The Impetus for Natural History Studies in Rare Disease R&D


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-04-01-2018
Volume 27
Issue 4

The use of natural history (NH) studies early in clinical research can help facilitate development programs for orphan drugs.

More than 7,000 rare diseases have already been identified, and this number is rising. The number of patients diagnosed with a rare disease will gradually increase as we move toward better and advanced diagnostic methods and genetic testing being able to identify people with rare disorders. 

One of the two main reasons that prompt the development of new drugs for rare diseases include the human need, i.e., an unmet medical need for millions of patients suffering from a rare disorder. The healthcare industry must invent new drugs to improve the lives of patients suffering from rare diseases. The second important reason is the sales opportunity for the developer once such drugs are introduced to the market. Worldwide orphan drug sales are forecasted to total $209 billion by 2022, which will represent 21.4% of worldwide prescription sales, excluding generics (see Figure 1).


The market for cystic fibrosis, for example, will grow rapidly at a compound annual growth rate (CAGR) of 30.6% over the period of 2012-2019.1

To obtain marketing approval, regulatory agencies across the globe require data from appropriately designed and controlled clinical trials for a new drug. Conducting clinical studies in rare diseases, however, is challenging for several reasons, some of which include unavailability of adequate number of patients, few experts in rare diseases, lack of validated biomarkers, poor understanding about the disease, lack of methods for diagnosis, and unavailability of historical information. To strengthen the understanding of rare diseases and their natural course of disease progression, it is essential to conduct natural history (NH) studies to support the clinical development program for orphan products.

What are NH studies? 

The NH of a disease is the natural course of a condition from the time immediately prior to its inception, progressing through its pre-symptomatic phase and different clinical stages to the point where the disease has ended without external intervention. NH studies track the course of a disease over time, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes in the absence of treatment. Thorough understanding of a disease’s NH is the foundation upon which a clinical development program for drugs, biologics, medical foods, or medical devices is built.2

Why are NH studies required?

Due to the lack of sufficient historical data to understand the clinical characteristics and NH of the disease, rare diseases are often poorly understood and there is a lack of availability of suitable data which can be used to design clinical development programs for a potential drug to treat the condition. As rare disease trials require more careful and rigorous planning, one of the initial plans should be to collect NH data that can be crucial for the entire drug development program.

Often considered the same as registries, NH studies are different in their definition and application in the overall drug development program. Registries are broader arrangements to collect data in the form of setting up the database and collecting general information about the patients, e.g., contact information, or they may be conducted as a post-marketing commitment to collect safety and efficacy data. 

However, NH studies are comprehensive, granular, and more specific toward collecting useful data on disease characteristics, its manifestation, and its natural course of progression to guide future research.

The main purpose of NH studies is to collect useful information to facilitate and advance drug development programs; however, in exceptional circumstances, NH study data can be used as a historical control. This may happen in special circumstances when the disease has a higher mortality and the intended drug has an immediate strong effect in reducing the mortality or in improving the patients’ lives. Even in these cases, the regulatory agency may not permit NH data to be used as historical control and such requests need to be discussed with the agency on a case-by-case basis. 

When should the NH study be conducted?

Drug development for any disease is a time-consuming and costly process; however drug development for rare diseases is predominantly complicated due to challenges associated with it and the usually high per-patient costs. Conducting an NH study at an early stage of the clinical development program helps sponsors to define the study strategy by developing a valid and robust protocol. The comprehensive understanding of the disease can save a significant amount of time, money, and resources. Starting the clinical development program without having useful data from the NH study is one of the most significant reasons why rare disease trials fail. The FDA advises sponsors to evaluate the depth and quality of existing NH knowledge early to make well-informed decisions in the drug development process.3

Types of NH studies

NH studies can be retrospective, prospective, or both. Typically, NH studies are a combination of retrospective and prospective data collection.

