Articles of Interest in ALS

June 2009

The care of the ALS patient and the search for the cure have both advanced significantly over the past decade.  At the Center for Neurologic Study (CNS) and Coordinated Clinical Research we have contributed to these efforts in the past and are currently working on important clinical trials and research.  We would like you to follow the links to the areas that interest you.

There are two articles in June 2009 Muscle & Nerve that discuss new approaches to conduction clinical trials in ALS.  I will discuss some aspects of the articles below and interject comments.

http://www3.interscience.wiley.com/journal/122337507/abstract
http://www3.interscience.wiley.com/journal/122337510/abstract

A placebo arm is not always necessary in clinical trials of amyotrophic lateral sclerosis.  Paul H. Gordon, MD

Can we eliminate placebo in ALS clinical Trials?
Zachary Simmons, MD

The gold standard for assessing the efficacy and safety of a drug is to conduct two placebo controlled Phase III studies that show positive results.  For statistical and common sense reasons the smaller the effectiveness of the drug the greater number of patients that need to be studied to show that it makes a difference in an illness.  In a disease like ALS where the number of patients are relatively small, a few large Phase III studies could tie up the majority of the eligible patients for a few years duration and still end up with negative results.  This placebo controlled strategy can seem unreasonably slow to make progress.  Furthermore the idea of using a placebo in a largely rapidly fatal disease is seen by many as non compassionate.  As a result the authors of the articles explore the pros and cons of using smaller Phase II trials without placebo groups in order to speed up the process of looking for s medications that can go on to a definite phase III trial with a chance of being positive.

One design called the futility design can use or not use a placebo but compares the results to historical controls.  We have lots of information on how fast ALS progresses using prior trial information.  The futility design works on a statistical idea that it can identify drugs that are futile, ones that definitely won't work so we don't waste valuable time on them.  The non futile drugs (still possibly useful) are those who need to be studied further and on a larger scale.  Its advantage is that it can reduce the number of patients needed by ten fold to obtain this type of preliminary data.  The disadvantage is that even the non futile drugs have no guarantee that they will succeed because the experiments are designed to show that a drug does not work.  It may seem illogical but understand that at this point in our scientific abilities, most of our ideas for drugs do not work.

A second design is called the selection paradigm which compares two or more drugs without placebo.  It answers a specific question about them such as which dosage is better to obtain blood levels or react with certain cells but doesn't tell you yet that it will be effective or safe.  Again, it answers some questions more quickly and can move along the process faster.

Multistage designs combine aspects of phase I,II and III studies into one trial to speed up the conclusions but ultimately they employ a placebo because of it's statistical power to answer the question of effectiveness and safety.

Personal Comment:

Not just ALS but in many terrible diseases, the patients and their families are desperate for help.  The uncontrolled therapies and claims that abound on the internet are not in the patient's benefit.  I do not believe in conspiracies that are keeping true therapies away from the patients and their doctors although it is true that the diseases that affect the most people are the ones that the pharmaceutical companies pursue first for the most profit.  The ALS community can be best served by questioning the status quo and also by contributing by being patients in FDA sponsored trials and raising awareness and money for future research.

Definitions:

What are the phases of clinical trials?

Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions:

In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.

In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

What is a placebo?

A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the experimental treatment's effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or experimental treatment.