Before the Trial Begins

Question 1

Outline what is meant by a pre-clinical stage trial

Answer 1

During the pre-clinical stage of drug development, the formulation and manufacturing technique for the product are developed.

Question 2

Outline what is meant by a Phase I Trial

Answer 2

Phase I studies relate to the safety of the drug under investigation usually in healthy volunteers. They involve the initial introduction of an investigational new drug into humans. The aim is to assess major safety issues and understand how the drug is dealt with in the body.

Question 3

Outline what is meant by a Phase II Trial

Answer 3

Phase II studies are early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. These trials are also used to establish which therapies have the potential to be investigated in full-scale, phase III randomised trials while further assessing the safety of these therapies.

Phase II studies are sometimes divided into Phase IIA and Phase IIB. There is no formal definition for these two sub-categories, but generally:

Phase IIA studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (‘proof of concept’ studies)

Phase IIB studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects (‘definitive dose-finding’ studies). The aim of Phase 11B studies is usually to determine the dose(s) and regimen for Phase III trials.

Question 4

Outline what is meant by a Phase III Trial

Answer 4

Phase III trials are full-scale randomised controlled trials evaluating the benefits and safety of a drug against a placebo or standard therapy in a substantial number of patients. This is the key stage in establishing the impact of a drug and the majority of drug trials you have come across in this course relate to this type of trial.

Clinical trial in patients with the disease/condition for which the drug under investigation will be registered. To confirm the drug has a therapeutic effect and to determine the optimal dose range and correct frequency of dosing.

Question 5

Outline what is meant by a Phase IV Trial

Answer 5

Phase IV studies relate to the stage after a drug has been approved and involves the long-term monitoring of the safety of the drug.

Question 6

List some advantages of conducting a multicentre trial?

Answer 6

Faster recruitment
Greater diversity of patients and more generalisable results
Capacity building in various centres
Setting up collaborations and teams which may be able to work on further trials in the future

Question 7

List some disadvantages of conducting a multicentre trial?

Answer 7

Variable infrastructure between centres
Different availability of trained personnel
Much greater co-ordination to:
- Standardise equipment and procedures
- Randomise patients
- Translate participant and staff materials
Different recruitment rates between centres
Greater resources required for quality control, assurance and monitoring

Question 8

List some qualities of a good principle investigator

Answer 8

Scutiny
Operational plan
Target acheivement 
Monitoring
Concept clearance 
Record keeping
Technical quality 
COmmunication 
Rapport
Decision making
Manpower Mx 
Sincerity and honesty
Hardworking
Ownership
Approach

Question 9

What is a Gantt Chart?

Answer 9

A Gantt chart is a graphical representation of the duration of tasks against the progression of time (also known as a timeline).

Question 10

Why is it important to set up a trial management plan?

Answer 10

Ensures common goals and clear understanding (the plan will be required by agencies that review the proposal for approval)

Facilitates anticipation and identification of any issues

It facilitates a good estimate of the staff and other resources needed and the setting up of the trial budget (the funder will require it)

It facilitates clear evaluation of the study process

Question 11

List some of the things that might be useful to include on a trial budget

Answer 11

Direct costs (staff and non-staff e.g. equipment, drugs and tests)

Overheads

Question 12

List some reasons to register a trial

Answer 12

1. It is a regulatory requirement
2. In order to let collaborators know you are open to adding new sites and for participants to join
3. Compiling evidence
4. Reducing publication bias and assessing quality of conduct and reporting
5. TO avoid duplication of work
6. To help investigators focus on unanswered questions and identify gaps in information
7. Credibility

Question 13

What agencies may you need to submit your trial protocol to obtain approval?

Answer 13

Regulatory agencies
Ethical and governance committees at trial sites
Scientific approval from local or national councils
Informal approval from local communities e.g. religious or political
Approval from health ministries or health services
Insurance
Licence of importation or exportation

Question 14

What considerations need to be taken into account when constructing a risk assessment?

Answer 14

Systematic review evidence 
Experience from previous projects 
Involve stakeholders 
Brainstorming with project team 
Scenario analysis 
Reviewing the proposed process looking for weakness

Question 15

For each risk identified in the assessment what information is worth exploring?

Answer 15

The nature of the risk and the exposure to the risk including probability of ooccurence 
THe proposed counter-measures 
WHo is responsible 
How risks will be monitored 
Risk triggers

Question 16

Within trials, risks are typically catagorised into three types.

Answer 16

Risks to participants in the trial
Risks to completion of the trial
THe reliability of the results

Question 17

Outline some risks to participants

Answer 17

Rights of the particiapants have to be safeguarded (informed, consent, confidentiality)

Adverse effects (expected and unexpected)

Question 18

Outline risks to trial completion

Answer 18

Study feasibility
Estimation of recruitment a SMART goal
Are staff experienced enough
Are procedures too complex for staff/patients
Is the intervention acceptable for the patient
Are my follow-up procedures robust enough to ensure minimal loss to follow-up

Question 19

Outline some risks to realiabilty of trial results

Answer 19

Underpowered 
Violation of eligibility criteria 
Fraud (false patients or results)
INsecure treatment allocations 
Biased outcomes 
Incomplete or inaccurate data

Question 20

What is a feasibility study

Answer 20

A feasibility study asks the question ‘can this study be done?’ and explores issues such as the characteristics of the outcome measure (which is needed to determine the sample size for a full study), the willingness of participants to be randomised, and the willingness of clinicians to randomise them, numbers of eligible patients and time needed to perform procedures e.g. informed consent or other examinations and data collection

Question 21

What is a pilot study?

Answer 21

The first stage of the intervention study where a small number of patients are recruited before the main trial starts. A pilot study is a version of the main study that is done in miniature to test whether the components of the main study can all work together. It is focused on the processes of the main study, for example to ensure recruitment, randomisation, treatment, and follow-up assessments all run smoothly.

Question 22

How can a pilot study clarify levels of risks to patients?

Answer 22

Patients can be asked feedback on acceptabiltiy of intervention, assessments etc. Identify constraints to participation or follow-up

Question 23

How can pilot studies help with risk reduction to staff?

Answer 23

Staff in the study sites and in the co-ordinating centre will also give feedback on the tools and processes. For instance, have investigators overestimated the number of eligible patients they can recruit over the time period? Are some procedures too complex to be done properly? Do the communications systems have unexpected problems?

Question 24

How can a pilot study help with quality control for the main study?

Answer 24

Quality control steps in the pilot can reveal unmet training needs, for example double assessment of outcomes could reveal large variation between assessors, so training and additional clarity on outcome assessment could help to improve the reliability of the study outcomes.