Rare Disease Drug Development: FDA Revises Draft Guidance Regarding Common Issues Sponsors Face During Orphan Drug Development

January 31, 2019

On January 16th, FDA issued a revised draft guidance outlining a number of common issues and challenges that many Sponsors face during the process of developing an orphan product.  Though the regulatory requirements and approval process is the same for both common and rare diseases, there is often limited medical and scientific knowledge, natural history data, and drug development experience available for rare diseases, making these issues more difficult to address.

The original draft guidance was published in August 2015 and addressed a number of important aspects, stating that Sponsors were more likely to have a productive meeting with the FDA if they were addressed efficiently and adequately. The revised document includes:

  • “Updates to the Natural History Studies section
  • Inclusion of issues for evaluation and validation of surrogate biomarkers
  • Description of nonclinical flexibility
  • Additional information on external controls and early randomization
  • Addition of a safety section
  • Retitled Chemistry, Manufacturing, and Controls section to Pharmaceutical Quality Considerations
  • Additional information on changes to drug substance or manufacturing process with clarification on areas of flexibility
  • Inclusion of an Additional Considerations section addressing several topics: participation of patients, caretakers, and advocates; consideration of pediatric issues; and interactions with FDA”

In a recent statement, Scott Gottlieb, M.D., FDA Commissioner, stated that many of the updates were made directly in response to the feedback the FDA received on the initial draft.  For example, Gottlieb notes that the Agency “updated the section describing the use of information about natural history as clinical comparators and added more information on the use of historical controls and early randomization.”

Natural History Studies

All drug development programs benefit from a firm scientific foundation, which includes an awareness of the disease’s natural history. In rare diseases, this history is often poorly understood, and “the need for prospectively designed, protocol-driven natural history studies initiated in the earliest drug development planning stages cannot be overemphasized.”  Although FDA does not require natural history studies, a comprehensive understanding of the disease can help Sponsors define the disease population, which is even more important when seeking approval of a product indicated for the treatment of a rare disease.

“Natural history study designs can be characterized as (1) retrospective or prospective and (2) cross-sectional or longitudinal.”

Retrospective vs. Prospective

  • Retrospective studies typically use existing information available in an individual’s medical records (e.g., patient charts) and have defined characteristics such as diagnoses and outcomes.
  • Prospective studies “collect and analyze new data generated from identified patients at specified time points after the natural history study has been initiated”

Cross-sectional vs. Longitudinal

  • Cross-sectional studies “collect data from individual patients at a single point in time. The point in time may be a specific date or set by stage of illness, date of diagnosis, onset of certain sign and symptoms, or other criteria.”
  • Longitudinal studies “collect data from patients with the identified condition over time. The length of time and frequency of data collections can vary considerably and should be tailored to the characteristics of the disease.”

The Agency suggests making data from these studies publicly available to help promote rare disease drug development.

Disease’s Pathophysiology & Clinical Manifestations

Information pertaining to a disease’s pathophysiology and clinical manifestations is frequently incomplete for rare diseases. This knowledge can help contribute “to the successful development of a treatment, for example, by:

  • Identifying clinical manifestations of the disease that may have greater or earlier responsiveness to treatment
  • Estimating the amount of effect that may provide clinically meaningful benefit
  • Identifying new biomarkers, or modifying the use of existing biomarkers that may indicate effects on different steps in the pathophysiologic processes
  • Identifying early biomarkers of disease or effects of interventions and biomarkers that could be used in adaptive and enrichment designs for greater efficiency”

Nonclinical Studies

Nonclinical studies demonstrate that the drug is “reasonably safe to conduct the proposed clinical investigations,” and are a required by the FDA. Data obtained at this stage is important to the design of early phase clinical trials and can help identify the drug’s possible efficacy, mechanism of action, pharmacokinetics, and metabolism.  The data can guide the selection process of patent eligibility criteria, and “will often determine important safety monitoring procedures based on the observed toxicologic profile.”

