Innovative Methods for Rare Disease Drug Development

Shein-Chung Chow

• Publisher: Chapman and Hall/CRC
• Year: 2020
• ISBN:
  9781000208337
• Edition: 1
• Topic: Mathematics
• Subtopic: Mathematics General
• Index: Mathematics

In the United States, a rare disease is defined by the Orphan Drug Act as a disorder or condition that affects fewer than 200, 000 persons. For the approval of "orphan" drug products for rare diseases, the traditional approach of power analysis for sample size calculation is not feasible because there are only limited number of subjects available for clinical trials. In this case, innovative approaches are needed for providing substantial evidence meeting the same standards for statistical assurance as drugs used to treat common conditions. Innovative Methods for Rare Disease Drug Development focuses on biostatistical applications in terms of design and analysis in pharmaceutical research and development from both regulatory and scientific (statistical) perspectives.

Key Features:

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• Reviews critical issues (e.g., endpoint/margin selection, sample size requirements, and complex innovative design).

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• Provides better understanding of statistical concepts and methods which may be used in regulatory review and approval.

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• Clarifies controversial statistical issues in regulatory review and approval accurately and reliably.

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• Makes recommendations to evaluate rare diseases regulatory submissions.

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• Proposes innovative study designs and statistical methods for rare diseases drug development, including n -of-1 trial design, adaptive trial design, and master protocols like platform trials.

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• Provides insight regarding current regulatory guidance on rare diseases drug development like gene therapy.

1
Introduction

1.1 What Is Rare Disease?

In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people (ODA, 1983). Under this definition, there may be as many as 7,000 rare diseases in the United States. The total number of Americans living with a rare disease is estimated at between 25 and 30 million. This estimate has been used by the rare disease community for several decades to highlight that while individual diseases may be rare, the total number of people with a rare disease is large. In the United States, however, only a few types of rare diseases are tracked when a person is diagnosed, including certain infectious diseases, birth defects, and cancers, as well as the diseases on state newborn screening tests. Because most rare diseases are not tracked, it is hard to determine the exact number of rare diseases or how many people are affected by those diseases. Rare diseases are also known as orphan diseases because drug companies were not interested in developing treatments under economic (or return of investment) consideration. To overcome this dilemma, in 1983, the United States Congress passed the Orphan Drug Act, which created several financial incentives to encourage pharmaceutical companies in order to develop new drugs for rare diseases.

Other countries have their own official definitions of a rare disease. For example, in the European Union (EU), a disease or disorder is defined as rare in Europe when it affects fewer than 1 in 2,000 people. Under this definition, there are more than 6,000 rare diseases. On the whole, rare diseases may affect 30 million EU citizens. Eighty percent of rare diseases are of genetic origin, and are often chronic and life-threatening. On the other hand, in Japan, according to the National Programme on Rare and Intractable Diseases (NPRID) launched in 1972, rare diseases are defined as those with a prevalence of less than 50,000, or 1 in 2,500, and with no known cause or cure. Under this definition, 123 diseases have been identified/specified by an Expert Advisory Board on the basis of research priorities, which include Behçet disease, multiple sclerosis, and amyotrophic lateral sclerosis. In China, thus far, rare diseases have not been officially defined. The definition that is commonly considered is based on a consensus of experts reached by the Genetics Branch of the Chinese Medical Association in May 2010. According to this definition, a rare disease is a disease with a prevalence of less than 1/500,000, or a neonatal morbidity of less than 1/10,000 (Ma et al., 2011; He et al., 2018). Since epidemiological data on rare diseases are lacking in China, the current list of rare diseases is based on actual conditions, and the list is mainly derived from the professional opinions of the Expert Committee on the Diagnosis, Treatment, and Care for Rare Diseases established by the Medical Administration Bureau of the former National Health and Family Planning Commission.

