Growth in Rare Disease Impacts Drug Development and Strategy

Rare Disease Impacts Drug Development

About 33% of all drugs in active R&D pipelines are now included in the rare disease category. This categorization presents scientific and operational challenges to sponsors and clinical trial ecosystem participants, the adoption of new strategies, operating models and processes, based on a recent report out of Tufts Center for the Study of Drug Development.

What is a Rare Disease?

A rare disease qualifies as an “orphan disease” and represents a medical condition that affects 200,000 or fewer people in the United States, or fewer than five per 10,000 in the European Union.  The U.S. organization Global Genes estimated that more than 300 million people worldwide are living with one of the approximately 7,000 diseases defined as rare in the United States.

The Situation

According to a recent study authored by Tufts Center for the Study of Drug Development, a material change has occurred in the drug development landscape. The share of new drug approvals worldwide for rare diseases doubled from 29% of all approvals in 2010 to 58% in 2018. This by itself has tremendous implications and we think of the analysis of the IQVIA study on the rise of the emerging biotech to capitalize on this trend.

We do see a trend unfolding alongside the rare indication movement.  With growing private equity pools interested in drug development, “emerging biopharma” have potentially more options to directly develop drugs and take to market without necessarily going to larger groups.  Although the Tufts report showcases longer approval rates, we posit that with the rapidly growing fast-track approval scenario, in some cases the approval process is becoming more streamlined and the costs of the studies, in some cases, actually lower, shaking up the world’s biopharmaceutical industry.  Patients can win if all of this if pricing is rational (e.g. priced so that the maximum number of patients with a specific rare disease can afford and consume).

Also provided by the Tufts study:

  • In the U.S., rare drugs are now approved at nearly the rate of non-rare drugs
  • Approval cycles can take four years longer on average; however, with orphan status there are significant benefits involving regulatory streamlining
  • Rare disease Phase I clinical trials can represent a more complicated affair.  According to Tufts, on average the rare disease trial takes six times the number of investigative sites to recruit a quarter of the number of patients, compared with non-rare disease.  This is an interesting number and we suspect some outliers can skew the data. More on this later.

What is the Real Driver for Rare Disease/Orphan Market Movement?

In 2010 the pharma industry faced an increasingly harsh future: growth was generally slowing down due to a number of material factors and forces, from intense generic competition to R&D productivity challenges with associated pipeline droughts to increasingly stringent regulatory guidelines. Many big pharma companies studied the future and many saw desert landscapes, water was needed and in sufficient amounts to not only survive but to thrive.

Economic conditions, pharma R&D productivity challenges and generic competition pushed the focus of biopharma companies (from large to new nimble upstarts) from new essential medicines to completely new operational model called “Niche Busters” or Orphan Drugs. Addressing the rare disease made sense from all points of view.

Enter the Niche Buster

Initially considered, by at least some, a strategic move to mitigate risk from loss of patents, generics and pipeline droughts.  In sufficient numbers, they can augment revenue generation.  Exotic gene therapies are an example of new complex treatment for rare disorders.  The price tags for these sophisticated new treatments are staggering.  We have recommendations for how pharma execs can price in a different way to supply more patients (consumers) and ultimately have larger markets, but they haven’t called us yet.

New Models for Pharma Means New Opportunity

Complex new treatments, such as genetic or personalized stem cell therapies for diseases classified as rare, can open up interesting new business models for pharma. For example, integrated healthcare solutions become feasible where the pharma company becomes a partner directly with the patient, potentially vying with what have been traditional gatekeepers to the patient including their primary physician, medical care teams, health systems and payers.  Opportunities started to open for pharma to develop new therapeutics, but also diagnosis approaches, treatment and new forms of monitoring with smart apps, the cloud, big data and AI, as well as patient support services.

Pharma now has an unprecedented opportunity to develop disruptive, new value-added models in patient care. The stakes are big, the winners can take away big hauls. The losers will be a foot note in industry a decade from now.

TrialSite News’ primary focus, research sites from major academic centers to niche commercial operations, become critically important. Their expertise, patient population and connection to their communities introduce bundles of value if positioned to the morphing needs of sponsors based on the changing landscape.

Orphan Drug Incentives

Regulatory bodies offer incentives for rare disease focused orphan classified drugs.  Nearly a decade ago they were seen as a path forward and that is why were are here today with Tufts report revealing over half of approved drugs in 2018 were for rare diseases.

IQVIA produced a report evidencing this trend.  Reaching back to the passing of the Orphan Drug Act of 1983, they reveal that since the passage of the Act, the number of orphan indications approved in the U.S. grew in dramatic fashion. If the numbers are reviewed carefully, however, the watershed year was 2010. 2010 was the year of reckoning and action, the year that many saw a very large, long bleak desert trek ahead. Of course, there were many unfolding factors and forces that needed to occur to make 2010 the pivotal industry transition year.

