Planning and conducting a clinical trial

Question 1

Describe and explain the clinical trial process (10 steps)

Answer 1

1. Aim + Objective (Define the aim and objective, primary and secondary, objective exp - assessing safety, determining efficacy or comparing it with 2 or more treatments)
2. Design the study (type of trial decided, randomised controlled trial, observational studies, trial phases decided, phase 1-4 usually)
3. Study population (inclusion and exclusion criteria defined, sample size determined to detect sig effect, diverse population in order to ensure broad applicability of the results)
4. Protocol development (must have clear protocols, competency of protocol detailing aspects of trial design to analysis, interventions and evaluations participant will undergo)
5. Budget + resources (Estimate of cost require, funding secured from funding agencies, resources and personal planned)

6.Regulatory and ethical considerations (Get approval from institutional review board of ethical committee, good clinical practice following ethical guidelines, informed consent documents signed so risks and benefits communicated)

7. Trial sites and investigators (Appropriate sites based in infrastructure, patient pop and expertise, trials must be conducted by qualified investigators)
8. recruitment and enrolment (recruitment strategy should be developed using adverts position referrals or patient registries. potential participants should be screened using defined inclusion or exclusion criteria. )
9. Data Management (structured and organised, case record form should be designed, data should be securely stored and retrieved, data quality should be reviewed for QA)
10. safety monitoring (system to monitor record and report adverse events, data monitoring committee should be established for large trials or significant risks)

Question 2

Explain the process of initiating a collaboration with a specialised clinical trial unit (starting a clinical trial process)

Answer 2

Sponsor or principal investigator (pi) expresses interest in conducting a clinical trial and contracts a clinical trial unit (CTU)

The sponsor sends to CTU confidential confidentiality disclosure agreement (CDA) or (NDA)

Upon signing CDA/NDA, the sponsor provides a feasibility questionnaire and detailed protocol of the planned clinical trials, as well as the facilities, equipment and population.

Sponsor budget and CTU quotation discussion; CTU can advise on protocols, approval, trial coordination, etc

Question 3

What does a Clinical Trial Unit do?

Answer 3

Provide the essential information, infrastructure expertise and operational support to the trials. Should be conducted ethically.

Question 4

Whats an NDA used in terms of a clinical trial?

Answer 4

Used to ensure confidential info related to the trial remains protected, data about drug, Device being tested, research methods, patient data, business arrangements and contracts.

Question 5

What must occur before a clinical trial can proceed?

Answer 5

The clinical trials must be approved by national and or regional regulatory authorities, as well as local ethics committees or institutional review boards in the countries where the study takes place

The sponsor/PI must complete and submit the clinical trial application form

Question 6

After the approval of the clinical trial by the regulatory authorities what is the next step?

Answer 6

The trial is required to answer the research questions.

There must be a balance between potential benefits to society and participants and the risks of harm to patients

Approval is also needed before participant recruitment from hospital staff,care organisations, ect.

Question 7

What is GCP?

Answer 7

Good clinical practice - international ethical and quality standard for designing, conducting, recording clinical trials that involve participation of human subjects

Question 8

What must be given to a participant before the clinical trial starts?

Answer 8

Informed consent form

Question 9

What is an informed consent form used for?

Answer 9

• must be provided to the prospective participant with sufficient information to decide whether to participate
• To include the purpose of the research, expected length of time of participation, description of experimental procedures, predictable risks and discomforts, participant rights, and confidentiality of info.
• To be signed by participant

Question 10

Explain the UK clinical trial application process

Answer 10

Submit application to the REC (research ethics committee), MHRA and the study wide review committee.

Response for more information received within 30 days.

Response must be given for further information within 14 days.

The REC and HMRC provide final response withing 16 days

60 day process

Question 11

What are the key aspects to patient safety in clinical trials; explain each aspect ? (12 points)

Answer 11

Ethical approval (research protocol must be approved by a review board or ethics committee, ensure the trial is ethical and safe)

Informed consent (given full explanation of study, objectives, potential benefits and risk, ensures they make an informed decision about study)

eligibility criteria (Specific inclusions and exclusions criteria should be followed so only suitable participants are selected, to ensure a representative sample, also to exclude patients that the study would be unsafe for)

safety monitoring (safety boards ensure there is no unnecessary risks to participants, if there are adverse risks they can terminate or alter the study)

adverse event reporting (any side-effects must be reported immediately, reports are monitored and reviewed for any patterns that may compromise patient safety)

protocol adherence (protocols designed to minimise risk and should be followed rigorously, deviation could cause harm and change validity of study)

qualified personnel (should be conducted by a qualified team including, clinicians, nurses, data manger and other professionals trained in the guidelines in good GCP guidelines)

confidentiality (Data should be securely stored and handled to ensure confidentiality, failure to do so compromises the trust and safety of participants)

regular communication (Regular updates should be given to participants and healthcare providers that are involved in the trial)

QA and audits (carried out to ensure compliance with the protocol and regulatory guidelines ensuring safety)

Termination criteria (criteria written to decide when a trial should end due to patient safety, high risk low benefits)

post trial care (After trial concluded should be framework for medical care for participants especially if they have suffered adverse effects from the trial)

Question 12

What are clinical trials for drugs used for?

