Rare Disease Report

Clinical Trials and Registries

The Need for Patient Data

There is a tremendous need to learn more about rare diseases (via registries) and their possible treatment options (via clinical trials). Clinicians should encourage their patients with rare diseases to enter a clinical trial and/or a registry.

Rare Disease Clinical Trials

A clinical trial is an experiment designed to determine various scientific and outcome aspects of proposed treatment. It is important to remember that there is no guarantee a proposed treatment will be effective.

Families should be prepared to balance the hope of participating in a clinical trial with the understanding that the therapy may not be optimal and could result in a serious negative outcome.

Since some rare diseases can progress quickly, families often are willing to participate in risky, unknown treatments. Before agreeing to participate, everyone involved should fully understand these risks by carefully reading the consent documents and asking questions of the trial investigators.

Most clinical trials related to treatments of rare diseases goes through 3 major phases:

  • Phase 1: A study to determine the safety of the proposed treatment
  • Phase 2: A study of dosing to determine optimal dosage
  • Phase 3: A broader study of patients to determine efficacy

Given the small patient communities associated with rare diseases, it is very common to combine the first 2 phases into a single phase 1/2 trial and even to combine the findings of phase 2 and 3 into a phase 2/3 trial. Phase 4 is a much broader study that most rare disease therapies never complete because of the relatively small patient populations.

Should a Patient Enroll in a Clinical Trial?

The decision about whether to enter a clinical trial depends on many factors, both personal and clinical. This guide will deal only with the clinical aspects and the realities of clinical trials in the rare disease community. For many rare diseases, treatment options are very limited or nonexistent. If a treatment is in development and is the only option, it is worth considering in order to:

  • Access a treatment that may show efficacy.
  • Be part of advancing understanding of the disease;
  • Be able to interact with other persons with the same condition: and/or
  • Be given access to specialty centers focused on a specific disease.
  • The above benefits of enrolling in a clinical trial may also be true if an approved treatment is already available.


The website ClinicalTrials.gov lists the details of most clinical trials, including many international trials. Each listing contains a description of the proposed treatment, the inclusion and exclusion criteria, and the contact information for the principal investigator, who can answer questions. If a trial is not listed on ClinicalTrials.gov, patients should be very cautious about participating, as the trial may not meet basic ethical, institutional review board, safety, or scientific requirements.

It is generally not possible to override inclusion or exclusion criteria because that would interfere with the statistical aspects of the design.

“Compassionate access” may occasionally be offered outside the bounds of the formal trial, but most clinical trials do not have funding or a provision for such access.

Clinical Trials and Travel

Many trial sponsors and patient advocacy groups work together to help pay for some or all of the expenses of families traveling to a clinical trial center, which may be located far from the patient’s home. Families are encouraged to contact the sponsors of the clinical trial to find out more about expenses. This information is also typically outlined in the informed consent document that patients need to sign before entering the trial.

For many rare diseases, there may only be 1 or 2 institutions that can conduct the study because of funding limitations and/ limited number of clinical experts available. Each trial is unique, and some are designed with the assistance of patient advocacy groups to make sure that a patient’s family is only marginally impacted. Every effort is made to advance the clinical trial with minimal disruption to families.

Sometimes, a clinical trial for a proposed therapy is offered only in Europe. Numerous factors could contribute to that scenario, including difficulty in obtaining FDA approval for the trial or the location of the treatment investigators. The European Medicines Agency (EMA) and FDA standards are very similar with regard to safety, science, and ethics.

Patient Registries

A patient registry is any organized system that collects data—the more data, the better—on a specific patient population. The data can be used for a variety of purposes, including developing a better understanding of the natural history of a disease, the treatment efficacy and safety of a given treatment, and long-term outcomes. With increasing frequency, patient advocacy organizations are defining and establishing patient registries, making the data available for research long after a specific clinical trial or study is over. Patient advocacy organizations are often in the best position to manage and operate registries for longevity, for breadth-of-study questions, and to incorporate the patient perspective into the data collection. When a patient advocacy group is considering establishing a patient registry, it should engage in discussion with a pharmaceutical company that may be developing a treatment to gain its support before selecting a vendor that requires a fee for services.

In 2012, the National Organization for Rare Disorders, the Canadian Organization for Rare Disorders, and the European Organisation for Rare Diseases recommended the following principles for a useful patient registry:
  • Recognized as a global priority in the field of rare diseases;
  • Encompasses the widest geographic scope possible;
  • Centers on a disease or group of diseases, rather than a therapeutic intervention;
  • Consistently pursues interoperability and harmonization between rare disease patient registries;
  • Consistently uses a minimum set of common data elements in all rare disease patient registries;
  • Linked with corresponding biobank data;
  • Includes data directly reported by patients, along with data reported by health care professionals;
  • Encourages public–private partnerships to ensure sustainability of rare disease patient registries;
  • Involves patients on an equal basis with other stakeholders in the governance of rare disease patient registries;
  • Serves as a key instrument to build and empower patient communities.

What Is a Natural History Study?

Natural history studies are becoming increasingly valuable in the rare disease community. When first diagnosed, many patients are asked to enter a natural history study. These studies examine the long-term progression and characteristics of the disease in untreated patients—sometimes treated patients, as well—by looking at a large pool of patients and watching for trends: when did the first symptoms appear? When do certain comorbid conditions appear? How long is treatment effective?

Because rare diseases are uncommon, many of the answers to these questions are not clear or have been inferred from a very limited number of case studies. A natural history study pools the medical data from as many patients with 1 rare disease as possible to see whether a pattern is present. This information can help families plan for future medical concerns and help researchers determine the best time to start a clinical trial or when to change medical procedures and make other treatment decisions.

Many patient advocacy groups have natural history studies in place, and patients are encouraged to contact their advocacy groups for more information. Natural history data are nearly always required by the FDA/EMA as a baseline to compare with the results of a clinical trial when additional study permissions are being sought or a potential treatment is being considered for market approval.
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