It is time to support patients who choose to prescribe their own treatments and manage their own healthcare outcomes.
Clinical trials are ALS patients’ only hope towards achieving an effective treatment in their lifetime. Yet, thousands of them will never enroll. That may be due to economic or geographical constraints. However it is more likely because they are excluded from participation due to specific enrollment criteria designed to facilitate the interpretation of a treatment benefit in the clinical trial.
So where do patients turn when they are no longer eligible to participate in the regulatory trial process? They turn to “experimental” options. Options where there are often no clinical data to support the treatment. Or even data to show it is safe.
But options they can self-prescribe and take “off-label”.
Every one of us on the planet is a patient at some level, striving for a higher degree of well being through fitness, preventive medicine, healthier lifestyle, emotional happiness and stability. And ALS patients want all of these things too. There is little to debate that patients now play a more active role than ever before in their health care decisions. Patients track their exercise activity, calorie intake, calorie burn, heart rate, body temperature, pulse with a multitude of devices from the iWatch to the Fitbit. They track their wellness via web-based portals such as PatientsLikeMe that provide sophisticated tools to monitor their disease progression that is presented in a well-designed cohesive manner.
Advances in wearable devices, implantable devices, and the ability to perform routine clinical read outs associated with disease are a part of our medical future as human beings and as patients.
ALS patients want all of these things. Patients will continue to manage their own healthcare decisions until effective treatment options for ALS have been proven through the traditional clinical trial process and regulatory systems. Until then, they will take supplements. They will take off-label medications with some scientific rationale even if it is not the strongest rationale. And they will even take experimental treatments not approved for any disease indication. They will do any and all of these things if they can get access to the treatment and they can afford to do so.
And they have the right.
But what if we encouraged them to tell us about it? What if we could do clinical trials on these potential treatments? Could we improve the interpretability of the outcomes? Could a more systematic approach be utilized to benefit the whole community? To facilitate informed decisions about which treatments might be working and which ones are actually doing harm?
Randomized Clinical Trials (RCTs)
For decades the gold standard for determining the effectiveness of a drug has been a method of randomized clinical trials (RCTs), where parallel groups of patients are randomized into treatment or placebo groups. The objective of RCTs is to determine the average treatment effect in a specific cohort of patients that meet specific inclusion and exclusion criteria.
Often these studies provide limited information on whether the treatment positively impacts a limited number of participants or even individual patients. In addition, these types of trials are often long and expensive and may not meet the needs of a patient seeking treatment due to confounding variables such as other medical conditions.
N of 1 Clinical Trials
So, how can the research and clinical community work together with patients in this framework to leverage the potential positive outcomes and eliminate negative outcomes as soon as possible?
The answer: By systematically adopting the principles of N of 1 clinical trials.
N of 1 trials are randomized trials for each individual patient with the goal of pooling individual patient data retrospectively to characterize treatment benefit. They are typically “crossover” designs with multiple treatments and often a placebo with randomization of treatment over specified time intervals.
N of 1 clinical trials have been used for decades in other medical practices such as cystic fibrosis, assessment of pain medications, respiratory function, anti nicotine treatments, and gastrointestinal disease to name a few.
The major challenge with N of 1 trials in ALS or other disease indications is in their design. How can we design them to be informative and impactful and ensure that the needs of the patient are aligned with the needs of the entire community?
The successful execution and interpretation of outcomes from N of 1 trials are dependent upon:
- The randomization of treatment for each patient into a treatment group on enrollment.
- The commitment of every patient to be randomized into multiple treatment groups during the trial period.
- The introduction of multiple randomized treatment intervals during the course of the study.
These processes are implemented into the design to eliminate “biases” of effective outcomes from the patients and prescribers in the trial process.
This is how it could work:
- Every ALS patient who wants to participate “enrolls” via an online system (similar to the system that ALS TDI has in place for its Precision Medicine Program). Once enrolled, they are assigned a patient portal where they can follow along in the data collection and data interpretation stages of the trial. They will have to comply with self-reporting of their wellness over the next 12 weeks. This period of time is called the “lead-in period” and it captures data using self-reported ALS FRS, motion tracking devices which can be provided, and in some cases, at-home blood tests for biomarkers of disease progression (I’ll get to this in a minute.)