For orphan drug designation, FDA considers using the mechanism of action (MOA) of the drug to determine what distinct disease or condition the drug is intended to treat, diagnose, or prevent. Whether a given medical condition constitutes a distinct disease or condition for the purpose of orphan drug designation depends on a number of factors, assessed cumulatively, including pathogenesis of the disease or condition, course of the disease or condition, prognosis of the disease or condition, and resistance to treatment. These factors are analyzed in the context of the specific drug for which designation is requested. During the course of reviewing a request for orphan drug designation, equipped with the most current scientific literature about a particular disease or condition, FDA may come to a new understanding about the nature of that disease or condition. Below is a list of some diseases or conditions for which FDA’s views on how it categorizes or otherwise understands the disease or condition have evolved. This is not a comprehensive list of orphan disease determinations, but reflective of some of the more common questions we receive. FDA will update this list as appropriate when it makes orphan drug designation determinations that change how we approach the disease or condition in question. For a complete list of orphan drug designations and approvals, see the searchable Orphan Products Designation Database (Table 1.1).

TABLE 1.1
List of Orphan Disease Determination

Disease or Condition	FDA’s Perspectives
Ovarian, fallopian tube, and primary peritoneal cancer	FDA considers ovarian cancer, fallopian tube cancer, and primary peritoneal cancer to be one distinct disease or condition
Metastatic brain cancer	FDA considers any primary tumor type that has metastasized to the brain to be its own distinct disease or condition. For example, breast cancer that has metastasized to the brain is a distinct disease from breast cancer
Pulmonary hypertension	FDA recognizes the five WHO classifications of pulmonary hypertension as distinct diseases or conditions
Scleroderma	FDA considers systemic sclerosis to be a different disease or condition than localized scleroderma
Lymphoma	FDA recognizes the WHO classifications of lymphoma as distinct diseases or conditions
Familial adenomatous polyposis	FDA recognizes familial adenomatous polyposis as a distinct disease or condition from sporadic adenomatous polyps
Medication-induced dyskinesia in Parkinson’s disease (PD)	FDA recognizes medication-induced dyskinesia in PD as the disease or condition. Levodopa-induced dyskinesia in PD is considered to be a subset of medication-induced dyskinesia in PD

As most rare diseases may affect far fewer persons, one of the major concerns of rare disease clinical trials is that often there are only a small number of subjects available. However, FDA does not have the intention to create a statutory standard for the approval of orphan drugs that is different from the standard for the approval of drugs in common conditions. Thus, in rare disease clinical trials, power calculation for the required sample size may not be feasible. In this case, innovative thinking and approach are necessary for achieving the same standard with a limited number of patients available. In this chapter, some innovative thinking such as (i) probability monitoring procedure for the justification of the selected small sample size, (ii) the concept of demonstrating not-ineffectiveness (non-inferiority) rather than demonstrating effectiveness (superiority) with a limited number of patients available, (iii) the combined use of data from randomized clinical trial (RCT) and real-world data and real-world evidence (RWD/RWE) in support of rare diseases drug development, and (iv) innovative two-stage adaptive seamless clinical trial design are proposed.

Section 1.2 outlines the regulatory perspectives (including regulatory incentives and regulatory guidance) regarding rare disease drug development. Section 1.3 discusses sponsors’ strategy for rare disease drug development; includes the unique and remarkable story of Velcade^® drug development; and posts the practical and challenging issues that are commonly encountered in rare disease drug development. Section 1.4 describes and discusses some innovative designs. Section 1.5 reveals the aim and scope of this book.

1.2 Regulatory Perspectives

1.2.1 Regulatory Incentives

As indicated in FDA (2015b), most rare diseases are genetically related and thus are present throughout the person’s entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30% of children with rare diseases will die before reaching their fifth birthday. FDA is to advance the evaluation and development of products, including drugs, biologics, and devices that demonstrate a promise for the diagnosis and/or treatment of rare diseases or conditions. Along this line, FDA evaluates the scientific and clinical data submissions from sponsors to identify and designate products as promising for rare diseases and to further advance the scientific development of such promising medical products. To encourage the development of rare disease drug products, FDA provides several incentive (expedited) programs, including (i) fast-track designation, (ii) breakthrough therapy designation, (iii) priority review designation, and (iv) accelerated approval for regulatory review and approval of rare disease drug products, which are briefly described below.