Retrospective chart review is useful and often necessary to collect the required data to understand the NH. However, retrospectively collected data have some limitations. They may be less accurate and inconsistent and, therefore, appear to be less reliable, e.g., useful information pertaining to disease history or concomitant medication might not be reported in the medical charts and there may be no other source to collect that information. The other administrative challenge would be to get access to the medical records. In some countries, medical records are available in electronic format and can be accessed through the institute and/or treating physician; whereas in most other countries, medical records are still in paper format and may not be with the patient or in one location. Patients, in these cases, may have been seen by multiple specialists across different institutions and, as a result, collecting this scattered information can be very challenging and time-consuming.

For ultra-rare diseases, the patient collective will be even smaller and sponsors may also need to collect retrospective data of deceased patients.

A prospective longitudinal NH study collects data in follow-ups and is more useful in collecting the NH of the disease. Such studies may run for decades to continuously collect data of disease characteristics.

An example of a longitudinal study is The International Collaborative Gaucher Group (ICGG) Gaucher Registry, which aims to enhance the understanding of the variability, progression, and NH of Gaucher disease, with the ultimate goals of better guiding and assessing therapeutic intervention, and providing recommendations on patient care to the medical community that will improve the outcomes for patients affected by this disease around the world. It started in 1991 and to date has enrolled more than 6,500 patients at more than 700 sites. Analyses of the extensive body of longitudinal data have increased the knowledge of the disease in a broad range of topics, including the NH of Gaucher disease; phenotypic and genotypic variation among patients; diagnosis, treatment, and management of the condition; disease manifestations in children; long-term treatment outcomes for ERT; bone disease and complications associated with the disease; and neuronopathic Gaucher disease. Data generated from the registry have been published in nearly 30 key articles and have provided much-needed and important insight into this rare genetic disease.4

At times, sponsors may collect data to explore disease characteristics by taking a snapshot of data as it stands at the time of study. Such studies are called prospective cross-sectional studies.

Cross-sectional studies provide a moderately detailed understanding of the disease and can be valuable for developing outcome tools; however, they do not provide any details about the pace of the disease progression, whereas prospective longitudinal studies provide the most comprehensive understanding of a disease, its course, and pace of progression. Cross-sectional studies are easier to conduct than prospective longitudinal studies, as the latter requires long-term commitments from patients, investigators, and other stakeholders and, hence, may extend the overall drug development timelines.5

How should an NH study be conducted?

Initiating and planning

  • At the planning stage of an NH study, it is important to reach out to all stakeholders (i.e., investigators, industry representatives, patients/caregivers, patient advocacy groups, etc.) to seek their opinion/feedback, ensuring there are well-defined objectives and then to delineate the strategy and tactics as well as the action plan to meet the study objectives.

  • Initially, the stakeholders may assess the limited knowledge about the disease characteristics and what is expected to be achieved from the NH study. The study should start with the broader criteria and as the study progresses, more specific objectives can be set. Thus, the initial plan needs to be progressively elaborated as more information becomes available.

  • Other aspects of the NH study that need to be considered are the data collection method, the frequency and type of data to be collected, and other areas with regards to scope, time, cost, quality, and risk management.

  • Communication with regulatory agencies is important. The developers must share their objectives of conducting the NH study with the agencies and seek their opinion and direction.

  • The FDA Critical Path Innovation Meeting (CPIM) is a means by which the Center for Drug Evaluation and Research (CDER) and investigators from industry, academia, patient advocacy groups, and government can communicate to improve efficiency and success in drug development. The CPIM can assist in the design of NH studies to increase the potential for the data generated by these studies to help in the design of interventional clinical trials and drug development programs.6

  • The European Medicines Agency (EMA) also has launched initiatives to encourage small and medium-sized enterprises to seek scientific advice at an early stage of drug development to increase the chances of obtaining marketing authorization.7


  • A successful NH study requires commitment and rigorous efforts from all involved stakeholders to be able to provide meaningful data.

