Rare disease drug development is gaining interest in the pharma industry. Large pharmaceutical companies have been working for many years. Now, startups, and small and mid-range pharma companies are also gaining traction in rare disease drug development. 

Developing medicines or drug products for rare diseases is always challenging. This applies to both the scientific and clinical development teams. The complexity of the biology involved, especially in genetic disorders, and the presence of multiple subtypes make clinical manifestations and disease progression unpredictable.

Here are some of the key aspects of rare diseases that differ from traditional drug development

• Very few affected populations and diseases not studied extensively
• Most of the diseases are genetical disorders and often affect the pediatric population
• Each disease contains multiple subtypes and unpredictable disease prognosis
• Lack of established standards, diagnostic tools, and treatment endpoints
• Proper design, planning, and execution of clinical trials as patient recruitment & retention is challenging in rare disease clinical trials compared with traditional clinical trials

Drug development in rare diseases

Developing drugs for rare disease indications can be financially challenging. Therefore, companies should pragmatically look into the recouping of the cost incurred in research and clinical development of drug substances for rare diseases.

For example, in acute disease conditions, medicine is given for a very short duration which results in less product-market. This should compensate for the population scattered across various regions. 

Key strategies to consider while developing orphan drugs for rare disease

• Overall market scope and competitors working on the same disease conditions
• Preferring “Drug Repurposing” in orphan drug development which reduces the risk of failures, developmental cost, and time significantly. 
• Establish proper disease mechanisms that are often complex in case of rare diseases, and multiple treatment pathway approaches.
• Measures to minimize developing timelines as usually, orphan drug development takes longer durations compared to traditional drug development. For example, clinical trials in rare diseases take a long time to complete due to poor patient recruitment and retention.
• Determine whether the drug you are planning can be designated as an orphan drug. This is important because many regulatory agencies provide tax benefits, financial incentives, and regulatory benefits for such designations.
• Determining proper treatment goals with primary and secondary endpoints.
• Identifying an ideal method for the production of the drug in small samples is crucial. This is because most orphan drugs have complex manufacturing processes. Additionally, preparing small samples during development further adds to the challenge.

Proper reasoning for the above points will reduce the chances of product failures.

Pre-clinical & early phase clinical trials

The goal of preclinical testing is to provide evidence that the drug is reasonably safe to conduct the proposed clinical investigations but unfortunately, most of the time orphan drugs lack animal models for testing, which may also impact clinical trial design, particularly for selecting the starting clinical dose, dose-escalation plan, dosing regimen, and route of administration.

Key strategies to consider

• Developing an animal model will be valuable in later stages of development (either by genetic modification of animals)
• Rigorously designed preclinical models
• Planning a brief observational study before initiating a clinical trial for a better understanding of the disease
• Considering new approaches such as Modeling and simulation which are ideal for the development of orphan drugs and are also encouraged by regulators. 

Which country should you prefer for your orphan drug clinical trials?

Several factors affect region selection for your clinical trials as the scenario in rare diseases differs from traditional drugs.

Regulatory approvals process and approval timelines, marketing benefits, qualified investigators and sites, patient population available for your orphan drug trials, government initiatives in creating awareness, and data acceptance are a few of them. let’s discuss a few of them

Patient population & recruitment for clinical trials

• Recruitment of patients in rare disease clinical trials can be very challenging. For any successful clinical trial, a sufficient number of sites with enough patient recruitment and retention are crucial for obtaining quality data to minimize timeline delays.
• Patients with rare diseases tend to be geographically scattered and coupling this with very few clinical trial centers makes the condition worse. Selecting a region that supports multicenter trials would be preferable for rare disease clinical trials.
• Some of the countries are active in promoting rare disease awareness across the country with disease-specific foundations, patient registries, databases, and other organizations. Preferring these countries may help in patient recruitment for rare disease clinical trials.
• The regulations that accept clinical trials for rare diseases with fewer study subjects shall also be considered.

Regulatory incentives & support

• Some countries like the USA, Europe, and Japan have been supporting drug development in rare diseases for several years by providing financial incentives, Fastrack approvals, and marketing benefits like market exclusivity, etc

Learn more about regulatory incentives provided for the development of orphan drugs in various countries – The United States, Europe, Japan, Australia, and in the Asian countries

Data Acceptance

• Regulatory authorities generally have some criteria for the level of evidence to determine the benefit/risk assessment that supports product approval. EU legislation, in certain exceptional circumstances, grants marketing authorization based on less comprehensive data, to address an unmet medical need in case of rare diseases.
• Some regulatory authorities, under special consideration, accept clinical trial data generated in other regions, with basic requirements such as reliable and authenticated clinical trial data, and compliance with the national and ICH good clinical practice.
• For example, India recognizes foreign marketing authorizations for orphan drugs from countries recognized by the CDSCO.
• China published its Technical Guidelines recently on July 10, 2019, for the acceptance of overseas clinical trial data for drugs. The guideline outlined for the first time a method by which foreign clinical data could be used to support an application

Clinical trial feasibility before rare disease clinical trials

Conducting clinical trial feasibility is one of the first and crucial steps involved in any rare disease clinical trial process. 

Most clinical trials experience delays and an increase in financial burdens due to several factors like poor patient recruitment, inefficient investigators selection, improper region preference, poor understanding of ethical and local regulatory aspects of the selected site and region for conducting the study, time delay and cost incurred due to delays.

• Conducting clinical trial feasibility minimizes these burdens incurred due to wrong assumptions and miss interpretations. 
• Clinical trial feasibility studies also help in identifying and understanding region-specific or even site/institution-specific practices and capabilities that may impact overall study completion.
• The process of selecting a region with a sufficient number of quality sites and investigators is one of the most challenging tasks in conducting clinical trials for rare diseases. conducting feasibility helps in understanding the country selection.

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Learn more about various clinical trial feasibility studies conducted on Credevo

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Improve cost-efficiency in the clinical development of orphan drugs

There may be a high expenditure for the development of orphan drugs for rare diseases compared to traditional non-orphan drugs for which the reasons include treatment failures, lack of established pathophysiology and treatment pathways, most of the diseases are genetic, long clinical trial timelines,

Key strategies to consider 

1. Looking for drug repurposing options for developing treatments in rare diseases which decrease the cost and failure risks.
2. Enabling Modeling and simulation methods 
3. Rigorously designed preclinical models
4. Optimal treatment designs for Phase 0 (proof of concept)
5. Conducting a clinical trial feasibility study to preview the clinical trial scenario for chosen countries which prevents lengthy clinical trial timelines
6. Looking for countries that FasTracks regulatory approvals, tax incentives, etc

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