Common Problems in Clinical Trials for Rare Diseases

Clinical Researcher—May 2020 (Volume 34, Issue 5)


Cody J. Bollerman


Although relatively rare, considered as a whole, orphan diseases are indeed quite widespread, with approximated 350 million people affected worldwide. The frequency of orphan attributions has increased since the implementation of the Orphan Drug Act in the U.S. in 1983, succeeded by regulations in Japan in the 1990s and the European Union (EU) Legislation on Orphan Medicinal designation in 2000. Thereby, if less than one out of 2,000 persons in the European Union, 1,500 in the U.S., and 2,500 in Japan are affected, a condition is regarded as rare. The frequency of rare conditions overall is estimated at six out of 8,000 individuals.

Despite the clear financial and legislative inducements implemented by regulatory authorities, clinical trial programs for rare disease treatment continue to be thwarted by numerous practical problems, owing to which most rare medical conditions are not adequately handled.

Orphan Drugs

Rare diseases lacking any clearly indicated and effective treatments are usually called “orphan” diseases, and several nations have embraced specific legislation on orphan drugs to garner enough motivation for the development of treatments for these diseases. Donors funding the treatment of rare diseases must first register for “orphan designation” with the appropriate regulatory body, along with undertaking a rigorous clinical trial plan customized to the particular condition and novel treatment criteria. If a drug earns an orphan status, the manufacturer may take advantage of a variety of opportunities to promote the medication further.

Funding teams can gain support at this preliminary stage by collaborating with legislative and epidemiologic professionals with expertise in the pertinent fields of study. It is crucial to grasp the importance of maximizing the resources provided in each area associated with how to advance development of the new treatment, how to fulfill regulatory standards, and how to guarantee that regulatory bodies recognize and endorse innovative facets of the trial program, including the target, patient demographics, and paradigms of the therapy.

Given the minuscule patient populations and the complicated nature of these diseases, medical research for orphan conditions may involve many different avenues of exploration aiming to identify and manage the symptoms, if not to vanquish their root causes. These avenues include oral, inhalable, and injectable therapies; behavioral alterations; devices, drug-device combination products, and diagnostics; and, of growing prominence in recent years, novel applications of gene therapy.

Some key facets for the development of orphan drugs in preclinical trials are:

  • Preclinical designs rigorously worked out
  • Fixing goal interaction
  • Studies in primates or other animals (non-human tests)
  • Modeling biomarkers and pharmacokinetics/pharmacodynamics
  • Chemistry, manufacturing, and control details for investigational product

During Phase I clinical trials, yet again, some key facets need to be highlighted:

  • Meeting legal standards required for first-time testing in human subjects, for both adults and children.
  • Providing patient referral services to clinics staging Phase I trials.
  • Maximizing efficiency during early-phase synthesis of clinical pharmacology and safety experience with medical awareness, as well as in the transition from Phase I to Phase II trials.
  • Data visualization for identifying trends and differences so as to minimize risks.

Conventional models for rare disease trials are generally not adequate, simply because they cease to be a particularly attractive option for patients with rare conditions. Patients are more willing to participate if they have an open-label or crossover design option, rather than a randomized, placebo-controlled trial.

Obstacles Faced in Conducting Clinical Trials

The foremost challenge faced is that there is often neglect or incompleteness of a thorough knowledge of the natural history of the rare condition or demographic group, which is essential to planning and guiding a study. Typically, this is because such illnesses are rare and only a very limited number of medical specialists may be found who have diagnosed and treated more than a couple of affected patients. Data may be restricted to reports of single cases or a small sequence of cases, usually based exclusively on one particular feature of the illness or cases that are too extreme to be handled in a tertiary care system.

Knowledge of a disease’s natural history and variations helps clinicians to understand the various phases of the disease, the probability and risk of development, the consequences of the ongoing treatment, and the variation in symptoms and effects of the disease. Comprehending the disease’s natural history also seeks to select the best response time points and concretion of the outcome variables for determining efficacy.

A further challenge is tracking results that are clinically significant. The goal should be to assess the way patients feel, perform, and endure. Endpoint goal selection should represent what’s most relevant about the disease to the patients. The endpoint goals should not vary frequently and should be sensitive enough to detect a noticeable change in a fair proportion of patients.

Yet another persistent problem is that while evaluation scales are commonly used to classify patients, they are not always effective for identifying clinically significant changes. Feedback collated from patient-reported outcome measures helps track patient improvement, enables effective communication between specialists and sufferers, and improves the standard of service provided by incorporating both what is really significant for patients, and what is considered positive results by experts.

It may also be important to rethink conventional research formats that demand patients participate in person for regular visits to test sites. In the case of many rare conditions, there exists very few dedicated treatment facilities around the globe, and reaching them would, for most patients, be highly burdensome. A few research trials have succeeded in radically overcoming this difficulty by reinforcing clinical outcomes for tests done at home. These trials used the internet for collecting datasets and evaluation services to reduce differences in ratings.

Sidebar: Anticipatory Action to Overcome Problems Faced in Clinical Trials

The U.S. Food and Drug Administration (FDA) has issued a draft guidance regarding challenges faced in rare disease trials and encompassing the following points:

Benefits of Natural History Studies

A strong base in scientific thinking and the importance of understanding a disease’s natural history is discussed elsewhere in this column.

Trial Prerequisites

The trial researchers should “consider enrichment strategies to decrease heterogeneity and to enhance the ability of the clinical trial to demonstrate a potential treatment effect.”

Choosing Dose and Dosage Limits

Dose determination is important in order to ensure patients do not quit taking drugs since their dosage levels are too low or too high.

Safety Cohorts

To supplement the premarket safety database, FDA proposes a trial regimen with a safety cohort operating at the same time as the efficiency trial. The data are to be collected and analyzed simultaneously with data from patients with expanded access to the drugs, and with records from other studies—for example, studies using the drug for conditions other than the given, or trials of similar drugs.

Sidebar: Are the Obstacles Overshadowing the Opportunities?

We must acknowledge the positive developments in rare disease projects from organizations like the International Rare Disease Research Consortium (IRDiRC), composed of funding organizations globally to organize efforts to promote the acceptance of potential orphan medicines and rare disease trials and examinations.

The subject of genome research is evolving rapidly, and it can be anticipated that in the foreseeable future it shall be able to provide additional insights into the complexities of rare genetic disorders and a greater comprehension of the relation between genotype and its peculiar clinical phenotypes.

With the current knowledge of the unique challenges faced during clinical trials for rare diseases, as well as how they influence the regulatory approval process, researchers and professionals should be newly aware of the importance of the attention that needs to be given to the incorporation of natural history, infant screening, early intervention, alternative disease markers, and innovative prototypes for clinical trials.

Further Resources

The Story Behind the Orphan Drug Act:

Clinical Researcher: A peer-reviewed article by Romina Iusem, “Conducting Research in Rare Diseases,” is included in the February 2018 issue of ACRP’s official journal at

Clinical Researcher: The October 2014 issue focuses on human subject protections and includes a featured article on rare disease advocacy groups. A full-issue PDF is available for download by logged in members of ACRP at

Cody J. Bollerman is a Digital Marketing Consultant for Synteract Inc., a full-service clinical research organization offering a variety of standalone services in such areas as clinical operations, biostatistics, and data management.