Why Registries and Natural History Studies Are Indispensable in Rare Disease Drug Development

Kris O’Brien - Executive Director Program Strategy, Rare and Pediatric Diseases, Premier Research

Increasing emphasis on rare diseases has led to a greater need to accurately define the profile, characteristics, and outcomes of patients living with those conditions. The development of safe and effective treatments of rare diseases requires a deep understanding of the disease of interest, including its frequency, clinical features, risk factors, outcomes, burden, and evolution. Unfortunately, for most rare diseases, this information may not be available. Observational studies — including both patient registries and natural history studies — help address this challenge by providing insight into not just the disease but also the endpoints and outcome measures that will be relevant and meaningful to patients and other key stakeholders in clinical trials.

Issues Faced in Rare Disease Development

In rare diseases, patient populations are inherently small and geographically dispersed. Due to the low incidence and prevalence of these conditions, diagnosis may be delayed, and data collection may be scarce, incomplete, or inconsistent. Understanding the disease is also complicated by:¹

• Disease heterogeneity, including multiple and atypical phenotypes
• Lack of clinical experience and expert guidelines
• Absence of validated methods for assessing disease-specific conditions
• Lack of natural history data

Observational studies play a critical role in filling these gaps in disease knowledge and informing the design of interventional studies to support successful drug development.

Observational Study Types

In clinical trials, patients receive interventions according to a pre-defined protocol with the objective of improving outcomes. In contrast, the overarching goal in observational studies is to observe natural relationships between disease characteristics and outcomes. Patients may receive but are not assigned to specific interventions.

Observational studies, also called epidemiological studies, are divided into two categories — patient registries and natural history studies. While the terms "registry study" and "natural history study" are often used interchangeably, they are not synonymous. Understanding the differences between them is important in applying them to product development programs. What both types of studies do have in common is their potential value beyond drug development in:

• Establishing communication pathways with patients, providers, and advocacy groups
• Identifying disease-specific centers of excellence
• Providing insight into the current standard of care
• Identifying opportunities to improve patient outcomes

Regulatory Considerations and Resources

While the distinctions between interventional and observational studies may appear straightforward, regulations and guidance on observational studies vary across geography or the disease being studied. For instance, in the EU, Directive 2001/20/EC specifies that no additional diagnostic or monitoring procedures beyond normal clinical practice shall be applied to patients in observational studies.²

EudraLex Volume 9A clarifies that interviews, questionnaires, and blood sampling may be considered normal clinical practice.³

Variability may still exist among member states, particularly regarding genetic testing or biomarker sampling, which may be viewed as non-routine biological sample collection. This need for additional diagnostic interventions may create a gray area in the delineation between observational and interventional studies. Under these circumstances, sponsors must ensure that the criteria for minimal risk are met. "Minimal risk" means that the likelihood and degree of harm or discomfort expected are not greater than those ordinarily encountered in daily life or during the performance of routine examinations or tests.

When the criteria for an observational study have been clearly met, these studies only require an Institutional Review Board (IRB) or Ethics Committee (EC) review. A review by a regulatory agency or competent authority is not required.

Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) offer resources to assist sponsors in designing and conducting observational studies in rare diseases (see Figure 1).

Using Patient Registries in Rare Diseases

A patient registry is an organized structure that uses observational study methods to collect, store, retrieve, analyze, and disseminate information about individuals who have one of the following:

• A disease of interest
• A condition or risk factor that predisposes them to a health-related event
• Previous exposure to substances that are known or suspected to cause adverse health effects

A small percentage of patient registries are designed for a specific purpose, for example, collecting certain demographic, epidemiological, efficacy, cost-effectiveness, quality of life, or care pattern data. Most registries, however, are less restrictive and less structured and can be set up to collect any data, including patient communications and post-marketing data.

