Drug development strategy in rare diseases

Clinical trials in rare diseases are more challenging than clinical trials in more frequent diseases for many factors such as the trial design, the number of patient populations available for recruitment, regulatory support, etc. Applying a perfect strategy for clinical development in rare diseases may help overcome these challenges and accelerate the drug development process in Orphan diseases.

Drug development strategy in rare diseases

Every step involved in the development shall be considered precisely and strategically planned to overcome all the challenges that arise in the clinical development process, which include

  • Choosing a modern adaptive trial design,
  • Conducting a country level feasibility even before initiating any clinical trial,
  • Considering the regulatory scenario (the incentives offered by the regulator which boost the development process),
  • Choosing the right qualified sites and clinical investigators,
  • Considering other factors such as site reachability, virtual patient monitoring

For example, If the trial design is such that If the burden of participation is considered to be out of proportion, recruitment may fail, or participants may drop out before trial completion. By avoiding unnecessary designs and considering adaptive trial designs is a strategy that may improve patient participation.

When it comes to maximizing the chance of a successful trial, the patients or parents of a child with a rare or ultra-rare disease can play a pivotal role when they are involved in an early stage as most of the rare diseases occur in the pediatric population.

Before moving into further details, let’s look at the statistics of rare diseases

Rare disease Statistics

  • 3.5 to 5.9% of the global population suffers from rare disease conditions.
  • The Global Genes Project estimates that around 300 million people are affected by a rare disease, which is about 4% of the world population.
  • More than 6,000 diseases are listed on Orphanet, from which 72% is genetic, and 70% start in childhood. Among these diseases, 149 alone are responsible for 80% of cases of rare diseases identified worldwide.

A total of 2,225 clinical trials are going on rare diseases globally with major studies in North America followed by Europe and East Asia.

From the statistics above, it’s clear that most of the clinical trials in rare diseases are preferred to be conducted in the developed regions like the USA, Europe, Japan, etc. and this may be due to the following reasons.

  • The strong and a clear regulatory pathway
  • Prevalence of disease and availability of patients for recruitment
  • Clinical trial awareness among patients
  • Regulatory support for conducting clinical trials in rare diseases, such as providing acceleration in the approval process, incentives, etc.

How clinical development strategy is different from other trial strategies

Global regulatory

  • The development of treatments and drugs for rare diseases is financially not viable and is more prominent in very rare diseases. Hence most of the companies require support from the regulatory in the matter of gaining faster approvals, financial benefits, and early access to the market.
  • Regulators of developed countries like the USA, EU, Australia, and Japan offer good benefits and incentives to push the rare disease drug developers and to foresee the best treatments available for unmet diseases.
  • Now even the regulators of countries like Russia, China, South Korea, India, etc. are working on the improvements in regulations for providing benefits for orphan disease drug developers.

Please look at our previous articles about various incentives provided by regulators for rare disease drug development in the USA, Europe, Australia, Japan and other Asean countries

Country selection for your rare disease

Choosing a perfect region for your rare disease clinical trial is crucial and determines the likely success of your clinical trials. It can be achieved by conducting a country level feasibility, to understand the chance of success and times for trial completions, estimate the disease prevalence and number of the patient population available for recruitment, qualified sites, and investigators, and many more

Please click on the following link to know more on conducting country-level clinical trial feasibility here

Clinical trial design and evaluation

Clinical trial design determines the number of the patient population required to be recruited for a study, the data to be generated that comply with the regulatory requirements, and with a minimum number of patients.

  • An important factor in the rare disease is that not all patients present with the same disease subtypes, and this makes recruitment more difficult.
  • Choosing adaptive trial designs, designs that involve infrequent patient visits, and minimum resources may be one of the strategies. Trial designs must be simplified, flexible, and attractive to enroll enough patients.
  • Choosing a trial design such as a platform, bucket, or umbrella shoots more flexibility and with few resources, yet extracting quality data.
  • The US FDA also recommends using such trial designs and provides guidance documents for such trials. Rare disease patient populations are often heterogeneous in disease subtype.

Here are some of the examples of using new trial designs for a better approach and adaptability.

Example 1

The BRAF-V600 study is a trial comprising multiple sub-studies to evaluate the efficacy of vemurafenib for non-melanoma BRAF V600E mutation-positive cancers. Hyman et al., Cunanan et al., and Woodcock and LaVange all classified this study as a basket trial. The sample size for each sub-study is determined by the Simon two-stage design.

Example 2

The FOCUS4 trial is a placebo-controlled multi-group multi-stage randomized trial to evaluate the efficacy of multiple targeted therapies for untreated colorectal cancer. Safety is evaluated in stage 1, and POC is confirmed in stage 2, short-term outcomes are evaluated in stage 3, and long-term efficacy is evaluated in stage 4 in a patient population with a particular molecular marker. 

This  FOCUS4 trial was categorized as an umbrella trial and can also be classified as a platform trial. 

Click here to know about RCT, Adaptive, Umbrella, Basket and Platform trial designs

Patient recruitment and retention

Patient recruitment and retention are another consideration in the clinical industry, as most of the trials fail in successfully recruiting patients and retaining them and prolongs the trial duration to many years.

It is mainly due to a lack of proper strategic planning and execution. Patient recruitment is a point of concern even before designing a trial as the trial design determines the number of patients and the type of patients required for a clinical trial.

  • Planning a country is a part of a strategy for patient recruitment where developed countries like the USA & Europe have many access points for patient recruitment such as applications, organizations database, websites, various portals that provide rare disease patient information. 
  • Another solution to this challenge is to use real-time patient data and physicians’ notes from electronic health records (EHRs) to model various recruitment scenarios,

Generally, patients in rare disease clinical trials are always scattered geographically, hence considering the frequency of patient visits to sites, travel incentives, direct-to-patient (DTP) methods, etc. shall be considered while designing a clinical trial.

Please click on the link here to know various considerations and strategies that help to improve patient recruitment.

Producing quality clinical trial data

Utilizing the designs that require minimum resources yet yield efficient and quality data is often challenging and can be defined in strategic planning. 

  • Measuring clinical trial outcomes, especially in rare disease patients, is challenging as they often exhibit diversity in their clinical presentation and histories.
  • Variables including age, disease progression, and disease severity influence reported outcomes, whether they are clinician-reported, observer-reported, or patient-reported outcomes (PROs).
  • Regulators like EMA, US FDA, recommend utilizing efficient trial designs that yield quality data within minimum patients is fetching for rare disease developers.
  • FDA offers guidance documents for such adaptive trial designs more frequently used in cancer rare disease trials.  

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  1. https://clinicaltrials.gov/ct2/results/map?term=rare+diseases&map=
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120722/
  3. https://www.iconplc.com/insights/blog/2019/10/24/4-challenges-to-successful-rare-disease-drug-development/index.xml
  4. https://www.sciencedaily.com/releases/2019/10/191024075007.htm