ethical and legal issues in clinical trials

Question 1

What is the Nuremburg Code?

Answer 1

A set of 10 guidelines aiming to regulate ethical principles of carrying out experiments on human subjects, e.g. voluntary consent. These principles were set out after the inhuman and unethical Nuremburg Trials.

Question 2

What is the Declaration of Helsinki?

Answer 2

These are a set of principles released as guidelines for human medical research. Although not legally binding, it is morally binding for physicians. It is revised regularly and includes principles such as: informed consent, right to make own decision, study must be ethically reviewed, etc.

Question 3

Name the principles of the Declaration of Helsinki.

Answer 3

DOH is revised regularly and includes principles such as:

1. informed consent
2. right to make own decision
3. study must be ethically reviewed
4. Must have scientific background knowledge before trial commences
5. Approved protocols must be followed and only trained personnel should be involved 6. Investigator must primarily ensure the safety of patient.

Question 4

What is Good Clinical Practice?

Answer 4

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurances that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial subjects are protected.

Question 5

What are the 11 components of the International Council of Harmonisation GCP guidelines?

Answer 5

1. The rights, safety, and well-being of the trial subjects should take priority over interests of science and society.
2. Each individual involved in conducting a trial shall be qualified by education, training and
   experience to perform their tasks.
3. Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects.
4. The necessary procedures to secure the quality of every aspect of the trial shall be
   complied with.
5. The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial.
6. Clinical trials shall be conducted in accordance with the principles of the Declaration of
   Helsinki.
7. The protocol shall provide for the definition of inclusion and exclusion of subjects
   participating in a clinical trial, monitoring and publication policy.
8. The investigator and sponsor shall consider all relevant guidance with respect to commencing and conducting a clinical trial.
9. All clinical information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected.
10. Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future
    patients. A trial should be initiated and continued only if the anticipated benefits justify the risks.
11. A trial shall be initiated only if an ethics committee and the licensing authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and
    may be continued only if compliance with this requirement is permanently monitored.
12. The rights of each subject to physical and mental integrity, to privacy and to the
    protection of the data concerning him in accordance with the Data Protection Act 1998 are
    safeguarded.
13. Provision has been made for insurance or indemnity to cover the liability of the
    investigator and sponsor that may arise in relation to the clinical trial.

Question 6

Why do we need Good Clinical Practice?

Answer 6

Before the implementation of ICH GCP guidelines, there were various disastrous events which occurred due to the lack of ethical and legal regulations preventing physicians from doing patient harm. For example, the ‘Tuskegee Syphilis Study’ in 1932 involved researchers aiming to assess the progression of untreated syphilis in black men. However no informed consent was received, they did not receive the treatment that they needed, and participants were bribed to take part, being told they could have free medical exams and free meals. The trial went on for 40 years. Furthermore, the Pfizer antibiotic trial in Nigeria occurred in 1996. 100 Nigerian children were treated with Trovan to determine its effectiveness, but 11 children died, others suffered brain damage, paralysis or deafness. Pfizer had not gained Nigerian government approval therefore involuntary experimentation had occurred.

Question 7

What is research governance and what is its purpose?

Answer 7

Research governance is defined as a range of regulations and principles which exist to improve standards and quality of research across all aspects of health and social care. The purpose is to safeguard research participants, protect researchers and enhance the ethical and scientific quality of the research. As a result, risk should be minimised and good practice is promoted. Also ensures patient confidentiality and data protection.

Question 8

Name some examples of research regulations and legislations.

Answer 8

EU Clinical Trials Directive, Human Tissue Act, Mental Capacity Act, DOH Research Governance Framework.

Question 9

What is the role of the Health Research Authority (HRA)

Answer 9

HRA oversees research ethics committee’s in the UK. Appropriate NHS REC approval is required for any research involving patients and/or access to organs, or other bodily material of NHS patients, or if NHS facilities are to be used.

Question 10

What is NHS Permission

Answer 10

This is permission required for the conduct of research within NHS facilities, even if REC approval is acquired. Often called NHS R&D Approval

Question 11

List the steps required for approval of a typical clinical trial involving patients.

Answer 11

As the project is classified as research, will firstly need approval from HRA. Then you would need NHS R&D Approval and REC approval (via an IRAS Form). Would also need Clinical Trial Authorisation (CTA).

Question 12

What is a sponsor?

Answer 12

An organisation or group that accepts responsibility for ensuring that there are proper arrangements to initiate, manage, monitor and finance a study. Organisations include: universities, NHS trust, the pharmaceutical company developing the drug, etc.

Question 13

What are the responsibilities of the sponsor?

Answer 13

Primarily, the responsibility is to safeguard the rights, safety, dignity, and well-being of research participants. In doing this, the sponsor takes responsibility for securing the necessary arrangements to conduct the research,
ensuring the required authorisations have been obtained before commencing the research and monitoring to ensure the research is conducted in accordance with legislation and guidance.

Question 14

What is the role of the Chief Investigator?

Answer 14

The chief investigator acts as the person who takes overall responsibility of the design, conduct, and reporting of the study. For multi-centre studies there is a Chief Investigator at the main sites, and other Principal Investigators at the other sites with delegated responsibilities. The Chief Investigator must ensure that all staff have the correct permission to work on the trial.

