Ken's Caucus

Sources:

1. ALS Association, “Principles for Urgent, Patient Centered ALS Clinical Trials http://www.alsa.org/assets/pdfs/Principles-for-Clinical-Trials-FINAL.pdf (Fall 2018)
2. 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.

	issue	MDA	ALSA
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.

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!).

Earlier this year, I began a term serving as a member of the ALS Association Board of Trustees, and also agreed to serve as Chair of the ALS Association Public Policy Committee. 

This was just before news broke of a dangerous new virus, COVID 19.

Over the past month, the Association has been in full emergency response mode as we respond to the dozens of  challenges COVID 19 creates for people with ALS, their families, the ALS clinics and ALSA chapters serving them, and for ALS research centers. Needless to say, it has been a baptism by fire for me.  

COVID 19 presents unique and exceptional dangers to people with ALS. Many to most of us with ALS have, in varying degrees, weakened respiratory functions, and so are at greater risk if we contract the disease and it spreads to our lungs. We may also face difficulties accessing critical care at hospitals where triage protocols could cite either our ALS diagnosis, or our reduced respiratory capacity, or both, as exclusionary criteria (though the Association is working hard on this issue, see more below).

Even if we avoid the virus ourselves, the support systems we rely on are being disrupted. Clinics are having to shift to remote consultations (in the long run, the shift to telemedicine is a good thing, but in the short run disruptive). Some families with a person with ALS are losing jobs and income. Some family caregivers with jobs outside the home are having to calculate how to provide care without exposing the person with ALS to possible infection. Families are also having to decide how to balance social distancing with the need for professional home care givers to support people with ALS. Lower income households are no doubt under particular strain.

At the same time, the 39 chapters in the Association’s federated system are – like all non-profits in this crisis – soon to face significant financial shortfalls as their fund-raising events have been cancelled. Some are in a better position to weather the storm than others. For them, the challenge is that demand for care services is spiking even as their resources will start to dwindle. The longer and deeper the economic crisis is, the worse the financial pressures will grow on non-profits, and on everyone else. The Association leadership is actively working on strategies to ensure that chapters and the services they deliver to people with ALS will be safeguarded.

There is more, but I think you get the point. 

What you need to know, if you are a person with ALS or a caregiver reading this, is that my new perch in the Association affords me a close look at how the organization is responding to the crisis,  and I can report with confidence that it is getting very good grades at crisis response.

In big ways and small, the Association’s team of professionals and volunteers are effectively troubleshooting immediate challenges, and planning to deal with medium and long term challenges. My new colleagues are working very long hours, late into the evenings and on weekends, working to ensure that care services are able to meet new needs, that guidance to people with ALS is clear and accessible, that clinics are reaching out to patients, that disruptions to research are managed and minimized, and that the Association maximizes its impact on critical public policy issues effecting people with ALS by signing onto letters and petitions with coalitions of patient advocacy groups.  The dedication these individuals have to the well-being of people with ALS is really coming out in this crisis.

You may agree or disagree with some decisions or positions the ALS Association has taken over the years, but know this – these are very good people working very hard on our behalf, often on issues that get no visibility but which have outsized impact.  They include skilled professionals with no direct personal link to ALS, but also hundreds of volunteers on boards and task forces at the national and chapter level, most of whom are former or current caregivers of a loved one with ALS, or people living with ALS, like myself. I am proud to work with this group.

I’m working most closely with our public policy response and so can speak to that in more detail.  Over the past month the Association’s lean but very effective public policy team has signed onto over a dozen coalition letters and petitions, including some that seek to protect people with disabilities from discrimination in health care related to COVID-19, and that guarantee that an ALS diagnosis is never used as an automatic exclusionary criteria in triage. These are going to be, literally, matters of life of death for some of us if triage is required in our areas. The ALS Association leadership team has had rich and – for me – emotionally draining debates over the positions we are advocating for, the principles that should undergird these positions, and the ethical and moral responsibility we have both to people with ALS and to the greater good. I have won some of the debates and lost some. But what has impressed me is the culture of open debate and the deep commitment to ethical principles that permeates the organization. That bodes well for the many policy decisions the Association will have to make in coming months as we respond to new health and economic challenges posed by COVID 19.

I’m a political scientist by profession, and so am not naïve when it comes to the study of organizations and organizational politics. No organization is perfect. They are built by and populated by humans, and are as flawed as we are – sometimes even more so. I can see the imperfections in the Association and the areas where it can, and will, be improved.  I also see opportunities for more effective cooperation and coordination across the many ALS care service, research, and advocacy groups, and hope that is something we can all work toward.

I don’t know how long I have before ALS progression forces me to stop advocacy work, but with the time I have left I hope I can be part of a collective effort to  get us closer to therapies that halt or reverse ALS, promote public policies that advance the interests of people with ALS and related diseases, and provide the best care services possible, so that people with ALS can live longer and better lives. The better we can work together, the faster we will achieve these goals.