The Importance of Natural History Data for Clinical Trial Development in Rare and Orphan Diseases
The return of in-person conferences coming back to Boston is great to see. The late Summer and early Fall have been busy with the very well-attended 42nd Canaccord Genuity Growth Conference in August, along with Citi’s 19th Annual BioPharma and Wells Fargo’s 2022 Healthcare Conferences in early September.
Bakx: What did you find most interesting about the conferences?
Sagan: I had the opportunity to sit in on several fascinating panel discussions focused on rare and orphan diseases with CEOs of companies who can truly be considered luminaries in their field. And a number of discussions in particular stood out around the issue of natural history studies – which, for those not familiar with rare disease clinical development, might seem an unusual topic.
Bakx: What are natural history studies in the context of clinical development?
Sagan: When you hear the words “natural history,” you might think of dinosaurs or geology exhibits at the museum. But in a clinical and medical setting, it means collecting and analyzing information on how a disease affects a patient population over a lifetime.
Bakx: Why are these studies particularly valuable for the development of therapies in rare and orphan diseases?
Sagan: Due to the often very limited information on many of these rare diseases, natural history studies can be important in developing therapeutics. In general, these studies can help therapy developers design clinical trials that are better tailored to the patient population and to the disease. This can influence everything in the trial design from patient selection criteria to endpoints to be measured and even drug dosages to be used.
A number of panelists indicated that creating, curating and analyzing disease natural history studies before starting clinical trials can not only provide the information on how to best design the trials, but also find and recruit patients into the trials.
One CEO stated, “Natural history is key. I actually believe that the natural history arm of a trial can be as important as the clinical achievement portion of the trial. As we continue to look to treat new and relatively unknown disease types, the development of this data needs more focus by scientists, physicians, industry developers – and particularly by the FDA – who are also new to many of these diseases.”
Bakx: How can such data be employed in the development of a trial design?
Sagan: To answer that question, let me provide a little context first. In rare disease therapy development, where you are dealing with a very small number of trial participants, who may sometimes be pediatric patients, and where there are typically no available alternative treatments, the gold standard of a placebo-controlled, double-blind trial design can be difficult to accomplish.
There are also ethical concerns when the disease is mortally serious and has no effective treatment other than what may be given in the trial. You’d want to be able to give every patient in a trial the potentially effective treatment.
As one CEO said: “In many rare diseases, it can be unethical to randomize a patient to a placebo-control or observation arm when you have a therapy that appears to be working and the patient, due to the progression of the disease, could potentially pass away in a few years.”
So, in special circumstances where the course of the disease is predictable and the effect of the treatment could be dramatic, a natural history study may be used to provide the control group. Sometimes called a “single arm” trial, this clinical development strategy gives all eligible patients the investigational therapy, which can have the benefit of encouraging patients to participate in the trial research while keeping the study ethically sound.
Bakx: What are the communications implications and potential benefits to conducting a thorough natural history study – not only for planning an interventional trial but for the potential commercial roll-out of a therapy?
Sagan: In our practice, we’ve seen the impact for a number of clients that a detailed natural history study can provide not only on the initial design of a clinical study and the determination of endpoints, but also on patient “find” efforts, trial recruitment and ultimately, on the definition and success of the commercial market. Communications are a major component in virtually all aspects of the process.
“In this day and age, you have to be aggressive in finding and engaging potential patients. This is where communications play a big role,” said one CEO. “You must communicate and identify patients early – not only for the pivotal trial, but also for the first one or two years of launch. This is commercially critical.
“Also, from a capital markets perspective, investors want to know that you are continually close to your patients – not just waiting to communicate to them after a therapy is launched.”
Bakx: What are the FDA’s approaches to the use of natural history data in rare disease clinical trials?
Sagan: In 2019, the FDA issued a guidance document, “Rare Diseases: Natural History Studies for Drug Development,” to help the drug development community design and implement natural history studies that support the creation of drugs and biological products for rare diseases.
In this guidance, while not its primary focus, the FDA discusses the use of natural history data as a potential external control arm in clinical trials.
“The FDA recognizes that a natural history study may provide an external control group for interventional trials if it is well-designed and conducted,” said another CEO. “So, if you can partner with patient groups and create a consortium with other companies collaboratively in a non-competitive way to build the data right – when you’re working on a therapy where a randomized trial is not the right way to go – you’ll really have something that the FDA can find valid and fit-for-purpose and ultimately be successful.”
“At the end of the day, if the right answer is a placebo-controlled randomized trial, that’s OK,” concluded another CEO. “But it is very valuable for both the drug development community and the rare disease patient population to have the option that a well-designed natural history study can offer.”
The more these studies can help us understand these diseases better – as early as possible – the better it will be for the therapeutic pipeline and ultimately for patients in the long run.
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