As long as guarantees for a drug’s safety and effectiveness are not compromised, FDA regulations state that the Agency may exercise flexibility when applying statutory standards for drugs indicated for the treatment of rare diseases.  “This flexibility includes determining the nonclinical data necessary to support clinical development programs. Factors that FDA evaluates when determining areas of nonclinical flexibility include the pharmacological and chemical characteristics of the drug, the design and objectives of the proposed clinical investigations, the anticipated risks to humans, and the existing accumulated nonclinical toxicology and human data. When determining the relevance of existing data, a sponsor may consider factors such as drug product constituents, dosage form, route of administration, dose levels, and dosing regimen plan.”

Efficiency Endpoints

Well characterized efficacy endpoints are not available for many rare diseases; however, they are crucial for a clinical trial. For Sponsors to define a trial endpoint, FDA recommends selecting “a patient assessment to be used as an outcome measure and define when in the trial the patient would be assessed.”

Endpoint selection for a clinical trial involves understanding the following:

  • “The range and course of clinical manifestations associated with the disease. Sponsors can often obtain this knowledge, along with possible differences among patient subtypes, from a natural history study of the disease (see section III., Natural History Studies).
  • The clinical characteristics of the specific target population, which may be a subset of the total population with a disease.
  • The aspects of the disease that are meaningful to the patient and that could be assessed to 398 evaluate the drug’s effectiveness.
  • The possibility of using the accelerated approval pathway.”

Effectiveness and Safety

Due to the limited number of patients, it is crucial for orphan Sponsors to standardize data collection and handling of data to ensure quality and interpretability. An adequate and well controlled investigation will provide substantial evidence that the drug will have its claimed effect. A safety evaluation during drug development can characterize the drug’s safety profile in a reasonable number of patients over a reasonable duration of time.

Pharmaceutical Quality Considerations

Drug manufacturing should undergo development simultaneously with clinical development. In an attempt to decrease the potential for delays in a drug’s development or approval, Sponsors are encouraged to discuss pharmaceutical quality development plans in early-phase and throughout the drug development process.

FDA recommends that Sponsors carefully assess any planned changes to the drug substance at any phase of development to determine if the changes could affect the safety or effectiveness of the product. Manufacturing changes should be made as early as possible to ensure there is time to evaluate potential effects on the drug’s safety and effectiveness.

Additional Considerations

  • FDA encourages direct involvement with patients, caregivers, and advocates to help provide input and important perspectives on patient experiences in the drug development process.
  • The Agency encourages sponsors to consider expedited programs, which includes fast track designation, breakthrough therapy designation, priority review designation, and accelerated approval for rare diseases because of the unmet medical need.
  • According to the draft guidance, about half of the people affected by rare diseases are children. FDA recommends conducting studies in pediatric patients to determine the safety and efficacy of medications. To develop data on the full range of people with rare diseases, pediatric patients should be included in premarketing clinical studies.

Interactions With FDA

Feedback from FDA may result in more effective drug development; therefore, Sponsors are encouraged to meet with the relevant drug review division throughout the development process.  FDA will also provide advice on “specific matters relating to an IND, including advice on the adequacy of data to support an investigational plan, the design of a clinical trial, and whether proposed investigations are likely to produce the data and information needed to meet requirements for a marketing application”.

The FDA announced plans to hold a public meeting to obtain the perspective of patients’ and caregivers on the impact rare diseases has on their day to day life. The Agency hopes that their experiences may develop a future understanding which will help guide the development for treatments for rare diseases potentially through the creation of novel endpoints or trial designs that focus on commonalities across a variety of rare diseases.

Are you in the process of developing a drug indicated for treatment of a rare disease? We can help you obtain orphan designation and achieve a successful interaction with the FDA. We know how difficult it can be to make sure you are adhering to all applicable FDA regulations, but that is why we’re here to help… Combining scientific expertise with extensive regulatory knowledge, we have helped numerous clients with orphan applications as well as all other FDA submissions. Contact us today to learn more about our services and how we can help you get through FDA successfully.


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