Industry Pushes—for More Value but are there Adverse Externalities to the Public?

No industry that survives in a global, hyper-competitive world stands still, and global pharma is no exception. Driving, extracting and realizing more value can come in many forms that fall in line with original Orphan Act intentions.  But now a possible distortion in the market of rare disease and Orphan Drug status is the fast-track drug approval.

Originally designed for emergencies, “Fast Track” designations are now are routine. According to a recent Wall Street Journal report authored by Peter Loftus, about 75% of new drugs receive expedited regulatory review, introducing a new reality that pushes doctors, families and payers “into a new world of trade-offs.” Many more drugs now move through the “fast lane.” 

Key FDA Acceleration Categories

Key categories include Fast Track (FT), Breakthrough Therapy, Accelerated Approval and Priority Review (PR). In the U.S. the current administration has embraced these options as tools to speed up new drug approval times. So, although according to the Tufts study Orphan Drugs on average represent longer approval times with the rapid evolution of use of accelerated review options, we believe drug development costs are contained and regulatory approval times are streamlined.

Fast…but Flawed?

Generally, within the Fast Track category a sponsor can apply for this status along with their investigatory new drug (IND) application. The FDA will render a decision within 60 days.  If designated fast-track status, then investigators can collaborate directly with the FDA as the trial is conducted and data is captured, analyzed and submitted.  Under fast track, the FDA can approve a drug after a single Phase 2 study.

The Numbers

In 1992, the FDA updated fast track with two more drug review processes, including Priority Review  (review process completed in 6 months against 10 month standard review schedule) and Accelerated Approval (based on its efficacy and shown by surrogate market).

Fast track-based approvals continue to grow at a rapid pace:

Year # Drugs Approved Under Fast Track Process (N=147) (% of total)
1998-2000 10 (6.8)
2001-2003 13 (8.8)
2004-2006 28 (19)
2007-2009 29 (19.7)
2010-2012 26 (17.6)
2013-2015 41 (27.89)


Note that from October 2016 to October 2017, 108 drugs were fast tracked. Backing the Wall Street Journal report, there has been a profound shift away, possibly, from the true intention of the legislation.

The policy design centered on life and death situations. In the 1990s, fast-track worked decently well based on the war on HIV and AIDs, as well as other malignancies.  Drugs such as lamivudine, imatinib, erlotinib, oxaliplatin and levofloxacin are actively used today.  But there are critics centering on the use of fast-track only when the drug is crucial and the process of proving the drugs as “non-inferior” to standard treatment raises some eyebrows, at least among some critically-minded folk.

For example, new noninferior molecules may have adverse effects and are usually costlier, according to Through the Looking Glass: Understanding Non-Inferiority  by J Schumi and JT Wittes.  Moreover, according to one study, 57% of fast-track molecules are tagged with “black box warning” and adverse events are on the rise.  An example this particular study from a few years ago is cangrelor, which was approved for adjunct in percutaneous intervention, at least according to some published materials. However, the drug evidences no additional benefits in trials comparing it to clopidogrel, except for increased bleeding during the procedure.

Back to Tufts and Change

The recent report, led by industry research guru Ken Getz, suggests that drug developers face a whole new class of strategic, operational and tactical challenges.  This would have to be the case because the whole industry has shifted.  They have done so because they had no choice. Back in 2010, many caravans were headed out into the Sahara Desert without sufficient water.  The industry’s entrepreneurs thought leaders, scientists and regulatory gurus, not to mention CRO partners, consultants and investors faced unprecedented pressure to evolve, morph and change to maintain sufficient levels of value creation.  Of course, revenue growth and profits are an important indicator.  They had to make sure that teams had enough water in the ensuing drought years.

The Tufts report appears to lead the reader to the exceptionally more difficult patient recruitment challenges faced by industry sponsors and research sites (clinical investigators) in this new world of rare disease, Orphan classification, fast-tracked reviews and generally fast lanes. It is live in the fast lane and under the existing U.S. administration we will stay in a fast lane.  Getz is a Board Member of WIRB-Copernicus, which is a private-equity-backed consolidator of clinical research services.  They have acquired a lot of companies ranging from patient recruitment services to site compliance to electronic trial master files. Undoubtedly, they are working on service and product offerings that will help industry sponsors and sites not only deal with, but thrive in changing landscapes. Other vendors appear to be bundling offerings (products and services) for sponsors and sites.  New accreditation models for site safety, quality and productivity emerge to help sites organize, prepare, navigate and strategically execute to a changing set of demands.