Rare and orphan diseases - SSNL

Interview: Rare and orphan diseases and personalized drug development and treatment

By Liza Laws

- Last updated on GMT

© Getty Images
© Getty Images

Related tags Rare disease orphan disease Research Patient centricity Data management Personalized medicine

Unfortunately, more than 700 rare diseases affect more than 30 million people in the US alone and with many of them being life threatening, it is still a concern that most still do not have treatments.

Complex biology and the lack of understanding of the natural history of many of them make the development of drugs, biologics and devices complicated. OSP had a very interesting discussion with Peter Benton, president and co-CEO with input from Michael Murphy, chief medical and scientific officer, both with Worldwide Clinical Trials. 

The industry has talked about the personalization of medicine for some time now, but there are many ways to define personalization. What does personalized medicine mean to you?

I’ve worked in this industry for more than 20 years. When I first started, most clinical trials focused on treating disease symptoms so patients could feel better and live fuller lives. A reduction in the symptomatic manifestations of an illness remains a key focus across therapeutic areas. However, today, we’re treating the underlying pathophysiology of diseases themselves. We’ve only touched the tip of the iceberg, but it’s incredible how far we’ve come in understanding conditions at the cellular and molecular levels, and how those abnormalities map into different disease manifestations. We’re learning just how nuanced diseases really are—how specific to someone’s biological makeup.

You can’t get much more 'personal' than your own cells and molecules! So, to me, personalized medicine describes what we can accomplish through precision medicine.

Although the terms 'personalized medicine' and 'precision medicine' are often conflated, they are slightly different concepts. Precision medicine involves what my colleague Michael Murphy (Worldwide’s chief medical and scientific officer) calls the 4Ps, which is the ability to: prevent disease, predict who might get a disease and/or treatment response, create a precise treatment strategy and entice patient participation.  

This is an entirely fresh way of looking at disease. It means using genetic information, drug- and disease-related biomarkers, knowledge of highly nuanced patient characteristics, innovative trial designs and analysis, and other tools to understand which individuals are at risk for a disease, which individuals will respond to treatment (or not), and how they’ll respond. Precision medicine enables us to determine how to treat people based on their individual cellular, molecular, or genetic makeup in ways that are uniquely meaningful to their lives.

How are technological advances transforming how we view and personalize drug development and treatment?

I can remember industry debates not too long ago that questioned: “Are we running out of diseases we can treat? Or are we running out of drugs to treat those diseases?”

If we think about the 4Ps of precision medicine, it quickly becomes clear that both questions are irrelevant. The more we learn and the more technology advances, the more medicine steadily evolves toward N=1.

By that, I mean that accomplishing each of the 4Ps requires us to acknowledge the phenotypic, genotypic, and molecular heterogeneity of disease. In other words, that disease is slightly different in everyone because we ourselves are all different. Therefore, patient populations must be broken down into smaller and smaller subsets for effective treatment strategies. Practically speaking, if every disease is trending toward N=1, then every disease could be considered “rare” or “orphan” eventually.

Technology plays a vital role in that breakdown. For example, genetic testing and biomarker technologies have become crucial tools for helping us understand why individuals may respond differently to the same molecule. Likewise, artificial intelligence (AI) is an exciting tool that allows us to link and relate disparate items in ways we might not initially appreciate. AI can take what looks like an amalgam of data and see various loci of effects based on phenotypic or genetic information.

However, none of these technologies are helpful if we can’t access appropriate patient populations. In that regard, technologies that support decentralized clinical trials (DCTs) and other innovative and evolving methods of study conduct are important enablers. 

It’s interesting to consider that every disease may, in essence, be ‘rare’ eventually. But this conversation is not about whether potential new treatments qualify for orphan drug status, correct?

Yes. That’s correct. It’s a critical clarification.

The terms 'rare disease' and 'orphan drug' have specific regulatory and legal definitions. In the U.S., for example, a rare disease​ is defined as one that impacts fewer than 200,000 people. In the EU​, it’s defined as one that affects no more than one person in 2,000. From a regulatory standpoint, the rare disease distinction can open expedited drug development pathways—something our rare disease and regulatory specialists are intimately familiar with.

