The development of drugs in rare diseases provides great opportunities to pharma companies along with challenges that are required to overcome during drug discovery, pre-clinical, and clinical stages of drug development.

Commercially rare diseases drug development differs from traditional diseases, as there are considerably few patients to take the drug, therefore pharmaceutical companies should consider reducing drug development costs and time to market 

Applying new emergent technologies can help in speeding up and reduce both the time and cost involved in drug discovery, preclinical, and clinical research.

Pre-clinical studies for drug development in rare diseases

Preclinical studies in animals help to determine the dose range of a test drug that will be evaluated in phase I clinical trial. The safety and other data from preclinical studies are crucial to determining before forwarding a drug to human studies.

The goals of preclinical drug development are to

  • Evaluate distribution, safety, and potential toxicity.
  • Drug efficacy in animal disease models
  • Characterize pharmacokinetics properties
  • Evaluate the pharmacologic profile of a drug utilized for clinical studies
  • Understanding of the drug properties in vino.

Some of the models utilized for testing include cell lines, organoids, yeast, worms, flies, fish, mice, or larger animals like rabbits, pigs, etc. Each model has unique advantages and limitations, and choosing such models will, in turn, depend on cost, speed, and tools available for assessing phenotype parameters in the organism and its validity as a model for human disease.

One of the key components for successful drug discovery is producing robust preclinical data. This is highly dependent on in-vitro and in-vivo study models that are used for various steps in the development process, For example, using juvenile animal models for drugs that involve the pediatric population for clinical trials.

Several genetic disorders occur naturally in animals that can be utilized or can create disease by using various techniques and utilize them for testing. For this, working with organizations having novel biologic technology platforms often helps. 

Organizations like the National Cancer Institute collect, study, and provide mice with genetic disorders to researchers.

Some of the key aspects to consider for the pre-clinical phase of drug development

  • Utilize studying juvenile genetic mouse models in reasonable cohort sizes in case of pediatric rare diseases.
  • Drug dosing and response may differ markedly between adults and children for reasons such as anatomical and physiological differences between pediatric and adult population, diseases or presentation 
  • Use of human cells, both normal and those derived from patients with genetic defects.
  • Using forward and reverse genetic manipulation in mice and occasionally with other animals. This approach although is expensive and time-consuming is now a fundamental experimental strategy.
  • Cultured cells from mouse models of rare disease.
  • Mice with humanized livers can be a boon in the case of drug toxicity testing.

Another important aspect of preclinical assessment is to find the carcinogenic properties of a drug, whether a proposed therapy may cause tumors.

  • FDA recommends carcinogenicity studies for any pharmaceutical for which clinical use is expected to be continuous over at least 6 months or to involve intermittent but frequent use in the treatment of chronic or recurring conditions. 
  • Long-term carcinogenic studies may not be required when the potential therapy is intended for patient populations for whom life expectancy is predicted to be short  (less than 2 – 3 years).

Novel preclinical techniques

It’s always preferable to go with new techniques that make the process agile and save both the cost and time involved in research and reach the market as early as possible. Here are a few new approaches

  • Induced pluripotent stem cells (iPSCs)
    • Advances in human pluripotent stem cell (hPSC) or tissue-resident adult stem cell (AdSC) research have led to the possibility to mimic any tissue in the human body
  • Organoids and organs-on-a-chip.
    • The Tissue Chip for Drug Screening is 3-D human tissue chips that accurately model the structure and function of human organs. Researchers can use tissue on a chip model to predict whether a candidate drug, vaccine or biological agent is safe or toxic in humans in a faster and more cost-effective way than current methods. These chips are lined with living cells and are designed to replicate the complex biological functions of specific organs.
  • 3D cell cultures, target validation, patient-derived cell assays, microfluidics, high-throughput cell image analysis, non-invasive drug delivery systems, and devices to measure drug safety or efficacy non-invasively. particularly in the case of pediatric drug discovery. 
  • Modeling and simulation – M&S
    • M&S is a multidisciplinary science, which integrates disease knowledge, drug characteristics, in vitro, in vivo, and ex vivo data, patient populations, and clinical trial parameters in order to optimize study design.