Answer 12

The phases involve a sequence of trials to bring an investigational medical product (IMP) to market use

The IMP starts in the pre-clinical phase

Question 13

What are pre-clinical trials for drugs?

Answer 13

Before a drug can be tested on humans, it undergoes preclinical laboratory and animal testing to evaluate its safety and potential efficacy.

Question 14

Explain phase 1 in clinical trials of drugs (aim, sample size, duration, repeatability)

Answer 14

Safety & tolerability

First-in-human trials

Aim: to assess the safety and tolerability of the IMP, targeting short-term effects to identify possible harm to the patient(s)

Sample size: 10 – 30 participants, usually based on healthy volunteers

Duration: up to several months

It targets the safety and side effects of the IMP, e.g. identifying tolerable doses,
information on drug metabolism, toxicity

It is not a controlled study(frequently)

Phase I trials can be repeated

Question 15

Explain phase 2 in clinical trials of drugs (aim, sample size, duration, repeatability)

Answer 15

Effectiveness, additional risks & safety

It depends on the quality and adequacy of the Phase I study

Aim: to indicate the efficacy of the IMP and explore different doses and frequencies of
administration.

Sample size: 30 – 100 participants with a given disease or condition

Duration: can take between several months and 2 years

Targets the relationship IMP organism response, e.g. blood level activity

Safety and tolerability of interest as Phase I trial conducted in healthy volunteers

Controlled clinical studies, often “blinded” / placebo studies

Question 16

Explain phase 3 in clinical trials of drugs (aim, sample size, duration, repeatability)

Answer 16

Effectiveness compared to “gold-standard”

Aim: to demonstrate that the IMP is more effective and/or safer than the current standard treatment

Sample size: large group >100 participants

Duration: up to a few years

Multi centre, conducted at national and even international level

Can include long-term surveillance “Phase IV” post-market surveillance, vigilance)

It is the most expensive and time-consuming

Randomised control trials

Question 17

Explain phase 4 in clinical trials of drugs (aim, sample size, duration, repeatability)

Answer 17

Post-marketing surveillance

Aim: To monitor long-term safety and efficacy.

Sample size: Those using the drug after it has been marketed.

Duration: Ongoing, often for several years.

Observational studies, registry data, etc.

Question 18

What went wrong with the Bial clinical trials in France (2016)(not that important)

Answer 18

Drug aimed at multiple disorders, including neurodegenerative diseases and anxiety, developed by Bial (Portugal)

Phase I clinical trial run by Biotrial, a private clinical trial expert company
from France

The study was conducted on healthy volunteers, leaving one person dead
and five others with suspected brain damage!

Why? Because pre-clinical trials led to laboratory animals’ death were
“hidden” and facts twisted

Question 19

What are clinical trials for medical devices?

Answer 19

Clinical trials for medical devices are rigorous studies that are conducted to evaluate the safety and effectiveness of a new device or an existing one

US FDA and the UK HMRA have laid down regulations and guidelines that must be followed.

Has several phases that must adhere to strict protocols

Question 20

What is a medical device?

Answer 20

According to the Medical Device Regulation 2017/745 of the European Union (EU MDR), a medical device can be defined as any instrument, apparatus,
appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for
diagnosis, prevention, monitoring, prediction, prognosis, treatment or
alleviation of disease.

Question 21

What are medical devices used for?

Answer 21

Use in the diagnosis of disease or other conditions or the cure,
mitigation, treatment, or prevention of disease

Intended to affect the structure or any function of the body (FDA)

Diagnostic and/or therapeutic purposes for disease, handicap or injury

Investigation, replacement or modification of the anatomy or a
physiological process

Control of contraception (MHRA)

Question 22

What factors decide whether a clinical trial is needed for a medical device

Answer 22

Depends on the risk stratification or class of device

class 1 = low risk = no
class 2 = med risk = maybe
class 3 = high risk = yes

Question 23

Describe what a class 1 medical device, give some examples

Answer 23

Simplest devices with low potential risk.

examples include stethoscopes, non invasive devices, and reusable surgical instruments

Question 24

Describe what a class 2a medical device, give some examples

Answer 24

Low to medium risk

Devices in this
class are more complex than Class 1 devices and
come with slightly higher risks.