Given that registries are typically broad in scope, registry studies may be useful at multiple time points during drug development. Common applications of patient registries include:

• Collecting more comprehensive disease information
• Gathering data on the standard of care or best practices
• Supporting recruitment for clinical trials
• Assessing or observing population behavior patterns
• Monitoring long-term outcomes

Using Natural History Studies in Rare Diseases

The natural history of a disease refers to its course over time without any intervention. The objective of a natural history study is to document this course, starting just before the disease begins and continuing through its different clinical stages until the patient is cured, chronically disabled, or deceased.

Unlike registries, natural history studies are designed with a specific purpose, such as tracking how a disease evolves, identifying factors that correlate with disease progression or outcomes in the absence of treatment or informing clinical trial design. These studies can play an important role throughout drug development, from discovery to clinical trial intervention. They can be used for:

• Identifying the patient population. This is important for rare diseases that exhibit significant genotypic and/or phenotypic heterogeneity. It may also be useful for differentiating among disease subtypes.
• Identifying prognostic factors. There may be demographic, genetic, environmental, or other factors that affect disease progression and outcomes.
• Developing and evaluating clinical outcome assessments. Natural history studies may be an appropriate setting for validating disease-specific scales or functional assessments that can be used in clinical trials to support marketing approval and, eventually, reimbursement.
• Identifying or developing biomarkers. These may include biofluid-, tissue- or imaging-based biomarkers that correlate either with a disease manifestation or an anticipated mechanism of action of potential therapeutics. These biomarkers can serve as primary or surrogate endpoints in clinical trials if robustly validated.
• Assessing background risks. Understanding the risks associated with the untreated disease can provide context for evaluating and managing potential risks associated with future therapeutic interventions.
• Refining elements of protocol design. This may include study duration, inclusion and exclusion criteria, and appropriate endpoints.
• Determining the optimal time for therapeutic intervention. Data collected from natural history studies may be useful for understanding laboratory and clinical changes that could affect the efficacy of treatment.¹
• Informing payor decision-making. Natural history studies may be used by payors to assess real-world disease burden and to identify those patients who are most likely to respond to new therapies.

In certain situations, natural history studies can serve as non-concurrent comparator arms for studies in which it is not possible or practical to randomize patients to placebo. The use of a natural history study as a surrogate for the control population must be reviewed and approved by the appropriate regulatory agencies.

Determining When to Perform Natural History Studies

In their draft guidance document, Rare Diseases: Natural History Studies for Drug Development, the FDA urges sponsors to consider the timing of natural history studies in the development process.⁴ The guidance includes a discussion of the advantages and disadvantages of implementing natural history studies at various stages of clinical development. These studies are likely to be more useful if they are completed before initiating interventional studies, but they can also be performed in parallel with clinical trials.

Designing Natural History Studies

There are several natural history study designs, each with pros and cons. The designs may be retrospective, focused on the present, or prospective.

Medical literature reviews are the simplest and least expensive way to gather information on a disease's natural history. However, data standardization is challenging, and these reviews may be insufficient in meeting natural history study objectives. Retrospective chart reviews are also relatively inexpensive and can often be completed quickly, though missing and nonstandardized data may be an obstacle.

Prospective natural history study designs may be divided into cross-sectional and prospective longitudinal studies. Cross-sectional studies collect data from a variety of patients at a single point in time. These studies may be useful for providing data on the generalities of a disease but do not provide insight into progression or patient experience. Longitudinal studies collect data over a pre-defined period. These studies can be lengthy — and expensive — but may provide valuable information on how the disease evolves.

Collecting Data in Natural History Studies

Though natural history studies may collect information on therapeutic interventions, it is essential to ensure that data gathering encompasses all facets of the disease of interest and is sufficiently robust to support the development of multiple therapeutic candidates. When considering which data to collect, sponsors should anticipate any questions that might arise throughout drug development. This includes disease presentation, manifestations, morbidity, progression, and standard of care. Natural history studies often include flexible protocols that enable data collection to be refined as new disease knowledge emerges.¹

Data collection requirements, assessment type, and frequency must align with the current standard of care, which may differ among providers and may even change over time. A thorough understanding of the standard of care will help inform the selection of meaningful endpoints and appropriate assessments for measuring or monitoring disease progression. It may also affect site feasibility, optimal study duration, and inclusion or exclusion criteria selection.