- After 12 weeks, patients are randomized into any possible treatment group including a placebo if it is designed into the trial. Patients then continue weekly self-reporting and any blood tests that are required. After 12 weeks they stop taking anything for 3 weeks, otherwise known as the “wash out period. ” Patients are then re-randomized into any of the treatment or placebo arms and the process continues.
- The key point is that each patient who enrolls is randomly assigned a group and all the medications including the placebo look the same.
For simplicity sake, let’s say there are three treatment arms in the trial. Every patient will be randomized three times in random order into any arm of the trial. At the end of the 18 months, the data is unmasked and shared with the community.
Figure 1: Graphical representation of N of 1 clinical trial workflow
At the end of an N of 1 trial like this one, there will be enough data to determine if a treatment actually slowed disease progression or made progression worse. Knowing either would benefit all ALS patients.
It’s not all roses
There are obviously many issues to be resolved with the execution of N of 1 trials.
- For instance, what are the possible drugs that are available?
What are the outcome measures?
This is a particularly challenging one. Ideally the outcome measure would be easy to measure, quantifiable, very accurate, reproducible, capable of weekly measurements, not require a clinical visit, and apply to all patients. As one can guess in ALS we don’t really have the perfect outcome measure. However we may be able to leverage real time accelerometer data and compare these data to self reporting scales such as ALS FRS. We may also be able to use an N of 1 trial as described to “validate” preliminary data on promising biomarkers from blood (NF-L, creatinine). These outcomes could be utilized in addition to more traditional outcomes in ALS such as forced vital capacity, time to assisted ventilation, and survival.
- Can we achieve compliance on the self-reported outcome measures?
- What standard clinical chemistries could be used to assess disease progression?
- How would the data inform future decisions for stakeholders in the ALS community?
This strategy however, still has a very significant potential upside, when it comes to the ALS drug development landscape.
Let me use a real time example:
In 2013 ALS TDI sponsored a clinical trial to test the safety of Gilenya, a treatment approved by the FDA for Multiple Sclerosis. Scientists at ALS TDI hypothesized it may provide therapeutic benefit in ALS patients. A trial was designed by a team of ALS neurologists and approved by the FDA to test the approved dose for MS patients in 30 ALS patients at 4 ALS clinics and treat them for 30 days to monitor potential acute safety issues. Since it was just a 30-day trial, there was no preconceived notion that the trial would impact any outcomes of slowing down disease or improving survival rates. It took 12 months to enroll the 30 patients at the 4 ALS clinics.
Now compare and contrast that time frame to the following scenario:
ALS TDI could design and execute an N of 1 trial for several potential “off-label” treatments that patients may be taking anyway in conjunction with our Precision Medicine Program.
We have enrolled 180 patients into the program in only 9 months. Based on patient inquiry, the program could have easily enrolled more than 400 in this time frame but we are limited by capacity per week. We have been tracking ALS FRS, speech recording, accelerometer data, biomarkers in blood, and a full genome sequence for all these patients. If we had randomized each patient into an arm of the N of 1 trial upon enrollment in the program, we would have already effectively completed a typically sized phase IIB trial in ALS for two potential treatments!
And more importantly we would now be sharing the data with the entire community to inform future decision making.
This could be a game changer.
We need to support the patient community when they do what they are going to do anyway. Seek alternative treatments that are safe until the traditional randomized clinical trial process can bring effective treatments forward. An effort has been made to accomplish this objective on patient forums as well as companies. But we need to help the community collect and aggregate the data as quickly as possible to actually see if the treatments are working..
We need to help the patients monitor their wellness during this process with web- based tools to monitor disease progression. We need to offer them technologies to more accurately capture their daily activities and quality of life. We need to develop safe, accurate and effective ways to measure biomarkers of disease progression without having to go for a clinical visit.
This is the future of Precision Medicine for patients afflicted with a disease for which there are no current treatment options. This is now a very strong option for ALS patients.
This is the solution for today.
It is imperative that we don’t miss another opportunity in the ALS patient community. I am willing to incorporate an N of 1 trial into the enrollment of our Precision Medicine Program if the ALS community is willing to give it a try.
It will take some effort to design the trial:
- What are the treatments?
- What are the enrollment criteria?
- What are the exclusion criteria?
- Where do we buy the drugs?
- Who will re package them and ship them in a blinded fashion to patients?
- What are the regulatory concerns?
- What are the outcome measures?
Many of these can be addressed expeditiously. Others will take some time.
But we should start today!