Common Issues in the Development of Products for the Treatment of Rare Diseases

By Robert Anderson, Ph.D.

While the FDA Guidance for Industry - Rare Diseases: Common Issues in Drug Development, Draft Guidance (August 2015) remains in draft we believe it’s intrinsic value in management of a drug development portfolio or assessment of risk in clinical development has not been fully realized. Directed at firms that specialize in the development of prophylactic and therapeutic agents for rare diseases these observations are more generalizable to the early life cycle management of both rare and non-rare diseases. The guidance is abstracted not to create a punch-list, but to facilitate discussion among Product Development Teams. We briefly outline Cote Orphan support services that may be applied by organizations largely focused on discovery or early investigational activities.

Adequate Description and Understanding of the Disease’s Natural History

·         Defining the disease population, including a description of the full range of disease manifestations and identification of important disease subtypes.

·         Understanding and implementation of critical elements in clinical study design, such as study duration and choice of subpopulations.

·         Developing and selecting outcome measures that are more specific or sensitive to changes in the manifestations of the disease or more quickly demonstrate safety or efficacy than existing measures.

·         Developing new or optimized biomarkers that may provide proof-of-concept (POC) information, guide dose selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy. In some cases, biomarkers can be used for surrogate endpoints.

Adequate Understanding of the Pathophysiology of the Disease and the Drug’s Proposed Mechanism of Action

·         Identifying clinical manifestations of the disease that may have greater or earlier responsiveness to treatment. These disease manifestations may be useful in the design of study endpoints.

·         Estimating the amount of effect on the drug molecular target that may provide clinically meaningful effects.

·         Estimating when to test the treatment in patients in the course of the disease.

·         Estimating the schedule of drug administration that will provide adequate drug exposure. The rate of pathophysiologic response to drug action on the target, both onset of action and washout, may guide the selection of drug regimen.

·         Identifying therapeutic targets that may lead to drug candidates for nonclinical and clinical testing.

·         Identifying new biomarkers, or refining existing ones, that may indicate effects on different steps in the pathophysiologic processes. These biomarkers may have critical roles in POC and dose selection studies, or in identifying characteristics of patients with a greater potential to respond to therapy.

·         Identifying early markers and responses that could be used in adaptive and enrichment designs for greater efficiency.

Nonclinical Pharmacotoxicology Considerations to Support the Proposed Clinical Investigation or Investigations

·         Toxicology studies that provide essential evidence that the drug is “reasonably safe to conduct the proposed clinical investigation.

·         Nonclinical studies also contribute to a better understanding of the drug’s mechanism of action.

·         Non-clinical studies are often useful in selecting the starting clinical dose level, does escalation plan, dosing regimen and route of administration.

·         The nonclinical data may help guide patient eligibility criteria and determine important safety monitoring procedures.

·         The ability of the non-clinical studies to support clinical studies is based on the design and objectives of the proposed clinical investigations, existing accumulated nonclinical and human data and experience with the drug and the possible risks to humans.

·         The relevance of non-clinical studies depends on the drug constituents, dosage form, route and dose and regimen of administration in the non-clinical studies.

Reliable Endpoints and Outcome Assessment

·         An understanding of the disease, including the likelihood, range, and course of clinical manifestations. Sponsors can often obtain this knowledge, along with disease characteristics of patient subsets, from a natural history study of the disease.

·         An understanding of the clinical characteristics (manifestations and timing) of the specific population targeted by the drug (which may be a subset of the total population with a disease).

·         An understanding of disease manifestations that are meaningful to the patient and might also be affected by the drug’s activity. This evaluation is influenced by knowledge of the pathophysiology of the disease and prior experience (if any) with the drug or related drugs, including nonclinical and clinical effects and pharmacology.

·         Knowledge of what patient assessments exist or might be refined or developed for use as outcome assessment tools to measure selected aspects of the disease.

Standard of Evidence to Establish Safety and Effectiveness

·         Fulfillment of the statutory requirement for marketing approval is “substantial evidence” that the drug will have its claimed effect.

·         Design features of an adequate and well-controlled study must include:

o   A clear statement of the study objectives.

o   A design that permits a valid comparison with a control.  Controls may be concurrent (e.g., placebo, no-treatment, active treatment, dose comparison) or, in limited and special circumstances, historical.

o   Well-defined methods of patient selection that result in the selection of an appropriate population for study.

o   Methods that minimize bias in assigning patients to study groups and ensure comparability between study groups (e.g., randomization).

o   Methods that minimize bias in study conduct, outcome measures, and analysis (e.g., blinding techniques).

o   Methods of assessment of patients’ response that are well defined and reliable (e.g., appropriate endpoints for the study objectives).

o   Methods of analysis adequate to assess effects of treatment (e.g., an appropriate statistical analysis plan).

Drug Manufacturing Considerations During Drug Development

·         Analytical and Manufacturing Technology Transfer Management

·         Comparability Testing Strategy

·         Changes in impurity profile and suitability of toxicology studies.

·         Changes in critical product attributes and impact on utility of existing non-clinical and clinical studies.

Cote Orphan Solutions

·         Gap Assessment

·         Risk Management Approach

·         Regulatory and Product Development Plan Support


·         Guidance for Industry - Rare Diseases: Common Issues in Drug Development, Draft Guidance August 201