However, the regulatory considerations are quite different from the point I’m trying to make about precision medicine. I can’t claim to know how precision medicine will affect legislation like the Orphan Drug Act. We may indeed have to rethink the rules at some point, but I’m giving a more colloquial meaning to the word “rare.” I’m saying that medicine is steadily evolving toward N=1—and you can’t get any “rarer” than a singular instance.

What impact is this 'rarefication' or 'hyper-personalization' having on clinical trials today? What trends are you seeing right now?

We’re already seeing an impact on clinical trial complexity. As mentioned earlier, patient populations must be broken down into smaller and smaller subsets, either in the design of the study or in the methods of accounting for this heterogeneity in analysis. So, we must have more patient stratification and segmentation processes that consider how patients present, how various biomarker signatures might look, and how the clinical outcome measures must increasingly be patient specific. That makes it not only harder to find, screen, and enroll the right patients in studies, but it also places a premium on those subject-matter experts who can design study methodology for increasingly diverse populations.

Patient retention is an ongoing issue, as well. While patient engagement tools can ease recruitment and retention efforts, we’re finding that building strong relationships with patients, caregivers, and patient advocacy groups is more essential than ever. Indeed, the incorporation of family and patient perspectives in program and study design Is instrumental to successful product evaluation

Fortunately, rare disease studies can teach the industry much about developing those relationships. Because rare disease research typically involves small, close-knit communities, we’ve learned how important it is to talk with patients early and often. Designing clinical trials around the needs of patients and their families is a key to success when dealing with small populations. 

That’s really what Murphy’s fourth ‘P’ of precision medicine—participation—is all about. It’s about letting the voice of the patient guide your study. Patient perspectives and patient-reported outcomes are ubiquitous across everything we do now, and rightly so. Clinical trials can no longer limit their measurements to the target outcome or to what a physician sees. The dominant question now is, 'how does the patient feel and function?'

To put it another way: How do we know that whatever change we just produced in the patient is meaningful to the patient and their family? The results can be surprising sometimes.

It may seem like a patient should feel better because the target is engaged, etc., but the patient still doesn’t perceive any benefit. So, unique study methodologies may be necessary to measure how patients feel and function—such as the increasing emphasis placed upon unique clinical outcome assessments like patient-reported outcomes as well as study exit interviews for interventional studies, that provide context and a three-dimensional assessment of product attributes. Biomarker development strategies, too, may be needed to judge whether we’re engaging the target meaningfully, or if that biomarker (or mosaic of biomarkers) can be qualified to predict a clinically relevant outcome. A CRO might not need to know how to create a biomarker, for example. However, we must know how to incorporate the assessment within the design and operational implementation of clinical studies, measure the response, and integrate those data into an overall pattern of therapeutic benefit.

Why do you believe that the personalization of diseases is a good step forward for medicine?

Imagine you’re diagnosed with a disease like cancer. What if we could zero in on the precise treatments that will work best for you by understanding the cancer at your unique cellular/molecular/genetic level? We could get to the point where we can preselect therapeutic options with the highest probability of efficacy with limited toxicity, no longer needing to “try” treatments to see if they work.

If we do this well, we could theoretically predict who might eventually develop a disease based on a number of risk factors—and maybe even prevent it from occurring. Once someone has a condition, we could specifically target the treatment regimen, dose, and duration so that it’s the least toxic and most effective for that individual. Hopefully, precision medicine is a step toward treating diseases faster and more effectively with less wasted time, effort, and suffering.

We’re just at the precipice of a greater understanding of genetics and precision medicine. Even identical twins can differ in how they respond to a drug, so there are no one-size-fits-all solutions. That’s the whole idea behind precision medicine. It makes clinical research difficult but also exciting and promising. We’re finally getting to the point of delivering the more personalized approach to care that we’ve talked about for the past 15-20 years.

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