The role of the sponsor and investigator in clinical trials / The setting up of a clinical trial

Question 1

List The 5 Rs after Sir Mene Pangalos AZ

Answer 1

Right target 
Right tissue
Right safety 
Right patient
Right commercial potential

Question 2

What is a clinical trial?

Answer 2

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.

Question 3

What is the timescale of drug development?

Answer 3

10-12 years

Question 4

List the stages of clinical trials and the preparatory work for a new drug application

Answer 4

Target product profile generation/research profile selection of compound/ intellectual property review

Decision to develop product

To CTA/IND filing

Phase 1

Phase 2

Phase 3

File MAA and NDA

Question 5

What is a phase 1 clinical trial?

Answer 5

50-200 subjects
Either health or patients
Not intending to benefit

Looks at if the drug is safe in humans, what the body does to the drug, what the drug does to the body and how might the drug work in patients

Question 6

What is a phase 2 clinical trial?

Answer 6

100-400 subjects
Patients with target disease

Looks at if the drug is safe in humans, what the body does to the drug, what the drug does to the body and how might the drug work in patients

Question 7

What is a phase 3 clinical trial?

Answer 7

1000-5000
Patients with target disease

Is the drug safe in patients?
Does it work?
Does it work better than other medicines available for the disease?

Question 8

What is a phase 4 clinical trial?

Answer 8

Many thousands or millions
Patients with the disease

How safe is the drug?
Does medicine work in the real world?

Question 9

Describe the set up of a clinical trial

Answer 9

Write clinical trial protocol synopsis
Carry out feasibility
Country and site feasibility
Patient and site selection
Complete final protocol and get approvals
Site contract
Study start-up activities

Question 10

Describe inclusion criteria

Answer 10

Defines the patients who have the condition (severity/type) for whom the trial is intended
And always includes confirmation that the patient freely gives their consent (note: emergency research without consent is possible in life threatening situations

Question 11

Describe exclusion criteria

Answer 11

Excludes the patients who have the above condition but for whom participation in the trial would

• be unsafe (concomitant disease/treatment),
• be unethical (not on standard of care already?)
• provide unreliable data (previous treatment could confound results / patient not likely to comply for other reasons … alcohol / drugs etc..)

Question 12

What is the patient population be defined by?

Answer 12

Eligibility criteria

Question 13

List some important points in relation to patient populations

Answer 13

Can only draw firm conclusions about these types of patients from the trial

In registration trials, the eligibility criteria defines the disease population for whom the drug will be approved (ref. SmPC)

A patient who fails eligibility criteria should NEVER be allowed into a trial. The Sponsor knowing allowing this is granting a PROTCOL WAIVER ..which are “condemned” by regulatory authorities

Question 14

Describe placebo control

Answer 14

test drug vs. matching placebo

The test drug should be superior to ‘no treatment’ at all (only permitted if there is no damage to the patient from giving no treatment for the condition
If an ‘add on’ design, the usual assumption is that test drug+SoC is better than SoC and trial is usually designed to demonstrate superiority - need to define a clinically meaningful difference

Question 15

Describe active control

Answer 15

test drug vs. “gold standard”

The accepted clinical ‘gold’ standard may vary from country to country or even within countries in different populations (e.g. ACEI in afro-caribbeans)
Blinding may be more difficult
Trial may have higher costs – need to pay for comparator
Ideally show superiority – but non-inferiority may also be tested – may have some advantages even if the clinical outcome is the same e.g. NOAC vs. warfarin (no monitoring with former - Need to set a margin of non inferiority (ie if there is a difference it is not clinically meaningful)

Question 16

What are the endpoints of clinical trials?

Answer 16

Safety and tolerability
Efficacy
Mortality/morbidity
Biomarker/surrogate

Question 17

What does efficacy involve?

Answer 17

Disease outcome
Morbidity/mortality
Surrogate endpoint /biomarker
Patient reported outcome measure e.g. Quality of life

Question 18

Describe the mortality/morbidity endpoint?

Answer 18

Often referred to as a “hard” endpoint - Clinically measurable and can be confirmed (Death, progression/relapse/increased activity of disease)
May require a large sample size
If a very large number of patients are needed, a “composite” endpoint may be used to enable feasibility e.g. all cause mortality + non-fatal MI + hospitalisations for heart failure (adv: increase no. of events, decreases sample size)

Question 19

What is a biomarker?

Answer 19

biological characteristic (molecular, anatomic, physiologic, or biochemical) that is objectively measured and evaluated as an indicator of
normal biologic processes,
pathogenic processes
or a pharmacologic response to a therapeutic intervention.

Question 20

What is a surrogate?

Answer 20

biomarker which is accepted by the regulatory agencies to correlate to a meaningful clinical outcome

Question 21

Give some examples of surrogates accepted for drug registration

Answer 21

HbA1c and microvascular disease in diabetes mellitus

LDL-cholesterol and cardiovascular events

Viral load for treatment of HIV and hepatitis C

Correlate of protection/immunogenicity endpoints in vaccine studies

Question 22

What happens after the study is designed and agreed?

Answer 22

Sponsor
Principal Investigator/Investigator site(s)
Patients (subjects for healthy volunteer studies)
Approvals
Logistics – including emergency out of hours support / unblinding
Transparency disclosures

Question 23

What is a sponsor?

Answer 23

An individual, institution, company or organization (for example, a contract research organization) that takes the responsibility to initiate, manage and/or finance the clinical trial

Question 24

What is an investigator?

Answer 24

Individual responsible for the selection and care of subjects/patients participating in the clinical trial

Question 25

List the responsibilities of investigators

Answer 25

Trial design and review
Investigator selection
Training of the Investigator/Site staff
Funding of the trial (it can be very expensive!)
payments for site/volunteer participation (patients are never paid except out of pocket expenses, unlike health volunteers)
providing trial insurance/enabling compensation of subjects for research associated injury
Investigational product supply
All approvals for the start and continuing conduct of the trial
Providing safety information to the investigators to enable patient management and reporting adverse drug reactions (ADRs) to regulatory authorities
Monitoring each participating site
protocol compliance
accuracy of data collection / no fraud
Trial analysis and reporting of results

Question 26

What are the responsibilities of investigators?

Answer 26

The Investigator must be suitably qualified to assume responsibility for the trial at the site
Must be familiar with the Investigational Product (IP)
Responsible for submitting the protocol to and communicating with the independent ethics committee prior to and as relevant data arise during the study
Recruiting subjects in compliance with the eligibility criteria defined in the trial protocol
Obtaining written informed consent from trial participants prior to starting trial treatment(s)
Ensuring training of site staff on the protocol requirements and patient care needs
Ensuring accurate recording of data collected for the study
Compliant reporting of any adverse drug reactions to the sponsor according to regulatory requirements
Ensuring compliance with Good Clinical Practice (GCP requirements) including permitting monitoring of trial data reported on the case report form, and facilitating audits and inspections as required to validate trial information
Keep records of patient participation and progress in the trial for required periods post study completion

Some responsibilities can be delegated to an appropriately trained person ( e.g. qualified study nurse or research physician)
completing the case report forms
bloods for safety tests
conducting physical examinations as required
Overall responsibility for the conduct of the trial at the site (and of any site staff to whom tasks are delegated) remains with the investigator

Question 27

What approvals are required before study start up?

Answer 27

Regulatory agency (MHRA, EMA, FDA)
Ethics Committee
Research & Development office of the NHS Trust / CCG