Examples include
dental fillings, hearing aids, and some diagnostic
imaging devices.

A notified body accredited to asses the conformity of products must be involved to certify that the device complies with the regulations.

Question 25

Describe what a class 2b medical device, give some examples

Answer 25

Medium to high risk

These devices present more risk than Class 2a
devices.

More extensive clinical investigations

Examples include surgical meshes, infusion pumps, and implantable
devices

Question 26

Describe what a class 3 medical device, give some examples

Answer 26

High risk

These are the most complex devices with the highest potential risk.

subject to the highest level of regulatory scrutiny, requires extensive clinical trials. Post market surveillance very high

Examples include pacemakers, heart valves, and implantable
defibrillators.

Question 27

What is an in vitro diagnostic device (IVDD)

Answer 27

These devices are used to test samples from the human body but do not directly affect the human body itself. They are separately categorised and can range from pregnancy test kits to blood glucose
monitors.

Have classes A,B,C and D
A = lowest risk

Question 28

What is an invitro medical device? Give an example.

Answer 28

In vitro outside a living organism, e.g. blood test, where a sample is
taken from the patient, but the test is performed in vitro

intended for use outside body usually in lab, sample taken from human

Question 29

What is an invivo medical device? Give an example.

Answer 29

In vivo within living organisms, e.g. a spectroscopic device for in vivo and intraoperative tumour detection

Interact directly with patient internally or externally

Question 30

What is a therapeutic medical device?

Answer 30

intended to treat a specific condition or disease

Can be invitro or in vivo

example surgical instruments, artificial limbs

Question 31

What is a diagnostic medical device?

Answer 31

acquires and provides information about the health condition

example lab kits

Question 32

Explain phase 1 of the clinical trials for a medical device

Answer 32

Phase 1
safety &performance

This is an exploratory stage of the medical device

Aim: to determine preliminary safety and performance information

Sample size: a small study on 10 – 30 patients with targeted condition

Iterative learning and product development

Question 33

Explain phase 2 of the clinical trials for a medical device

Answer 33

Phase 2 (Pivotal): efficacy & adverse effects

It is a definitive study, typically the last step in the medical device approval process

Aim: to determine effectiveness and adverse effects

Sample size: a larger study of 100 – 300 participants

It requires careful design consideration and trial design

assesses how well device works compared to existing devices continues to monitor safety

Question 34

Explain phase 3 of the clinical trials for a medical device

Answer 34

Phase III (Post approval): long-term data

Aim: to collect long-term data for clinical data support and identify and record adverse effects

Sample size: as large as possible (> 300 participants)

It involves post-market monitoring with a focus on adverse events/effects due to medical device use

After device approved ongoing studies conducted to prove effectiveness or long term safety

Question 35

Explain the case study for StAmP

Answer 35

Research project: Statins to Ameliorate early onset
Pre-eclampsia (sTaMp)

Pre-eclampsia can lead to serious complications, e.g.
fetal growth restriction

Statins - class of drugs used by individuals prone to heart disease

Statins are used to lower cholesterol in patients at risk of heart disease and work by inhibiting
cholesterol-producing enzymes in the liver.

Research showed that statins have a pleiotropic (multi-faceted) effect

Pre-clinical studies (Aston Vascular Research Team) indicated that statins reduce the two proteins,
which were previously identified as being elevated in patients with pre-eclampsia

Sponsor: University College London Hospitals NHS Foundation Trust (UK)

Funded by: the Medical Research Council (MRC)

Question 36

Explain how the clinical trial was conducted on StAmP

Answer 36

Participants: pregnant women with severe preeclampsia from 15 centres across the UK

Double-blinded study: control and test group to
be revealed after data has been collected – to
lessen any preconceptions and bias

Study duration: June 2011- July 2014

Question 37

How was TELEGAP study conducted?

Answer 37

Investigation into the usefulness of telemonitoring technology and to assess whether this device improves markers of control of diabetes, glycaemic control and cardiovascular risk factors

Sponsor: Kaiser Permanente

Collaborator: Samsung

Aimed at 40 participants: 18 – 75 years Santa Rosa Diabetes Care Management

Centre with Type 2 diabetes mellitus

Devices installed in participants’ homes

Expected study duration:6 months