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). There are an estimated 7000 rare diseases, but only 300-400 of them have approved treatments. Since many of the approved drugs and clinical trials are focused on rare cancers (see Figure below), clinicians should encourage their patients with rare diseases to enter a clinical trial and/or registry.

What is a clinical trial?

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 that a proposed treatment will be effective. A successful clinical trial answers some question about the proposed treatment. It is not uncommon for a clinical trial to produce a “no” answer—that the proposed treatment is not safe or effective. Families should be prepared to balance the hope of participating in a clinical trial understanding the reality that the therapy may not be optimal and may result in serious negative outcomes, sometimes including death.

Rare diseases often progress quickly and have very serious symptoms, so families often are willing to participate in riskier, unknown treatments. It is very important to fully understand these risks by carefully reading the consent documents and asking lots of questions of the trial investigators before agreeing to participate.

After years of laboratory, bench, and often animal studies, a potential therapy is proposed to an Institutional Review Board (IRB), which considers many aspects of the proposed trial, with a focus on  the risks, procedures, safety, ethics, and study design. In the United States, the FDA and Department of Health and Human Services (HHS) – specifically the Office for Human Research Protections – have regulations that empower IRBs to approve research require modifications in planned research prior to approval, or disapprove research. Trials are designed to gather data that have scientific analytical value to answer predefined hypotheses and questions.

It takes years to plan, run, and analyze the outcomes of clinical trials. Often, the outcomes are compared with a natural history study that represents a study of the course of the disease when no treatment is present.

There are 3 major phases of clinical trials of concern to those with rare diseases:
Phase 1 – A safety study to determine the safety of the proposed treatment
Phase 2 – A study of dosing to determine an optimal dosage
Phase 3 – A broader study of patients to determine efficacy

With 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 will be dependent 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, there are no treatments, or treatment options are very limited. If a treatment is in development and is the only option, it is worth considering in order to:
(1) access a treatment that may show efficacy;
(2) be a part of advancing understanding of the disease;
(3) be able to interact with other persons with the same condition; and/or
(4) 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.

How can I learn more about the specifics of a clinical trial? lists the details of nearly every clinical trial, including many international trials. The listing contains a description of the proposed treatment, the inclusion and exclusion criteria, and the principal investigator’s contact information. If a trial is not listed on, patients should be very cautious about participating, as the trial may not meet basic ethical, IRB, safety, or scientific requirements. If not listed, patients should question the principal investigator very carefully about the trial design and supervision. Trials that are not listed are typically scams that prey on the desperation of families with rare diseases with a positive-sounding proposed treatment that in actuality has no clinical value, and is designed primarily to separate patients from their money. Often, communities of families and/or advocacy organizations focused on a disease can help patients weed out these so-called clinical trials.

How can a patient determine whether he/she is eligible for a clinical trial? lists the trial details, including inclusion and exclusion criteria and contact information for a principal investigator who can answer additional questions. It is generally not possible to override the inclusion and exclusion criteria, because this 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 compassionate access.

Who will pay for travel and lodging?

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 in another city. 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 will need to sign before entering the trial.

Why are the clinical trials available in only specific locations?

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

Sometimes, a clinical trial for a proposed therapy are offered in Europe and not in the United States. This can be a result of many factors, including difficulty in obtaining FDA approval for the trial and the location of the treatment investigators. The European Medicines Agency (EMA) and FDA standards are very similar with regard to safety, science, and ethics.

Will health insurance cover participation in a clinical trial?

Many insurance policies exclude coverage of experimental therapies; however, it does not hurt to ask and explain the potential benefit and overall cost savings compared with the alternative of the expenses related to progression of the disease. Asking for a special advocate to be assigned by the insurance company, often a RN, can sometimes be helpful. The ACA contains a provision that health insurance plans must cover routine costs associated with approved clinical trials beginning in 2014. What constitutes routine costs during a clinical trial remains to be established, and is typically outlined in the informed consent document.

If a patient enters a phase 1 or 2 clinical trial, will he/she be eligible for later trials (ie, will he/she no longer have access to a proposed treatment that appeared to be working)?

Many sponsors, especially those for extremely rare diseases, will allow patients to enroll in other clinical trials after completing an earlier one. This is because the population pool is so small that the option of enrolling “drug-naïve” patients for a trial is often impractical. In addition, many sponsors keep patients on the treatment in an “open-label extension” study after the completion of the initial trial. These extension studies provide valuable information about the long-term effects of a drug and are of significant value to the sponsors of the trial. Patients should ask about extension studies when inquiring about the clinical trial, and where possible, have the details of extension study participation and any cost change information in writing before starting the trial.

How does a patient registry work?

A patient registry is any organized system that collects data on a specific patient population. As with any such system, the more data the better. 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 the pharmaceutical company developing the treatment to gain its support before selecting a vendor that requires a fee for services.

In 2012, NORD, Canadian Organization for Rare Disorders (CORD), and EURORDIS recommended the following principles for a useful patient registry:

1. Recognized as a global priority in the field of Rare Diseases
2. Should encompass the widest geographic scope possible
3. Should be centered on a disease or group of diseases rather than a therapeutic intervention
4. Interoperability and harmonization between Rare Disease Patient Registries should be consistently pursued
5. A minimum set of Common Data Elements should be consistently used in all Rare Disease Patient Registries
6. Should be linked with corresponding biobank data
7. Should include data directly reported by patients along with data reported by healthcare professionals
8. Public-private partnerships should be encouraged in order to ensure sustainability of Rare Disease Patient Registries
9. Patients should be equally involved with other stakeholders in the governance of Rare Disease Patient Registries
10. Should serve as key instruments to build and empower patient communities

What is a natural history study?

Natural history studies are of increasing value in the rare disease community, and many patients are asked when first diagnosed to enter a natural history study. These studies examine the long-term progression and characteristics of the disease in untreated patients—and sometimes treated patients as well—by looking at a large pool of patients and looking 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. The natural history study pools the medical data from as many patients with one 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 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 to 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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