- ALS Association, “Principles for Urgent, Patient Centered ALS Clinical Trials http://www.alsa.org/assets/pdfs/Principles-for-Clinical-Trials-FINAL.pdf (Fall 2018)
- Muscular Dystrophy Association, “Redoubling the Urgency for Innovative ALS Clinical Trials” (May 27 2020) http://cqrcengage.com/mda/file/o0IMFxnubSN/MDA%20ALS%20Clinical%20Trial%20Design%20Statement.pdf
On May 27 2002, the MDA released a statement calling for rapid innovation in the design of ALS clinical trials, and calling on “all stakeholders from across the therapeutic development spectrum to commit to think more creatively on how to address these surmountable challenges, and to heighten the urgency to find solutions.”
The statement was welcomed by the ALS community.
Some individuals on social media used the MDA statement to criticize the ALS Association for its failure to lead on, or even take a position on, this issue.
In reality, the Association has taken public positions on clinical trials. So the question is really whether the Association’s position on clinical trial innovations is lagging behind the thinking among other patient advocacy groups.
That question prompted this short analysis – I wanted to see where the MDA statement and ALS Association’s positions converged and diverged. What follows is a very quick comparison of the May 27 2020 MDA statement on clinical trials and the most recent 2018 Statement of Principles from the ALS Association (from its website) on clinical trials.
I broke down each of the specific topics MDA addressed in its message, drew direct quotes from the MDA statement, and then searched the Association’s 2018 Statement of Principles for positions on each of those issues, taking direct quotes from that document as well. In a few instances the issue in question was discussed in more than one part of a document; in that case I included both quotes. The results are provided in the table below.
|1||Date of statement||May 27 2020||Fall/summer 2018|
|2||Trial inclusion criteria||While trial sponsors may be concerned that expanding the inclusion criteria for the trial may jeopardize findings of efficacy, the use of multiples arms that enroll ALS patients in different stages of progression should be explored||Enrollment criteria should be based on a clear rationale and preclinical data to ensure the correct study population. Simply adopting criteria from previous trials is not acceptable. Many people with ALS want to participate in trials. Every effort should be made to be inclusive while ensuring the trial provides clear answers about treatment efficacy. Adaptive designs and other innovative practices from other disease areas should be used to conduct fast, impactful trials.|
|3||placebos||We remain hopeful that FDA, working with sponsors, will eliminate the use of placebos in ALS clinical trials, but placebos are clearly still being employed in newly announced clinical trials. We recognize that the use of placebos will not disappear overnight, and the lack of established scientific understanding on the heterogenous progression of the disease poses challenges, but we ask that FDA and sponsors redouble their efforts to avoid placebos wherever possible (Calls for): Collaborative development of innovative clinical trial designs that employ historical controls, Bayesian statistical approaches, and cross-over designs with the FDA, the biopharmaceutical industry, and patient advocacy organizations leading the way.||Reduce the size and ratio of placebo groups and consider eliminating them completely when efficacy is not a trial outcome, and/or when additional natural history progression models, crossover studies, or other approaches provide informative comparative data.|
|4||Continued access to therapy post -trial (open label extensions)||Sponsors of ALS therapies to commit to considering expanded access and open label extensions at the outset of their clinical studies. Sponsors should meet with patients, their loved ones, and their advocates before clinical trials commence to ensure the approach is supported by the patient community.||Access: Trial sponsors need to increase access to experimental treatments. Trial participants originally on placebo or who believe the treatment impacted their disease should have access receive the experimental treatment, through open-label extensions or expanded access options, provided that the additional access does not slow or reduce the impact of the trial itself.|
|5||Funding to cover costs of expanded access programs and open label extensions||Innovative financing mechanisms to overcome the financial disincentives associated with including expanded access programs and open label extensions within ALS clinical trials, including ongoing late-stage or Phase III clinical trials. Congressional consideration of legislative interventions that would lower financial and logistical barriers to employing scientifically sound, but also patient-centric, approaches in ALS clinical studies.||People with ALS and caregivers should be consulted on trial design to minimize the risks, discomfort, loss of control, hassles, financial barriers and logistical challenges of trial participation. IRBs, the FDA, funders and other oversight groups should favorably consider trial features designed to reduce burden on people with ALS and their caregivers. We appreciate the ethical challenges of spending resources on access to experimental treatments, when many families with ALS are already overwhelmed with the financial burden of ALS (loss of income, home modifications, copays, etc.). Providing financial support for access to experimental treatments could draw resources away from the broader community to the handful of people willing and able to take experimental treatment outside of a clinical trial. Additionally, there is the potential that trial sponsors may profit from experimental treatments by exploiting people with ALS. The Association will continue to explore this issue, while honoring the rights and wishes of people with ALS.|
|6||Biomarker development||Greater effort and urgency behind ALS biomarker development that can hopefully inform surrogate endpoint development (clinical trial endpoints that likely predict effective clinical outcomes) and eventual qualification to facilitate use of FDA’s accelerated approval pathway.||Experimental treatments need testing to determine their effectiveness and safety using the fewest possible participants, shortest length of follow-up, and least burden on participants. Approaches include: Developing and using valid surrogate endpoints and biomarkers when possible to measure impacts quickly and precisely.|
|7||Expanded/early access||FDA consideration of the utilization of innovative approaches towards expanded access, such as the Oncology Center of Excellence Project Facilitate, in progressive neurological diseases without satisfactory therapeutic alternatives, including ALS. –||Trial sponsors should strongly consider companion studies where patients ineligible for clinical trials assessing efficacy can still participate to provide safety and tolerability information. The entire ALS community should have access to experimental therapies under clinical supervision, provided that the additional access does not slow or reduce the impact of the trial itself.|
Assessment: For the most part, the 2020 MDA statement aligns very closely with the Association 2018 Statement of Principles.
In addition, both documents use qualifying language like “should consider,” “should be explored,” “when possible” or “provided that” to express preferences without locking themselves into unconditional positions on complex issues. This diplomatic language has the virtue of allowing readers with opposing views to feel that their position was supported, without actually committing to that position in full.
The one real divergence is on the question of funding to cover costs of expanded access programs and open label extensions (item #5). The new MDA position embraces the creation of a government fund to cover costs associated with extended access to therapies still in clinical trials (though the MDA does soften this position a bit by asking legislators to “consider” this option). By contrast, Association takes a more cautionary tone, arguing that funds diverted for experimental therapy for a few could come at the cost of research on other promising therapies.
This latter issue is especially relevant now, as legislation has been introduced in the House (“Accelerating Access to Critical Therapies for ALS Act”) that would, if passed, establish a $75 million fund to cover fees charged by pharmaceutical companies to people seeking early access to therapies still in clinical trial. The efficacy, ethics, and other aspects of this kind of government funding of expanded access to therapies still in clinical trial are complex and deserve a careful, thoughtful discussion and debate in the ALS community.
(NOTE: There are currently two bills pending in Congress on expanded/early access to ALS therapies. The House bill described above includes the $75 million fund proposal. The Senate bill, proposed by Senator Braun, focuses on creating a new pathway for expedited access to therapies still in clinical trial, does not include a government funding mechanism, but apparently creates other incentives for therapy developers to participate. More on all this soon; stay tuned!).