Patient & Family Resources

Basics of Drug Development

You, your child or someone else you love has Friedreich’s ataxia. Maybe you found out a year ago, maybe five, maybe you found out yesterday. Most likely by now you’ve read everything you could possibly read on the subject. Or, possibly, you are still frantically researching. Despite the significant progress that has been made on the road to finding answers and solutions for FA, there still is no silver bullet, no “get out of jail free” card. And this is an incredibly vibrant and passionate research community, committed to finding treatments and ultimately a cure. So what’s the hold-up? Why is it taking so long?

For any disease, whether cancer, muscular dystrophy or Friedreich’s ataxia, there are phases of research that scientists must go through to understand a disease and discover potential treatments, as well as a series of steps before a drug or treatment can be prescribed to a patient. In this journey, the number one priority is to ensure patient safety. To be successful, each phase or step demands significant resources—financial, human and organizational. And the highest levels of scrutiny are required in order to ensure a safe and effective outcome. These activities must be done carefully, methodically, usually with several being done at the same time as scientists explore multiple treatment avenues. They explore drugs to slow or stop the underlying disease as well as drugs or interventions to reverse the disease. Additionally, a disease such as Friedreich’s ataxia could benefit from the use of different drugs, each addressing specific aspects of the disease. If different drugs are used together, you might hear this referred to as the “cocktail” approach or the combined therapy approach.

Section contributed by Kristi Wright in collaboration with FARA. Kristi is the author of The Basker Twins in the 31st Century. 75% of all royalties from this novel are donated to FA research.

What We Understand

Fortunately, scientists have pretty much nailed down the cause for Friedreich’s ataxia. Since 1863, when the condition first was described by physician Nicholas Friedreich, scientists have learned a great deal about Friedreich’s ataxia. In 1996, they identified the gene responsible for the disease; they’ve cloned it and decoded its sequence; they’ve looked hard at the protein the gene produces and the function of that protein. Because of basic research conducted, researchers now know a lot about the causes of FA:

  • Both parents have to be carriers of the mutated gene in order for a child to inherit the disease (recessive inheritance).
  • The protein frataxin (previously unknown) is severely decreased in FAers (because of the gene mutation).
  • Frataxin functions in a specific part of the cell called the mitochondria—the part of the cell responsible for energy production. Many individuals with FA will confirm that they have decreased energy and that they fatigue easily.
  • Part of frataxin’s job in the mitochondria involves iron and the formation of iron-sulfur clusters that are critical to the energy production process. Some scientists have found abnormally high levels of iron in the mitochondria of heart tissue and parts of the brain in people with FA.
  • With much less frataxin protein around to do its job with iron handling and the formation of iron-sulfur clusters, the mitochondria of FAers produce far less energy and far more “free radicals” otherwise known as “oxidative stress” which can damage the mitochondria and eventually even kill the cell.

All of this knowledge is crucial in helping scientists come up with theories about how to treat or possibly cure the disease.

Developing the Research Questions

Once the cause is identified, then scientists can develop research questions or possible explanations (hypotheses) regarding potential treatments or even a cure. Current research questions for FA are aimed at:

  • How to raise frataxin levels, by adding frataxin or by manipulating the gene
  • How to lower iron levels in the mitochondria
  • How to decrease “oxidative stress” and/or increase mitochondrial energy production


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Drug Discovery & Development

FARA currently supports a type of basic research called high-throughput screening where scientists develop laboratory-based cell models for screening lots of compounds (hundreds of thousands of compounds) to identify “hits.” For example, one model screens compounds to find drugs that can improve the energy production problem in FA. Usually, this type of screening leads to many hits (a hundred or more.) Then scientists narrow them through more focused experiments. The end goal is to have a few potential drug targets that advance to the next phase of research which, often, is testing in FA specific cell and animal models.

With animal model testing, of course, the better the animal model, the better the test. Scientists have developed FA models in mice, worms and flies, for example. Some of these animals have frataxin protein deficiencies that cause the neurological symptoms of FA, while others have the cardiological symptoms. Still others have genetic mutations on the FA gene that are almost identical to the human mutations so they are excellent models for testing drugs that might be able to address the gene mutation itself.


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Safety Testing

Safety testing in healthy animals is required by the FDA in order to show that the drug is unlikely to be hazardous to humans. This is federal law. This testing is usually required in two species of animals (for example, dogs and rats). The testing questions are: 1) How does the animal’s body process the drug (absorb, distribute, metabolize, and excrete it), and 2) Do the animals show any signs of toxicology (adverse side effects) and, if so, at how high a dose?

