Lecture 6: Clinical trials Flashcards
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
Principles for the Conduct of Clinical Trials
- Nuremberg Code
- the rights, safety and wellbeing og an individual subject are unqualifiable/qnati?. full stop
- Declaration of Helsinki
o The international doctrine that describes the biomedical ethical responsibilities of medical professionals when conducting human research studies - Good Clinical Practice
o ICH-GCP - Regulatory Compliance
o TGA/NH&MRC
Nuremberg Code
Collection of principles for guiding scientific
experiments involving human subjects and human experimentation
Specifically identifies voluntary consent, trials based on animal experimentation, and appropriate
risk:benefit considerations
Declaration of Helsinki (October 2013)
- Safeguard the health of the people
- Act only in the patient’s interest
- Purpose of research must be to improve procedures and the understanding of disease
- Risk/benefit
ICH GCP
Strict implementation of GCP led the FDA to reject
data from many countries
* International Conference on Harmonisation (ICH)
– USA, Europe and Japan with Australia, Scandinavia, Canada and WHO as observers developed a
harmonised set of GCPs in 1996
Good Clinical Practice
(GCP) ICH E6
A standard for the design, performance, monitoring, auditing, recording analysis and reporting of clinical trials that provide assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are
protected.
- E6 R2 (June 2017) - clarification of documentation etc.
- E6 R3 (May 2023) - data “fit for purpose”
GCP ensures:
- Subjects are properly
protected in studies - Studies are based on
good science are well
designed and properly
analysed - Procedures are
properly undertaken
and documented
If not followed:
- The subjects who take part may be at risk
- The data collected
may be unreliable - The study will be
rejected by FDA, TGA and Boards of Health
Principles of ICH GCP
- Clinical trials should be conducted in accordance with the ethical principles (Declaration of Helsinki) -Consistent with GCP and regulatory requirements (2.1)
- Before a trial is initiated, risks should be weighed against benefit for subject (2.2)
- Rights, safety, well-being of patients is most important (2.3)
- Available non-clinical and clinical informationshould support proposed trial (2.4)
- Trials should be scientifically sound and described in a clear, detailed protocol (2.5)
- Trial should be conducted in compliance with protocol that has HREC approval (2.6)
- Medical care given to study patients should always be the responsibility of a qualified physician (2.7)
- Individuals involved in conducting trials should be qualified by education, training, experience to perform study tasks (2.8)
- Freely given informed consent should be obtained from every subject (2.9)
- All trial information should be
recorded/handled/stored in a way that allows for accurate reporting, interpretation, verification (2.10)
–
Addendum: This principle applies to all records referenced in this guideline, irrespective of the type of media used. - Investigational products should be manufactured, handled, stored according to GMP (2.12)
- Systems with procedures that assure quality of trial should be implemented (2.13)
– Addendum: Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be the focus of such systems
THE THREE PILLARS of GCP
- Responsible Sponsor
- Suitably Qualified Investigators
- Appropriate Patients
- Overseen by an Independent
Institutional/Human Research Ethics Committee which must approve every study conducted at the Institution, and within an appropriate
Regulatory Framework
ICH GCP in Australia
TGA has adopted ICH GCP in principle but has recognised that some elements are overridden by the NHMRC National Statement.
TGA vs NHMRC
TGA
- Unit of the Federal Department of Health and Aging
- Therapeutic goods act 1989
- therapeutic goods
NHMRC
- Independent statutory body
within the portfolio of the Commonwealth Minister for Health and Ageing
- National Health and Medical
Research Council Act 1992
- Research, Health advisory,
Ethics, Licensing
ARTG
Australian
Register of Therapeutic Goods
clinical trials can be undertaken on drugs/devices not listed on the (ARTG) if they are to be used in a clinical trial
TGA approval is by either
o Clinical Trial Notification (CTN) or
o Clinical Trial Application (CTA) scheme
you have to have ethics committee approval and then also either CTA or CTN approval
CTN
Clinical Trial Notification scheme.
* CTN is submitted (online) following approval by HREC.
* Authority to grant permission sits with HREC but subject to TGA guidelines (receipt of CTN and
fee).
CTA
- Clinical Trial Application scheme.
- TGA engaged to formally evaluate product
(substantial fee involved). - Extensive review of scientific data
o (e.g. in vitro studies, animal studies). - TGA grants permission to conduct multiple trials of product within approved “usage guidelines”.
- HREC application still required !
Ethical Issues
Governed by the provisions
of GCP and the Declaration
of Helsinki
Human Research Ethics Committee (HREC)
an independent authority with
the responsibility and authority to protect
research participants.
Each HREC
o Has the right to disapprove, require changes, or to 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
Composition of an HREC
Minimum membership of an HREC is 8 members
(equal numbers of men and women):
o A Chairperson
o At least 2 members (one man and one women) who are lay people
o At least 2 members with current knowledge and experience in the areas of research usually considered by the HREC
o At least one person with current knowledge and experience in the professional care of people
o At least one person who is a minister of religion/performs pastoral care
o At least one member who is a lawyer
o At least one third of all member should be from outside the institution
National Mutual Acceptance (NMA) SchemeFor Multi-center Studies
- A designated “Lead” Committee (at the Lead Site) conducts full review
- At other sites the “Approving Authority” conducts a Site Specific Assessment (SSA) to confirm adequate resources, facilities, and infrastructure. Site assessment documents are reviewed by the research governance officer (RGO).
- Following endorsement, the application is forwarded to the Chief Executive (CEO)/Director of the site for final consideration and authorization
- Authorization by the CEO should be communicated to the PI followed by registration with the clinical trials registry
Intellectual Property
- Ownership of Data
- Ownership of Novel Findings
- Confidential Information and Public Disclosure of “Interesting” or Significant Findings
- Section 3 of Investment Corporations Act
Duty of Disclosure of Public Companies
Investigators Brochure (IB)
Compilation of the clinical
and non-clinical data on the
Investigational product or
products that are relevant
to the study of the product in
human subjects
Provide information to facilitate investigator
comprehension of trial rationale
* Facilitate Investigator’s compliance with many key
features of the protocol, such as:
o Dose
o Dose frequency/interval
o Methods of administration
o Safety monitoring procedures
* Provide insight to support clinical management of
study subjects.
* Concise, simple, objective, balanced, non-promotional
whats included in an IB
Title page
- Sponsors Name
-Identity of each investigational product and release date
- Edition number / Reference number/Date of edition it supersedes
Confidentiality Statement
- Sponsor may include a statement that IB is a confidential document, for sole information and use of Investigational Team and IRB/IEC
Contents Section
INVESTIGATOR COSTS
- Schedule of Assessments
- Schedule Fees (Blue Book)/
“Market Price” - Clinic visits
- Laboratory Assessments
- Scans/x-rays - inc specialist
interpretation - Premium for early Phase or
complex design
INSTITUTIONAL COSTS
- Equipment/facility charges
- “Hotel” costs - for hospital beds
- Ethics Committee review
- *Pharmacy - Formulation, dispensing, drug accountability
SPONSOR COSTS
Staffing levels
o Direct employment
o Equipment/facilities
Consultants/Contractors
o Specialist Consultants
o Regulatory
o Manufacturing
o Monitoring
3 of the key principles of GCP
- rights, safety and wellbeing of patients is most important
- trials should be conducted according to ethical standards (helsinki)
3 freely given informed consent needs to be obtained from every subject
