Clinical Trials

What are the steps to getting a drug into clinical trial?

There are many steps prior to testing a drug in a clinical trial.

  1. basic science research is important to understand the underlying genetic defects and what repercussions those defects have in the muscle cell and brain.
  2. registry gathers CMD affected individuals for future clinical trials
  3. therapeutic targets need to be identified based on the basic science research and CMD disease understanding
  4. a biorepository that is matched to a longitudinal data base needs to be established to act as a source for human tissue and blood specimens and to contribute to underlying knowledge of disease progression
  5. animal models need to be developed or identified to contribute to basic science research and to test therapeutic target hypothesis
  6. biomarkers or signs within the animal model or human tissue need to be identified to show that a drug is or is not having an effect.
  7. high throughput screening systems needs to be developed to screen multiple drug compounds in animal or tissue models, using biomarkers or other markers to look for an effect.
  8. identify new drug compounds: discover, purify, characterize, test in test tube (invitro) or animal model (in vivo)
Basic Science Research → Animal Models → Therapeutic Targets → Drug Identification

Preclinical Trials → Phase I → Phase II → Phase III RCCT (randomized control clinical trials)

FDA approval, drug to market and to patients

Once a drug is identified, several decisions need to be reached prior to launching a preclinical trial.

  • What will the drug be compared to? Different dosages of the same drug, placebo, existing treatments (unlikely in CMD given that there are currently no treatments) or understanding of natural disease progression (not well characterized in CMD)?
  • How many patients will it take to prove a clinical effect when a drug is given? Given that the CMDs are rare diseases, registry participation and clinical trial participation will be rate limiting steps to moving forward with clinical trials. The number of enrolled patients affects the statistical power of the clinical study. A small number of enrolled patients will require a greater drug effect in order to prove the hypothesis that the drug works. A larger number of enrolled patients followed over an extended time period can prove a smaller but still significant drug effect. Given the small number of affected individuals with CMD, it will take a drug with a large effect to prove efficacy.
  • Will the FDA, EMEA (European FDA), TGA (Australian FDA) grant orphan drug status to drug being tested? Orphan drug status allows a company to obtain government support to test drugs in rare diseases, given the limited population who may benefit from the development of that drug. Government support is mediated through tax reductions and marketing exclusivity for extended time periods, allowing a company to recoup revenue lost on developing a drug for a small audience.
  • Type of study? Observational and case reports, less rigorous not used to prove drug efficacy. Randomized Blind Control Studies are rigorous clinical trials that randomize patients into receiving the drug or placebo, or various dosages of drug, blinded to principal investigator (ie, investigator does not know who received the drug or placebo) and control refers to control group either being placebo or active comparator (standard of care).

Preclinical trials examine the drug in both the test tube environment and in animal models, studying safety, toxicity, and biokinetics of drug.

What are the steps to get a CMD drug target into a clinical trial?

There are 4 phases of putting a drug through clinical trials: phase I, II, III, and IV. During a clinical trial, researchers recruit patients, administer the medication (s), collect data on biomarkers and patient’s health and perform statistical analysis on data collected. Each phase is treated as a separate clinical trial on the path to bringing the drug to market. The average drug takes 8 years to get from phase I to completion of phase III. Sometimes a phase 0 clinical trial is employed, to evaluate subclinical doses (microdoses or very low doses) in healthy volunteers to expedite a later transition from phase I to phase II by assessing safety profiles and efficacy early on. This type of phase trial allows researchers to determine how the drug works in the human, as efficacy in mouse models does not always translate into efficacy in humans.

  • PhaseI: This represents the jump from the laboratory setting and animal models into using the drug in humans. A small group (20-80) healthy volunteers are selected to receive varying dosages or escalating drug dosages in an inpatient setting where their responses are closely monitored. For volunteering, they receive a small stipend. This phase assesses safety, tolerability, and how the drug behaves chemically in humans. At times patients who have an end stage disease, without any other viable treatment will be allowed to participate in phase I trials.
  • Phase II: This trial takes the drug testing one step further, using a larger group (20-300) patients, not healthy volunteers to establish dosing requirements (what are the dosing ranges and what effects do they have) and how well does the drug treat the particular disease (how efficacious).
    At times these two goals are separated out into: Phase II a (dosing requirements) and Phase IIb (efficacy).
  • Phase III: This trial is usually a large multicenter randomized control clinical trial, with 300-3,000 patients. In rare disease, the large numbers needed to prove an effect are difficult to obtain. The size, the duration, and the logistics of multiple centers participating make this phase expensive. During this phase, there is the possibility to expand the drug label and explore efficacy in related diseases. Though not required, it often takes two Phase III trials to obtain FDA drug approval.
  • Phase IV: This represents a post marketing trial targeted at surveillance of the patient population now taking the drug. Safety and technological support for drug administration play a role.

What are the biggest barriers to getting a drug to and through clinical trials?

  1. Funding
  2. Funding
  3. Shortage of trial participants
  • Congenital Muscular Dystrophy

    A group of diseases causing muscle weakness at birth. Several defined genetic mutations cause muscles to break down faster than they can repair or grow. A child with CMD may have various neurological or physical impairments. Some children never gain the ability to walk, while others lose the ability as they grow older. Learn more...

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