Lecture 6: Clinical trials Flashcards
(50 cards)
What is a Clinical Trial
- A scientific study or an organised test of medicines and new treatment options involving patients and non-patient human volunteers.
- Confirm whether medicines are safe and effective to introduce as new treatments for a particular disease or condition.
Why Conduct a Clinical Trial?
Australian community expects that medicines and medical devices in the marketplace are safe and of high quality, to a standard at least equal to that of comparable countries
The Drug Development Timeline
- Basic Research (1-3 years)
- Non clinical studies (3-5 years)
- Clinical studies (3-7 years)
- New drug application and review (~1 year)
- Approval and launch
- Post marketing surveillance and clinical studies
Pre-Clinical Testing
- Review of substances Chemistry
(characterization and stabilization for
production) - Toxicological studies
- Pre-clinical Review
- 1-6 years
Phase I
Primary purpose
– To establish safety of a drug in humans
Typically involve
– 20-80 normal volunteer subjects (patients with
some diseases eg cancer, HIV)
– In-patient setting
– Begin with a single dose administration of the
investigational drug and progressing to multiple or higher doses, provided safety is demonstrated at the previous dose
– Constant and critical subject monitoring
– Pharmacokinetic profile of the drug in humans– Determining the maximum tolerated dose
(MTD) in humans
– Establishing a preliminary human profile of
potential toxicity of the drug
– Short-term duration
Phase II
Primary Purpose
– To provide evidence of confirmation of the effective dose; to establish the safety of the drug in the intended human population
pretty much trying to decide the best does from what works therapeutically to what creates a risk
- try to have clean patients (no other health conditions)
- always placebo control
- sit down and reach registration decision point; is the product worth pursuing registration
Typically involve
– multiple and/or escalating doses to identify a doses range giving a therapeutic effect
– Identifying a dose that provides balance between therapeutic benefit and risk
– May be in-patient or out-patient depending upon the disease under study
– 100-250 study subjects with well defined
entry criteria (“clean” patients)
– Short-medium duration
– Placebo control
– REGISTRATION DECISION POINT !
Phase III
Purpose
– To establish both the safety and efficacy of a drug in the intended human population
big, long, costly, expensive
gold standard!!
placebo control!
Typically involve
– The optimal dose identified in Phase II
– Large multi-centre studies
* from several hundreds to thousands of patients
* may be international
– Placebo control
– Active comparator (usual “gold” standard)
– Treatment conditions as close as practicable to “usual clinical practice”
Phase IV
Purpose
– Monitor safety and efficacy when used in the wider population (may be condition of Registration)
– Compare new medicines to wider range of existing medicines/ therapies
may look for extensions:
extension of dosage, formulation, when to take etc
phase 3b: product already received regulatory approval but you’re now looking at it from a different indication or difference dosage level or different form.
Typically Involve
– Post marketing surveillance studies
– Head to head comparison studies
– Thousands of patients
– General usage
– With or without comparator
Effect of covid on clinical trials
Clinical trials reached an all time high after covid in 2021 but fell again in 2022. But still improved a lot since covid overall.
Key issues for clinical trials
- Conduct of clinical trials
(Clinical trial design, selection and training of investigators, HREC, informed consent, clinical trial monitoring) - Protecting rights and wellbeing of research participants
- Ensuring objectivity in research
Clinical trial design
Define potential medical product
Target indication
Patients
Phase
Power
Research question!
Provide background, what does the product do?!
Protocol (in clinical trials design)
List of instruction for one study/one question
(Background, study aim, inclusion/exclusion criteria, instructions for ethics committee submission)
Use boilerplate statements where possible
(: a message used with minima, effort for multiple different situations)
Protocol headings:
* General Information
o Protocol title, identifying number, version and date
o Name and contact details of the sponsor, monitor (e.g. CRO), sponsor’s medical expert for the trial, clinical investigator and clinical site, clinical laboratory and other medical or technical department(s) involved
Clinical Trial Design: Background Information
o Name and description of the investigational product(s)
o Summary of risks and benefits from preclinical studies and other relevant clinical trials
o Route of administration, dosage regimen and treatment period(s)
o Population to be studied
o References to relevant literature and data
Trial Objective and Purpose
* Trial Design
o Specific statement of primary and secondary end points to be measured
o Type/design e.g. double-blind, placebo-controlled
o Measures to avoid bias e.g. randominisation
o “Discontinuation criteria” for subjects
* Selection and Withdrawal of Subjects
o Inclusion/exclusion criteria
* Treatment of Subjects
o Monitoring subject compliance
statistical issues
Randomisation - Allocation to treatment group by chance eg “toss of a coin”
Parallel Group - Different groups studied at same time and compared
Cross-over - Each patient receives both/all treatments (act as their own control)
Double-Blind - neither patient nor Investigator knows the treatment group
Significance
o Statistical significance p < 0.05 (less than a 1 in 20 chance that this was a random result)
o Clinical significance - the result has real meaning and relevance to a treating physician over existing/other
treatments
o Clinical relevance - the result is relevant to the clinical setting based on risk vs benefits
Selection of Investigators
Investigators should be selected on the basis of:
o Qualifications and training in a field relevant to the study
o The potential to recruit subjects
o Have the time and ability to conduct clinical trials in accordance with ICH GCP
Training of Investigators
Investigators and the clinical site staff are trained on:
o The study protocol
o Obtaining ethics committee approval
o Predicting recruitment potential and identifying suitable subjects
o Undertaking the informed consent process
o Checking that Case Report Forms are completed correctly
Human Research Ethics Committee (HREC)
An HREC is an independent authority with the responsibility and authority to protect research participants
* Each HREC
o Has the right to disapprove, require changes or approve
the clinical trial before participants are enrolled
o This decision is taken after review of the protocol, subject information and consent form, subject recruitment procedures (advertisements) and payments and/or compensation available to subjects
Clinical Trial Monitoring
- Trials are monitored either directly by the sponsor or by a Contract Research Organization (CRO) using
appropriately qualified Clinical Research Associates
(CRA) - The monitoring will take place against a set of Standard Operating Procedures (SOPs) provided by the sponsor or the CRO
CRO
Contract Research Organization
= provide sponsors (pharmaceutical, biotech and medical device companies) with research management services
SOPs
Standard Operating Procedures
CRAs
Clinical Research Associates
(CRA)
verify compliance with ICH GCP, including (but not limited to) adherence to the protocol, enrollment of study participants and the accuracy and complete reporting of clinical trial data
- If monitoring shows that a clinical investigator is deficient in any area, the sponsor will either work with the investigator to achieve compliance or discontinue their participation in the study