Drug Formulation & Quality Control

One critical decision is how the drug will be taken by the patient. Is this going to be a pill, and if so will it be chewable or a capsule or a gel tab or some other form? Will it be injectible? Or a patch? These important decisions are based on the chemical properties of the drug and how it is best absorbed by the body and metabolized.


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Putting Together a Clinical Trials Team

Finally, researchers are ready to move into human trials which begin with Phase I clinical trials for a new drug. Or maybe a drug has made it through Phase I and is on to Phase II, III, or IV. Each clinical trial requires a team of scientists, organizations (pharmaceutical companies, research organizations, universities, etc.) and patients to get the job done. And from those various organizations there are researchers, study doctors, study registered nurses (RNs) and nurse practitioners, trial coordinators, study pharmacists, data managers, statisticians, and data and safety monitors. These key players must collaborate and have access to the appropriate level of funding to ensure a successful clinical trial.

The Clinical Trial

The collaborative team works together to identify the research question to be answered by a particular trial—i.e. what do we want to learn from giving this drug to FA patients? For instance, with the Phase I clinical trial of Idebenone, the primary questions were about dosage and safety (typical Phase I questions): “What’s the highest amount of Idebenone that can be taken without harmful side effects in children, teenagers, and adults with Friedreich’s ataxia?” The researchers use all of the data and findings from earlier lab steps to set up the study.


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Importance of Good Trial Design

It is critical that the clinical trial be set up for success. These are very expensive and time consuming endeavors and nearly impossible to recreate. They are emotional for the patients and their families. The last thing anyone wants is to rush through the set up and end up with a clinical trial that doesn’t move Friedreich’s ataxia research forward. A crucial activity is the design of how the trial will be conducted as well as the primary questions and measures to be monitored. Questions that must be considered include:

  • How old should the FA patient be?
  • What types of tests will adequately answer the research question?
  • Do we have quantitative tests and measures that will demonstrate statistically significant improvement?


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Measuring the Results

Every disease requires natural history data and consistent measures to ensure that clinical studies move the research forward. FARA and MDA have invested significant money and resources to ensure that FA has a strong database that documents the clinical symptoms and progression of FA and evaluates specific tests or measures, such as a neurological scale, timed walk, speech, vision, and quality of life measures.

For FA, outcome measures include a 9-Hole Peg Test (9HPT), timed 25-Foot Walk (T25FW), Low-Contrast Letter Acuity test (LCLA), International Cooperative Ataxia Rating Scale (ICARS), and Friedreich’s Ataxia Rating Scale (FARS).


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Key Partnerships

Through all these stages, partnerships are essential—partnership with a pharmaceutical company or drug development company is required to optimize development of a new drug and produce the drug in sufficient quantities so that clinical tests with humans can proceed. Organizations, such as FARA, offer grants to companies in order to facilitate the drug development process. Many of the pharmaceutical companies we work with are smaller companies with fewer resources available to them. They can develop the drug to a certain point, but they need help with funding the drug development for a specific compound and to develop FA therapeutics. For instance, FARA and the MDA have given grants to the basic scientists who discovered HDAC inhibitors for FA and to Repligen (a pharmaceutical company) to develop HDAC inhibitors for FA. Also, FARA and the National Institutes of Health (NIH) have provided support to Edison Pharmaceuticals for the development of drugs that improve mitochondrial function (eg. A0001). Santhera Pharmaceuticals has worked closely with FARA, and the NIH and the NIH did the Phase I and Phase II studies of Santhera’s Idebenone in FA.


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Helpful Resources

All of these steps happen over and over again for different treatments/potential cures. We all—patient, parent, friend, doctor, administrator—wish we could speed things up, but as you can see, there are many activities required to ensure patient safety. Meanwhile, it’s critical that we stay focused on the successes along the way, both large and small. We know the cause of FA, and we have many drugs already in various stages of development and phases of clinical study. We have a database that documents natural history and outcome measures. There is so much progress with FA research, so much hope and confidence. Together, we will find a cure for Friedreich’s ataxia.

Here are some helpful websites to further demystify clinical trials:

Drug Development Process:

Clinical Trials FAQs:

Should Your Child be in a Clinical Trial?

Informed Consent: