outcome measures such as mortality. When evidence for an intervention is almost exclusively based on trials that used surrogate outcomes, it is challenging for decision makers to determine the appropriateness of the use and reimbursement of an intervention. The common tendency in evidence-based medicine is to view results based on surrogate endpoints as less certain than results based on long term, final patient-important outcomes. The authors of this paper use the contemporary and highly debated example of the surrogate endpoint ‘sustained viral response’ (i.e., viral eradication considered to represent successful treatment) in patients treated for chronic hepatitis C virus infection to demonstrate how the validity of a surrogate endpoint can be critically appraised to assess the trustworthiness of the evidence and the implications for decision-making. They outline how the GRADE system for determining the certainty in the evidence can be used in situations where decisions for clinical practice and health policy have to be based on evidence that mainly comes from trials with indirect outcome measures.

Beyond assessing the quality of the evidence, potential benefits and harms of the intervention need to be weighed against each other and factors such as patient values, impact on healthcare equity, acceptability by patients and feasibility of the intervention need to be considered. The authors conclude that considering all these factors, a conditional recommendation for direct acting antiviral agents to treat chronic hepatitis C virus infection may be appropriate.


Reference: Dobler CC, Morgan RL, Falck-Ytter Y, Montori VM, Murad MH. Assessing the validity of surrogate endpoints in the context of a controversy about the measurement of effectiveness of hepatitis C virus treatment. BMJ evidence-based medicine 2018: 23(2): 50-53. https://ebm.bmj.com/content/22/6/199

Research Shorts: Treatment Burden

Contribution from Claudia Dobler, MD, PhD

2018 U.S. GRADE Workshop Scholarship Recipient

Treatment burden is the work that patients need to do to implement treatments and its effect on patient functioning and well-being. The work that patients do to manage their health often remains invisible to health professionals, who might therefore overestimate patient’s capacity to take on more interventions. Treatment burden includes filling prescriptions, taking medications, attending medical appointments, monitoring their health, making lifestyle or behavioral changes, managing medical equipment or devices, and having to deal with insurance companies and the financial burden of health care. The evidence to decision framework developed by the GRADE Working Group addresses some parts of the construct of burden of treatment in the domains of acceptability and feasibility, but burden of treatment is currently not included as a discrete construct. The authors of this paper explore the idea of including information on treatment burden associated with interventions in clinical practice guidelines. Information on treatment burden would enable patients to make informed decisions about treatments. High-quality methods for assessing treatment burden need to be identified and meaningful ways of adding this information to clinical practice guidelines need to be explored. In the paper, practical examples are outlined of how treatment burden could be included in guidelines for chronic obstructive pulmonary disease, type 2 diabetes, and chronic kidney disease. Making treatment burden explicit for adhering to a special diet for chronic kidney disease, for example, could include information on foods that should be avoided, extra time spent on grocery shopping and cooking, challenges when eating out, the typical number of consultations with a dietitian, transport requirements to see a dietitian, time spent documenting the diet, and required intensity of blood tests to monitor electrolytes.




Clinicians should discuss values and preferences with patients, especially for treatments associated with a high workload. This would help clinicians to understand how individual patients prioritize different outcomes and treatment burden and would help patients to understand what components of their treatment are the essentials, even on a bad day, so that they can prioritize treatments appropriately.


Dobler CC, Harb N, Maguire CA, Armour CL, Coleman C, Murad MH. Treatment burden should be included in clinical practice guidelines. BMJ 2018: 363. https://www.bmj.com/content/363/bmj.k4065

Drug Value Symposium

The first Drug Value Symposium was held in Cleveland, Ohio on May 5th, 2018 in conjunction with the 8th Guideline Development Workshop using the GRADE approach.

Attendees found the inaugural Drug Value Symposium to be engaging, appreciating the opportunity to share ideas on how to systematically approach making evidence-based drug-coverage decisions at their institutions.

Attendees from all over the world with various backgrounds and expertise attended. The symposium opened with a thought-provoking presentation from Yngve Falck-Ytter, one of the founding U.S. GRADE Network members. His presentation highlighted why healthcare costs are becoming an increasing challenge and how incorporating a methodologically rigorous framework, such as GRADE, to formulary decision making can facilitate sensible decisions. 

Dr. Falck-Ytter opens the symposium with an overview of how GRADE includes both cost and cost-effectiveness when making health-care decisions.

Representatives from local healthcare systems then offered varying perspectives on the institutional successes and challenges of managing high cost drugs. Presenters included Mandy Leonard from Cleveland Clinic, Indrani Kar from University Hospitals, Christina Wadsworth and Jan Kover from MetroHealth, and Candice Wenzell from the Northeast Ohio VA Healthcare System. 

       Lessons learned from managing costly drugs within the Cleveland, OH 

Veteran's Administration, as presented by Ms. Wenzell.

The symposium concluded with an interactive session facilitated by Yngve Falck-Ytter, Candice Wenzell, and Kelsey Rife that allowed attendees to apply the GRADE methodology to evaluate a drug for a specific indication and then make a decision on whether or not they would recommend the use of the drug.