Guest Column | May 2, 2018

5 Proposed Solutions To FDA For Optimizing Clinical Trials

By Joan T. Merrill, M.D., Oklahoma Medical Research Foundation and Lupus Foundation of America; Susan Manzi, M.D., Allegheny Health Network and Lupus Foundation of America; and Victoria P. Werth, M.D., Perelman School of Medicine, University of Pennsylvania


Lupus is a complicated imbalance of the immune system with a spectrum of manifestations that vary from patient to patient and may change in the same person over time. This complexity makes treatment development challenging.

To address these challenges, the Lupus Foundation of America convened a committee of lupus clinicians and clinical trial investigators to evaluate the field and propose solutions. We reviewed lupus trial data from the last 30 years and consulted with experts from companies with significant experience developing lupus treatments. From this first-in-lupus effort came the publication of the white paper Lupus Community Panel Proposals for Optimizing Clinical Trials: 2018.

This effort is timely because standard-of-care treatments are not working for patients with this chronic, often serious, sometimes life-threatening condition. Even for those with less severe disease, the combination of side effects and inadequate long-term disease control has a major impact on health and quality of life. In a poll conducted by the Lupus Foundation of America (collaborating with Eli Lilly and UCB), 45 percent of patients indicated the effects of medication impair their daily activities and work. Furthermore, patients report taking an average of eight prescription medications daily. Despite this (or perhaps because of it), 87 percent say the disease affects their work life, and 55 percent said they can only work part-time or intermittently because of lupus. Seventy-six percent report that ongoing fatigue limits their social activities. Therefore, if you ask lupus patients, the current standard of disease control is unacceptable.

And that should not be surprising. The few advances in treatment in the past 60 years only happened with a lot of trial and error. The current standard of care includes far greater use of steroids than we are happy with. A variety of treatments that suppress the immune system are also used, but these were originally developed for other diseases and have never been properly studied for lupus.

For more than 50 years, the only approved treatments for lupus in the United States were aspirin, steroids, and antimalarial drugs such as hydroxychloroquine (Plaquenil). None of these went through a rigorous FDA approval process, and they were automatically approved as “known treatments” in the 1950s. In 2011, the lupus community experienced its first win with the FDA approval of belimumab. This is the only lupus treatment that has so far survived a rigorous Phase 3 international development program.

Many other lupus treatments have been tested in the past few decades, and most failed to complete the approval process. There are many reasons for this. Obviously, it could be that some of these treatments do not work. On the other hand, issues with complexity of the disease, competition for difficult-to-find patients with diverse genetic backgrounds, and facilitating their access to the few trained trial sites around the world may get in the way of fair trials for effective treatments.

Another major problem is the practice of conducting lupus trials by superimposing a study drug on top of various optional standard-of-care treatments. Selection of background agents and optimization of their dosing has never been a strategic process, because little is known about how to do this. Various combinations of these treatments distributed across an already immunologically diverse patient population have unknown effects on investigational drugs. In different subsets of patients these other agents might inhibit, synergize, or just be redundant to the intended effects of the agent being studied. These issues defined the problem.

This community panel proposed the following:

1. Increase collaborative efforts to make trials available to all patients with lupus, especially minority groups that are underrepresented worldwide in trials.

2. Design smaller trials. Smaller trials can succeed only when they are designed to demonstrate a robust difference between effective treatments and placebo. This needs to be done safely. There are several ways to approach this, including:

a. using outcome measures that can more easily show differences between effective treatments and placebos, such as measurements of one organ of the body at a time or measurements that do not show high responses in placebo groups

b. restricting background medicines appropriately so they are only given in the amounts and timeframe necessary for the safety of the people participating in the trial

c. studying the background medications to see how they may interfere with the treatments being studied so they can be selected and used more appropriately and lessen their interference in the trial.

3. Don’t restrict all treatment development to only “systemic” lupus. Let people who have bona fide lupus in one or more organ, but who might not meet the classification criteria for systemic lupus, participate in trials. This has a particular urgency for people with skin involvement, since these manifestations can be evaluated objectively, and this is a large, commonly underserved, true lupus population.

4. Use recent scientific insights into how lupus affects different people to better select people for trials of a given, targeted treatment and, later, be able to select the best treatments for individual patients in the clinic.

5. Understand the symptoms of people when they enter a study. Are these symptoms the right type for the treatment being tested? Are the symptoms from lupus itself or from other illnesses, treatment side effects, or damage that would not be likely to respond to a lupus therapy?

These key proposals for optimizing lupus clinical trials are relevant for other complicated diseases in underserved, diverse, geographically dispersed populations. In the coming weeks, we plan to formally present our proposals to the FDA, with the goal of helping to optimize lupus clinical trial design and outcomes so new, safe, and effective treatments can get into the hands of people who need them more quickly.

About The Authors:

Joan T. Merrill, M.D., is the director of clinical projects in the Arthritis & Clinical Immunology Program at the Oklahoma Medical Research Foundation, OMRF professor of medicine at the University of Oklahoma, and chief advisor for clinical development at the Lupus Foundation of America. She has participated as an investigator in more than 30 multicenter trials for lupus and served as global principal investigator or coordinating investigator multiple times as well as designed and executed novel protocols for lupus trials. She has authored more than 240 peer-reviewed publications on lupus pathology, outcomes, and clinical trial results.

Susan Manzi, M.D., M.P.H., is the chair of the Medicine Institute at Allegheny Health Network. She is a professor of medicine at Temple University School of Medicine and is the medical director of the Lupus Foundation of America. Manzi co-founded the Lupus Center of Excellence as a new model for integrated patient care and clinical-translational research. She has also served on numerous NIH study sections and is a member of several data safety and monitoring boards for the NIH as an advisor to the industry on drug development for autoimmune disease. Manzi has published hundreds of scientific articles and abstracts on lupus and related illnesses.

Victoria P. Werth, M.D., is a professor of dermatology and medicine at the University of Pennsylvania Perelman School of Medicine and past-president and co-founding member of the Rheumatologic Dermatology Society. She has a long-standing interest in clinical and translational research of cutaneous lupus erythematosus, with a focus on improving the treatment and outcomes of autoimmune dermatologic diseases. She initiated a multicenter collaborative, Web-based database to collect prospective information on patients with skin and systemic manifestations of lupus erythematosus. This was the first systematic epidemiologic study of cutaneous lupus erythematosus in the United States, with a goal to assess disease severity, quality of life, and response to treatment.