In the JournalsPerspective

Smaller, shorter trials, more flexibility needed for lupus treatment development

Joan T. Merrill

The current standard of lupus disease control is unacceptable, and smaller and shorter drug trials are required to develop more effective treatments, according to a white paper published in Lupus Science and Medicine.

“Trial failures of more than 30 promising treatments for lupus represent more than a billion dollars in lost research and development funding for lupus,” Joan T. Merrill, MD, chief advisor of clinical development at the Lupus Foundation of America, a member of the Oklahoma Medical Research Foundation and the paper’s lead author, told Healio Rheumatology. “Yet all of these treatments were theoretically promising. It became clear to many people in our community that something might be wrong with how we were conducting the trials.”

The paper, “Lupus Community Panel Proposals for Optimizing Clinical Trials: 2018,” identifies multiple issues with the status quo of lupus treatment development, including the “unwieldy size” of current trials, combined with global competition for patients “who meet the stringent entry criteria at limited numbers of adequately trained trial sites,” the authors wrote.

The current standard of lupus disease control is unacceptable, according to experts in the lupus clinical community.
Source: Shutterstock

“It has also been difficult to arrive at reliable study endpoints given the complexity and user-unfriendliness of accepted, but often misunderstood outcome measures,” Merrill and colleagues wrote. “The heterogeneity of the disease itself and the superimposition of background polypharmacy to this immunological complexity has created enough noise to ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results observed may not have been negative, but merely uninterpretable.”

To address these issues, and to give recommendations for new approaches to the FDA, the authors sought and received input and guidance from nearly three dozen experts in the field of lupus, including consultations with scientists from various biopharmaceutical companies, as well as government and volunteer stakeholders.

According to the Lupus Foundation of America, the paper represents the first time the lupus research community has grouped its efforts to issue recommendations to the FDA for improving clinical trials. It follows the Lupus Foundations of America’s 2009 Lewin report, which also including recommendations for overcoming barriers obstructing lupus treatment development.

The authors discussed five solutions for improving lupus clinical trials. They include making trials open to people with all types of lupus; decreasing the size of trials; using recent scientific data to select patients who are most likely to benefit from a given treatment; improving choices in the background medications used; and improving the way in which symptoms are tracked and graded.

Specifically, to achieve smaller and shorter trials, the authors recommended:

  • Decreased or controlled background medications;
  • Pharmacodynamic-based selection of background medications;
  • A focus on patients based on disease severity or biomarkers; and
  • More discriminatory primary endpoints.

For more flexibility in development programs, the authors recommended:

  • Adaptive trials;
  • Using phase 2 trial data as proof of efficacy; and
  • Single-organ endpoints that justify approval for all affected patients, rather than only those with systemic lupus erythematosus.

Lastly, to improve on unmet needs requiring community action, they recommended:

  • Identifying and training more trial sites;
  • Better outreach to minority patients;
  • More patient-reported endpoints, to include patient perspectives; and
  • Advancing precision medicine concepts for lupus.

“The main themes address the fact that lupus is a complicated, heterogenous disease so we need robust trial designs that strongly discriminate between an effective treatment and placebo,” Merrill said. “Some of the major proposals are to design trials that lower placebo group responses either by including only the more acutely ill patients or else decreasing or at least simplifying background medications. Outcome measures must also be more robust. Single organ outcomes, achievement of very low disease activity and measurements of sustained response are all approaches that can increase the difference between effective treatments and placebo.” – by Jason Laday

Disclosure: Merrill reports grant funding from Bristol-Myers Squibb Company, GSK group of companies, Xencor and the Office of Minority Health, as well as consulting fees from Anthera, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb Company, Celgene Corporation, Eisai, EMD Serono, Exagen Diagnostics, Genentech, GSK, Gilead, ImmuPharma PLC, Horizon, Incyte, Janssen Pharmaceuticals, Mallinckrodt Pharmaceuticals, MedImmune/AstraZeneca, Neovacs SA, Pfizer, ReAlta, RRD International, Sanofi, Takeda Pharmaceuticals USA and UCB. See the full study for additional authors’ disclosures.

Joan T. Merrill

The current standard of lupus disease control is unacceptable, and smaller and shorter drug trials are required to develop more effective treatments, according to a white paper published in Lupus Science and Medicine.

“Trial failures of more than 30 promising treatments for lupus represent more than a billion dollars in lost research and development funding for lupus,” Joan T. Merrill, MD, chief advisor of clinical development at the Lupus Foundation of America, a member of the Oklahoma Medical Research Foundation and the paper’s lead author, told Healio Rheumatology. “Yet all of these treatments were theoretically promising. It became clear to many people in our community that something might be wrong with how we were conducting the trials.”