Clinical studies for drug development in rare diseases

After a successful pre-clinical assessment, clinical trials are conducted to evaluate the safety and efficacy profile of the drugs. As a general process, sponsors must submit an IND application, which shall include the results of the preclinical studies.  

Phase I studies lasts several months, and drug doses usually start with low doses. Phase I studies are conducted to evaluate

  • New drug’s safety
  • Pharmacokinetics properties (absorption, distribution, metabolism, and excretion) 
  • The tolerated dose range of the drug

In rare disease clinical trials, the low prevalence of disease leads to a limited number of population, affected by each condition, and this is more complicated in the pediatric population of rare diseases.

Here are some of the challenges in rare disease clinical trials

  • We need to set up multiple sites in different countries to compensate for a few patient populations.
  • Difficulty in finding clinically relevant study population, as most of the rare diseases are heterogeneous 
  • Difficulty in assuming the appropriate duration of the study due to the limited knowledge about the natural cause of the disease
  • Difficulty in finding patients and achieve sufficient study subjects, as 85 percent of clinical trials fail in retaining enough patients and up to 50 percent of sites enroll one or no patients in their studies.
  • Drug approval problems due to limited evidence resulting from clinical trials in small populations
  • Logistical issues that arise due to scattered patient populations, and clinical trial sites across the geography.

Some of the regulatory agencies, like the US by draft guidance and Europe by EMA, provide guidance documents defining the levels of evidence, pharmacological considerations, choice of endpoints and control groups, as well as methodological and statistical considerations in small population clinical trials like rare diseases.

Designing a clinical trial

Clinical trial designs with orphan drug approvals differ in non-orphan drugs such as small pivotal studies, do not use placebo control, and use nonrandomized, un‐blinded trial design.

Various rare disease registries may serve as an important source of information to study the natural history of a disease and also to improve the designing aspect of a clinical trial from different perspectives. 

It is recommended to put efforts into observational studies such as 

  • Self‐ controlled observational studies, 
  • Case‐control studies and 
  • Prospective inception cohort studies. 

However, high heterogeneity in the phenotypic expression of many rare diseases shall be considered before going with these registries’ information. 

The second important factor in designing clinical trials is the inclusion and exclusion criteria, which may impact patient recruitment. stringent inclusion and exclusion criteria may narrow the window to include many subjects into the trial.

Some of the key aspects to consider for the clinical phase of drug development in rare diseases

  • Choosing a longer trial duration can reduce sample size requirements by capturing more events among the clinical trial participants.
  • Maximizing the information from a few patients.
  • Focusing on high-risk patients can reduce sample size and study duration.
  • Using genetic testing can reduce variability between individuals and allow the inclusion of patients before they experience symptoms.
  • Factorial designs provide answers to multiple questions within the same study population. This reduces the total number of patients required to answer all of the questions of interest but does not reduce the number of patients required to answer each individual question.
  • Build networks to allow broader access to trials. The development of clinical trial networks for rare diseases can facilitate the conduct of multicenter and even multinational randomized trials.
  • Randomized controlled trials are the gold standard for testing the efficacy, safety, and benefit-to-risk ratio of new treatments.
  • Methods to combine observational and clinical data.
  • Detailed knowledge of the epidemiology and pharmacology of the medicine may help when designing studies, helping to identify sources of heterogeneity.

Adaptive designs in rare diseases

Small trials exhibit more variability than larger trials and this is more prominent in rare disease clinical trials. Some of the useful characters of adaptive designs

  • Treatments effectiveness can be identified earlier 
  • Shorten the development process without compromising on efficacy or data validity
  • Permit a more efficient use of resources.

Click here to understand various trial designs such as RCT, Basket, Platform, and Umbrella trial designs

Clinical trial feasibility

Clinical trial feasibility is an important tool before conducting any clinical trial in a particular region. This may reduce the bias or probability factors which may lead to clinical trial failures. 

A proper clinical trial feasibility study helps in assessing the following crucial aspects, particularly in rare disease clinical trials

  • Region suitability, and available subjects for recruitment
  • Scrutinize, and recruit qualified clinical investigator’s and capable sites for your rare disease clinical trials
  • Understand regional regulatory aspects and ethical approval processes and more particularly in clinical trials involving pediatric populations
  • Understand various timelines involved in initiating the clinical trial and trial durations

Learn more about clinical trial feasibility and how it can help you

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