Natural history study data can be collected at local sites or at single or multiple central sites. Using local sites, data is collected by a patient's existing provider and submitted to central data collection. This approach minimizes the participation burden for the patient but may introduce variability. Using central sites, all study assessments are performed at a select number of experienced sites. This approach increases consistency and minimizes the risk of missing data or protocol deviations but may be more burdensome for patients, which may adversely impact participation.

Sponsors may design a hybrid approach in which complex or specialized assessments are performed at central sites while routine assessments are completed at local sites. Sponsors may also opt for a patient-reported model in which all assessments and data collection activities are performed in the patient's home. When deciding how data will be gathered, sponsors should consider the overall study objectives and select the data collection model most appropriate for achieving those objectives.

Collaborating with Patients, Caregivers, And Providers

In their draft guidance on natural history studies, the FDA recommends that sponsors collaborate with disease-specific patient advocacy and support groups. The agency also advises sponsors to seek input from patients, caregivers, and providers with expertise or experience in caring for patients having the target rare condition. This input helps ensure that the outcomes assessments selected for clinical trials measure relevant, meaningful aspects of the disease and meet the requirements for regulatory submissions.

Conclusion

Rare diseases represent a significant unmet public health need as most of these conditions still have no approved therapies. Observational studies play a crucial role in helping sponsors collect real-world data that can be used to inform and accelerate the development of safe, effective drugs that make a meaningful difference in the lives of those living with these conditions.

References

1. Lapteva L, Vatsan R, Purohit-Sheth T. Regenerative medicine therapies for rare diseases. Trans Sci Rare Dis. 2018;3(3-4):121-132.
2. European Commission. Directive 2001/20/EC. Available at http://ec.europa.eu/health//sites/ health/fi les/fi les/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf.
3. European Commission. EudraLex: Volume 9A of The Rules Governing Medicinal Products in the European Union. Available at http://ec.europa.eu/health//sites/health/fi les/fi les/eudralex/vol-9/ pdf/vol9a_09-2008_en.pdf.
4. U.S. Food and Drug Administration. Rare Diseases: Natural History Studies for Drug Development — Draft Guidance, Published March 2019. Available at https://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM634062.pdf
5. European Medicines Agency. Sponsor’s Guide to an Orphan Designation. Available at http:// www.ema.europa.eu/docs/en_GB/document_library/Other/2015/08/WC500191754.pdf.
6. U.S. Food and Drug Administration. Meetings with the Office of Orphan Products Development – Guidance for Industry, Researchers, Patient Groups and Food and Drug Administration Staff . Available at https://www.fda.gov/downloads/ForIndustry/ DevelopingProductsforRareDiseasesConditions/UCM454058.pdf.
7. European Medicines Agency. Guideline on Clinical Trials in Small Populations. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientifi c_guideline/2009/09/ WC500003615.pdf.
8. U.S. Food and Drug Administration. Rare Diseases: Common Issues in Drug Development – Guidance for Industry (Draft Guidance). Available at https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf.
9. European Medicines Agency. Reflection Paper on the Regulatory Guidance for the Use of Health-Related Quality of Life (HRQL) Measures in the Evaluation of Medicinal Products. Available at https://www.ispor.org/workpaper/emea-hrql-guidance.pdf.
10. U.S.Food and Drug Administration. Guidance for Industry and FDA Staff -- Qualification Process for Drug Development Tools. Available at https://www.fda.gov/downloads/drugs/guidances/ ucm230597.pdf.
11. Centers for Disease Control and Prevention. Lesson 1: Introduction to Epidemiology, Section 9: Natural History and Spectrum of Disease. Available at https://www.cdc.gov/csels/dsepd/ ss1978/lesson1/section9.html.

Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special
offers from Pharmaceutical Outsourcing – all delivered right to your inbox! Sign up now!