  • There are various methods for setting up and running NH studies. Some studies may require patients/caregivers to complete questionnaires, which can either be completed online or sent to patients/caregivers with the request to return the completed ones. The advantage with such an “off-site” process is that patients/caregivers are not required to visit the sites, whereas other studies may include protocol elements that require patients to undergo certain procedures at the site (e.g., diagnostic tests, activity assessment, etc.). It is important to take into consideration the burden of invasive tests on the patient, with the aim to limit these. Patient advocacy groups can provide valuable information as to what, in a practical context, will be acceptable and doable.

  • As the number of expert doctors in the field of rare diseases is limited and since they are mostly located at larger treating hospitals in bigger cities, patients must usually travel further to these identified centers. Such a setup requires continuous engagement from the patients and, therefore, those that implement the study should consider an action plan for keeping patients engaged and encouraged. This includes travel reimbursement for the trial participants and arrangement for their travel, i.e., airlifting the patients/caregivers/families.

  • Patients play a vital role in an NH study, as the entire foundation of these studies is built on the idea of data collection from patients suffering from a rare disease. The community of rare disease patients and caregivers like to connect with other patients and families affected by the same disease, while participating in the NH study. It is known to patients and families that there is no therapeutic advantage from their participation in the NH study; however, their participation will help to advance future drug development efforts. Patient advocacy groups support patients/families by providing them with information, resources, and services, and encourage their continuous engagement in the NH study.

  • Patients and families participating should be encouraged for their participation and, hence, patient groups play an important role in identifying patients and keeping them interested in these studies.

  • The sponsor should initially have a broader perception to assess more biomarkers and outcome measures. Due to diverse clinical characteristics, one patient may demonstrate a set of symptoms that are very different from the other patient suffering from the same rare disease. As more data are collected, the developers can decide upon the appropriate biomarkers and outcome measures for the clinical development program.

  • NH studies are intended to be disease-specific and not therapy-specific. It is imperative to understand that sponsors may face challenges in rigorously following regulatory requirements such as good clinical practice (GCP) for such studies. This does not lessen the importance of quality data from these studies, as the most important objective of any NH study is to enable the sponsor to make informed decisions about the drug development program. Data of poor quality may be misleading, which can harmfully impact the overall therapy development program. This makes it important for the sponsor to consider monitoring of data on an ongoing basis, although the required frequency and extent of monitoring may differ from one study to the other.

  • Conducting NH studies in rare diseases can be costlier than anticipated and may result in sponsors not being able to fund such studies. As there is an immense importance of conducting such studies to support the overall drug development process, government programs have been put in place that encourage and assist with the design, funding, and implementation of NH studies.

The goal of FDA’s Orphan Products Natural History Grants Program, for example, is to support studies that advance rare disease medical product development through characterization of the NH of rare diseases/conditions, identification of genotypic and phenotypic subpopulations, and development and/or validation of clinical outcome measures, biomarkers, and/or companion diagnostics.8


NH studies, which provide comprehensive information about a disease, are an essential element for orphan drug development programs. Conducting NH studies requires careful planning, and significant thought needs to be invested to make them achievable. Rare disease drug development is challenging and requires a lot of patience, money, resources, and time; however, it can be rewarding for all parties involved. Conducting NH studies is the initial and important step aimed at supporting the orphan drug development process. It gives a ray of hope to patients affected by a rare disease and their families and informs them that the process of finding a therapy has started.


  2. Conditions/OrphanProductsNaturalHistoryGrantsProgram/ucm487336.htm
  3. Rare Diseases: Common Issues in Drug Development (Guidance for Industry)
  4. AHRQ Registries for evaluating patient outcomes: A user’s guide (Third edition)
  5. Natural history studies workshop
  6. Critical Path Innovation Meetings (Guidance for Industry)
  8. Conditions/OrphanProductsNaturalHistoryGrantsProgram/ucm487336.htm


Thomas Ogorka is Chief Executive Officer of Orphan Reach,

Gajendra Chanchu is Senior Manager, Clinical Data Operations of Orphan Reach,

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