The below article was originally published in the Winter 2015/2016 edition of the FARA Advocate.
"Drug Development Series: The Drug Development Pathway"
By Jane Larkindale, PhD

One thing that we all agree on in the FA community is the fact that we would like a treatment or cure for the disease, and we would like it now (if not sooner). This urgency drives everything that FARA does, as we try and get treatments to patients as soon as possible. However, drug development is a tricky business—it takes a lot of steps to go right in order to get an effective new drug to patients. In this series of articles, we will talk about the various steps that are needed in order for us to have a safe and effective new treatment (or at least one where the benefits outweigh the risks).

In this article we will talk through the steps that are required scientifically, and by the Food and Drug Administration (FDA), to go from a good idea to a drug that could be approved by the FDA through standard channels. In future articles (published mainly online) we will talk about the next steps – the process of approval in the US, how to get that drug to patients (through pharmacies and doctors), and how to get it paid for by insurance. In the final article in the series we will discuss the differences between drugs and supplements in how they are regulated and marketed, and the differences between approved drugs, approved drugs that are used off label and supplements, as well as the legal ways to access drugs that may not yet be approved in the U.S. 

 Drug Development and Clinical Trials

Drug development in FA is at a very exciting time right now. For the first time we have multiple drugs that are being tested in patients, and some are reaching the final stages of testing (see the FA treatment pipeline HERE). As such, it is an important time for FA patients to understand the process of drug development, so that they can make informed decisions about what role they wish to play.

Drug development is typically split into three areas:

Discovery research is where scientists try to understand the disease and figure out processes that can be affected by potential drugs. If researchers identify new targets and ways to affect those targets the resulting molecules are called “drug candidates.”

Preclinical research is where a good idea is turned into something that could be a real drug. Chemists tweak the drug candidate to make sure it is as effective as possible. For example, Biomarin has been working on HDAC inhibitors to increase the amount of frataxin they induce, to increase the drug’s ability to get to the areas of interest (heart and nerves) and to reduce the possibility of side effects. Once the best molecule or “clinical candidate” has been identified, there are a series of standard tests that are completed to assure us that we understand the side effects of the drug (termed “toxicology studies”), and the appropriate dose range to try in humans. These studies are typically done alongside other work, such as figuring out how to make the compound in a reproducible way, how to deliver it (Orally? Intravenously? Injection?) and what happens to it in the body—which affects how often you would need to take the medicine and at what dose over time, as well as possible side effects. If all these studies are successful, the owner of the compound can apply to the FDA for an “Investigational New Drug” license, or IND.

Clinical Research is studies in human subjects. IND packages to the FDA are hundreds of pages long, and include all the details of the preclinical work and the plans for the next studies that will be done in humans. The FDA scrutinizes all of this information carefully to determine if the proposed studies are ethical and to determine risks to patients.

If the IND is granted, the sponsor (person developing the drug) is free to start trials in humans. However, depending on the drug, the first time a drug goes into humans it is not tested in patients. Phase I trials, the first trials on a new drug, are usually done on healthy people to look purely at the safety of the drug. However, in some cases the safety studies will be done in patients—for example in gene therapy studies where there is risk involved in undergoing the procedure that cannot be justified in someone that could not benefit from the treatment. In these cases, the safety studies are done in small numbers of patients initially. In all Phase I studies, the dose of the drug is carefully monitored, and typically increases over time as lower doses are determined to be safe.

If the Phase I trial is successful, the drug will be moved into Phase II studies. These studies are larger and involve only a couple of dose groups and usually include a placebo control. A placebo is a group of patients who do not get the drug—although neither they nor their doctors know who they are (they get a sugar pill or injection of salt water that resembles the treatment). The placebo is necessary to ensure that any effect seen in the trial is because the drug works, not because the patient thinks the drug works (the “placebo effect” where patients in trials improve slightly is well documented—a drug must help the patient improve more than they do on placebo to be deemed effective).

In traditional drug development, a successful Phase II trial is followed by an even larger Phase III trial that involves thousands of patients. In FA, of course, we couldn’t find thousands of patients, even if they were willing! The FDA understands this, and in orphan diseases like FA, a drug may be able to be approved on a larger Phase II trial, or on a Phase III trial that is much smaller in size. However, the bar is still set high—the sponsor still needs to prove that the drug causes a significant improvement in a measure that is meaningful to patients’ lives over the course of a trial. In FA, this typically means that you can measure a reduction in the decline of something important over the course of a one- to two-year period. Currently, the FARS score is the most common measure, but FARA is working with clinicians to develop additional endpoints that could be used.

Getting through all of these steps takes a long time. FARA is working hard to ensure that no time is lost, however—while a two-year trial will take two years, whatever you do, FARA is working to develop new trial designs, biomarkers and endpoints that can detect changes more quickly, particularly for the earlier phase trials, so that we can more quickly figure out if a treatment might work (or not). We also work to reduce the time lost at every other stage in development! One way that you can help is if you are interested in taking part in clinical research, make sure that you are registered with the FARA registry, and that your profile is up to date, so that you can be easily contacted if you are eligible to take part in a study.

Read Part Two: "Accelerating Drug Development and Clinical Trials" →