The paper, “Lupus Community Panel Proposals for Optimizing Clinical Trials: 2018,” identifies multiple issues with the status quo of lupus treatment development, including the “unwieldy size” of current trials, combined with global competition for patients “who meet the stringent entry criteria at limited numbers of adequately trained trial sites,” the authors wrote.

The current standard of lupus disease control is unacceptable, according to experts in the lupus clinical community.
Source: Shutterstock

“It has also been difficult to arrive at reliable study endpoints given the complexity and user-unfriendliness of accepted, but often misunderstood outcome measures,” Merrill and colleagues wrote. “The heterogeneity of the disease itself and the superimposition of background polypharmacy to this immunological complexity has created enough noise to ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results observed may not have been negative, but merely uninterpretable.”

To address these issues, and to give recommendations for new approaches to the FDA, the authors sought and received input and guidance from nearly three dozen experts in the field of lupus, including consultations with scientists from various biopharmaceutical companies, as well as government and volunteer stakeholders.

According to the Lupus Foundation of America, the paper represents the first time the lupus research community has grouped its efforts to issue recommendations to the FDA for improving clinical trials. It follows the Lupus Foundations of America’s 2009 Lewin report, which also including recommendations for overcoming barriers obstructing lupus treatment development.

The authors discussed five solutions for improving lupus clinical trials. They include making trials open to people with all types of lupus; decreasing the size of trials; using recent scientific data to select patients who are most likely to benefit from a given treatment; improving choices in the background medications used; and improving the way in which symptoms are tracked and graded.

PAGE BREAK

Specifically, to achieve smaller and shorter trials, the authors recommended:

  • Decreased or controlled background medications;
  • Pharmacodynamic-based selection of background medications;
  • A focus on patients based on disease severity or biomarkers; and
  • More discriminatory primary endpoints.

For more flexibility in development programs, the authors recommended:

  • Adaptive trials;
  • Using phase 2 trial data as proof of efficacy; and
  • Single-organ endpoints that justify approval for all affected patients, rather than only those with systemic lupus erythematosus.

Lastly, to improve on unmet needs requiring community action, they recommended:

  • Identifying and training more trial sites;
  • Better outreach to minority patients;
  • More patient-reported endpoints, to include patient perspectives; and
  • Advancing precision medicine concepts for lupus.

“The main themes address the fact that lupus is a complicated, heterogenous disease so we need robust trial designs that strongly discriminate between an effective treatment and placebo,” Merrill said. “Some of the major proposals are to design trials that lower placebo group responses either by including only the more acutely ill patients or else decreasing or at least simplifying background medications. Outcome measures must also be more robust. Single organ outcomes, achievement of very low disease activity and measurements of sustained response are all approaches that can increase the difference between effective treatments and placebo.” – by Jason Laday

Disclosure: Merrill reports grant funding from Bristol-Myers Squibb Company, GSK group of companies, Xencor and the Office of Minority Health, as well as consulting fees from Anthera, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb Company, Celgene Corporation, Eisai, EMD Serono, Exagen Diagnostics, Genentech, GSK, Gilead, ImmuPharma PLC, Horizon, Incyte, Janssen Pharmaceuticals, Mallinckrodt Pharmaceuticals, MedImmune/AstraZeneca, Neovacs SA, Pfizer, ReAlta, RRD International, Sanofi, Takeda Pharmaceuticals USA and UCB. See the full study for additional authors’ disclosures.

    Perspective
    Monica Richey

    Monica Richey

    Systemic lupus erythematosus is one of the most complex diseases in the rheumatology world. The fact that no two lupus patients are alike makes diagnosis and treatment extremely difficult. Over the last 50 years, the FDA has only approved one medication for lupus – belimumab in 2011 – which was almost denied, as it did not meet the primary endpoint.

    In this white paper, the authors explored the various obstacles that plague research studies, such as shortage of patients, complicated combinations of disease measures, polypharmacy and large trial size, just to name a few. Their proposal to improve the current state of clinical trials brings forth several different measures, including: small trial size; training and education of new trial sites; uncomplicated disease measurement tools to include patient-reported endpoints; as well as participation of minorities, including Hispanics, African American and North American Indians.

    Most patients are either unaware of or are afraid of entering clinical trials, therefore, patient education regarding availability and safety of clinical trials is paramount in order to attract patients to research studies. The Lupus Foundation of America and the HHS Office of Minority Health have jointly developed and launched a new website specifically intended for patient education about clinical trials, which is a ‘must-read’ for lupus patients.

    This paper starts a great conversation on how to bring more needed medications to patients with a most complex disease, but it is a conversation that needs to persist.

    • Monica Richey, MSN, ANP-BC/GNP
    • Board member, Rheumatology Nurses Society Nurse practitioner Division of rheumatology Northwell Health

    Disclosures: Richey reports no relevant financial disclosures.