Rare Disease Research Employs Uncommon Methodology: Q&A with Dr. Murphy on Orphan Disease Trials

rare disease research, rare disease clinical trials
rare disease clinical trials, Michael Murphy


This year’s World Orphan Drug Congress USA features a roundtable session hosted by Worldwide Clinical Trials and titled “Clinical Development – When the Sum Is Greater Than the Parts: Academic, Pharmaceutical and CRO Collaboration in Orphan Disease Drug Development.”

rare disease clinical trials, Michael Murphy

Facilitating the April 26, 2018 session is Worldwide’s Michael Murphy, M.D., Ph.D., Chief Medical and Scientific Officer. In a recent blog post about collaboration in rare disease research, Talking Trials asked Dr. Murphy to reflect on what makes these uncommon collaborations successful. In this Q&A, we ask about the unique methodologies that characterize rare disease research.

What’s driving these collaborations in rare disease research?

Collaborative research efforts in the current R&D development space, and in orphan disease research particularly, are mandated by the fact that the science supporting the technology is frequently radically unique (there being no previous therapeutics nor even an attempt to define such) and frequently employs advanced therapy medicinal products (stem cells, tissue-based therapeutics, gene therapies) that have had no prior clinical study to inform methods of trial design and operation. Even clinical research for repurposed products (e.g., compounds that have already been in the clinic and occasionally used for other indications) requires a mastery of an intervention’s pharmacological and biodisposition properties and how those properties map against the unique attributes of a rare disease clinical trial.

Are these advanced products treated differently during orphan drug development?

Importantly, given the rapid changes in regulatory guidance that have occurred within rare and orphan disease research, the current clinical research environment not only facilitates innovative trial designs but also demands them.

For example, when there are only 120 children worldwide with a given disease (one of Worldwide’s current ongoing initiatives), then a strategic program could not easily consist of replicate clinical studies – one does not have the luxury of replicating rare disease trials in a prototypical sequence of events that might be encountered in traditional programs (e.g., well-established indications with multiple therapeutics available). Also, because orphan diseases frequently have multi-organ expressions – i.e., perhaps a genetic defect that affects multiple different body systems – then a diverse collection of measures frequently are required to describe the overall impact of therapy. Selecting those measures and managing the implementation and analysis represents a key contribution for the CRO as a stakeholder.

What are some of the keys to managing rare disease clinical trial operations?

Few patients, novel technology, uncertain measures and durations of therapy, and an uncertain regulatory environment collectively drive the need for extreme innovation in rare disease clinical trial operations to maximize the contributions of each patient and to occasionally truncate the overall clinical development program required. Classically, operational solutions that are applicable across orphan diseases will include:

  • Creation of a unit that specializes in orphan disease research (the same individuals involved for all orphan diseases independent of the apparent therapeutic area of the target);
  • Extensive clinical site training supervised by the CRO, as most key opinion leaders – by definition – have not had an opportunity to engage in interventional research previously for the index condition and may be unaware of the regulatory demands attended to their participation;
  • Family engagement using participatory research models both for purposes of rare disease study design and to facilitate patient accrual and retention. For example, given the inordinate burden on families for many neurodevelopmental disorders and the geographical dispersion of clinical sites’ “visit frequency and visit density” (how busy are the visits) must be considered before the rare disease study is launched. Family members become integral to both design and clinical operations of the rare disease study. And, increasingly, families are involved in the interpretation of results.
  • Special patient identification and accrual methods, which include the following:
    • Snowball survey method – Use of one primary “source physician,” a specialist in the rare disease, who can recommend other physicians in the field. These secondary physicians identify others with potential patients and so on, creating the “snowball.”
    • Snowball sampling or “chain-referral sampling” – A nonprobability approach to sampling design in hard-to-reach or hidden populations.
    • Data mining for undiagnosed patients – Using advanced search techniques, analytical methods, and machine learning algorithms from claims data, cloud analysis, and other healthcare platforms to “mine” and identify patients who do not have a diagnosis. Provided through Worldwide’s partners, access to these techniques, as well as others, is invaluable when there are no clinical trials within the data to model rates of patient accrual and possible retention, which is a common and very useful technique for traditional indications (AKA bootstrapping).

Providing Value for Your Rare Disease Clinical Trial

Within the many rare disease clinical studies completed by Worldwide Clinical Trials, the integration of new research methods to support advanced technologies is a hallmark of success. Let’s talk about translating these research assets into value for your clinical trial. To learn more about how Worldwide is changing how the world experiences CROs, get in contact with us by filling out a general inquiry form.

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