Fast-Track Designation – Fast track is a designation of an investigational drug for expedited review to facilitate the development of drugs, which (i) treat a serious or life-threatening condition and (ii) fill an unmet medical need. Fast-track designation must be requested by the sponsors. The request can be initiated at any time during the drug development process. FDA will review the request and make a decision within 60 days.

Fast-track designation is designed to aid in the development and expedite the review of drugs, which show a promise in treating a serious or life-threatening disease and address an unmet medical need. Serious condition is referred to as the determination of the seriousness of a disease. The determination is a matter of judgment, but is generally based on whether the drug will affect the factors such as survival, day-to-day functioning, or the likelihood that the disease (if left untreated) will progress from a less severe condition to a more serious one. For a drug to address an unmet medical need, the drug must be developed as a treatment or preventative measure for a disease that has no current therapy. If there are existing therapies, a fast-track eligible drug must show some advantages over the available treatment, e.g., (i) showing superior effectiveness, (ii) avoiding serious side effects of an available treatment, (iii) improving the diagnosis of a serious disease where early diagnosis results in an improved outcome, (iv) decreasing a clinically significant toxicity of an available treatment, and (v) addressing an expected public health need.

Once a drug receives fast-track designation, early and frequent communication between the FDA and a drug sponsor is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients. Note that the drug sponsor may appeal to the division responsible for reviewing the application within the Center for Drug Evaluation and Research (CDER) at the FDA if its request for fast-track designation is not granted or any other general dispute. The drug sponsor can subsequently utilize the agency’s procedures for internal review or dispute resolution if necessary.

Breakthrough Therapy Designation – Breakthrough therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate a substantial improvement over the available therapy on a clinically significant endpoint. To determine whether the improvement over available therapy is substantial is a matter of judgment and depends on both the magnitude of the treatment effect, which could include the duration of the effect, and the importance of the observed clinical outcome. In general, the preliminary clinical evidence should show a clear advantage over the available therapy.

For the purposes of breakthrough therapy designation, clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A clinically significant endpoint can also refer to the findings that suggest an effect on IMM or serious symptoms, which includes, but are not limited to, (i) an effect on an established surrogate endpoint, (ii) an effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard), (iii) an effect on a pharmacodynamic biomarker that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease, and (iv) a significantly improved safety profile compared to the available therapy (e.g., less dose-limiting toxicity (DLT) for an oncology agent), with an evidence of similar efficacy.

A drug that receives breakthrough therapy designation is eligible for the following: (i) all fast-track designation features, (ii) intensive guidance on an efficient drug development program, beginning as early as phase 1, and (iii) organizational commitment involving senior managers. Similar to fast-track designation, breakthrough therapy designation is requested by the drug sponsor. If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the sponsor consider submitting a request provided that (i) after reviewing submitted data and information (including preliminary clinical evidence), the agency thinks the drug development program may meet the criteria for breakthrough therapy design...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Table of Contents
• Preface
• Author
• 1 Introduction
• 2 Basic Considerations
• 3 Hypotheses Testing for Clinical Evaluation
• 4 Endpoint Selection in Clinical Trials
• 5 Strategy for Margin Selection
• 6 Probability of Inconclusiveness
• 7 Probability Monitoring Procedure for Sample Size
• 8 Real-World Data and Real-World Evidence
• 9 Innovative Approach for Rare Diseases Drug Development
• 10 The n-of-1 Trial Design and Its Application
• 11 Two-Stage Adaptive Seamless Trial Design
• 12 Master Protocol – Platform Trial Design
• 13 Gene Therapy for Rare Diseases
• 14 Clinical Development of NASH Program
• References
• Index