Question 15

What is the role of the Principal Investigator?

Answer 15

The Principal Investigator is an authorised healthcare professional who takes responsibility for running the study at their trial site. PI may also be the CI in single-centre trials.

Question 16

Name examples of Research Sites.

Answer 16

You can have sites for various activities of the clinical trial, e.g. patient recruitment, informed consent. These may not occur in the same place as the research activities, e.g. these may occur in a University setting, but research activities may occur in the Toxicology Unit of the Newcastle RVI.

Question 17

What is peer-review in the research authorisation of clinical trials?

Answer 17

Peer review refers to the scrutiny of a clinical trial protocol by independent experts to ensure only high quality research is carried out. Either the funder or the sponsor must acquire this.

Question 18

Name the risk assessments that are required for studies.

Answer 18

Patient Safety Assessment, Financial Risk Assessment, Organisation Risk Assessment (sponsorship, insurance and indemnity, Investigator/Research Staff Risk Assessment, Scientific Risk Assessment (scientific quality of the research via good design, etc.)

Question 19

What is insurance and indemnity and why is it required?

Answer 19

For a clinical trial, insurance and indemnity must be set up by the Sponsor to ensure there is compensation available for patients if any harm is to be suffer after involvement of the research trial.

Question 20

What is a Research Passport

Answer 20

A research passport is the mechanism for non-NHS staff to obtain an honorary research contract to conduct research in the NHS. It provides a set of checks on the researcher and allows a faster study start up.

Question 21

What is the Institutional Review Boards and what are their roles?

Answer 21

Institutional Review Boards are the ethics committees in the USA which receive ethical applications for the conduct of clinical trials. IRB must approve or reject applications for ethical approval, as well as monitor and audit whether trials in place are abiding by the ethical and legal regulations to protect patients from physiological and psychological harm.

Question 22

When evaluating research proposals, what do IRBs look at?

Answer 22

These ethics committees will evaluate the proposal of research and how patients may be affected, the emergency use of consent methodology, the investigator qualifications, subject compensation plans, the study consent materials (consent forms, recruitment forms, study outline forms, etc.) They also ensure that once the study is underway, there are no deviations (if so, these must be approved). They must also ensure that documents are kept for at least 5 years after trial close-out.

Question 23

What is informed consent?

Answer 23

This is the ethical and legal obligation to obtain voluntary consent from a patient, after all aspects of the trial have been explained, and the patient has had time to contemplate their participation.

Question 24

Why is informed consent important?

Answer 24

All persons are entitled to their own right make their own decisions about whether they wish to receive treatment or not, even if it could be life-saving. Patients also have the right to withdraw the consent at any time. Failure to achieve this is a serious criminal offence, and in the past has led to trials which have had debilitating consequences to the patient. It is ultimately the principal investigators responsibility to obtain informed consent from the patient.

Question 25

How is informed consent achieved?

Answer 25

The patient must be competent to provide consent. The consent must be given voluntarily without coercion, and the patient must be fully informed of the following:

1. The nature of the treatment and investigation.
2. Why the investigation is required.
3. How the procedure for the treatment will be performed.
4. Risks and benefits of the treatments.
5. Alternative treatments that are currently available.
6. The likely success of the treatment.

Question 26

What is ctIMP

Answer 26

This is ‘Clinical Trials for Investigational Medicinal Products’ and are regulated by the MHRA in the UK.

Question 27

What are the approval requirements for a ctIMP?

Answer 27

Before conducting trials, ctIMPs must be registered with the EU Clinical Trials Directive to obtain an EudraCT number. A Clinical Trial Authorisation must then be obtained from the MHRA through IRAS.

Question 28

What is the essential documentation needed for Clinical Trials?

Answer 28

Must have the Trial Master File (TMF) and Investigator Site File (ISF). The TMF must be in place throughout the whole duration of the study, and should include evidence to prove compliance with GCP, ethics, patient safety, and trial integrity. Will include the responsibility delegations, the timetabling, and evidence of investigator qualifications. The ISF document should be in place at each research site to prove that the study is being conducted in accordance with regulations, protocol, etc. This document may contain patient identification details, however this must NOT be shared with anyone. Also require source documentation to prove that data has been recorded, measured, and analysed correctly (no false data produced). There must also be evidence of monitoring through the clinical trial period.

Question 29

What is the Mental Capacity Act

Answer 29

This is an act which assesses patient capability of giving informed consent via a single, clear test. This aims to protect patients who may be deemed as incompetent. Physicians may make the decision on your behalf, as long as they are acting in the best interest of the patient. Carers or family members may be consulted, however they cannot make decisions for the patient unless this is pre-specified.

Question 30

What is the Human Tissue Act?

Answer 30

This is an act which governs the removal, handling, and storage, use, and disposal of human bodies, organs, and tissues from the living and deceased. Consent to tissue use is required.

Question 31

What tissues are not included under the Human Tissue Act?

Answer 31

Excluded under the act are embryos outside the human body, cultured cells which have divided outside the human body, artificially created embryonic stem cells, cell lines, extracted DNA, plasma extracted DNA and nails from the living. Regardless, an ethics review is required, even if approval from the Human Tissue Act is not necessary.

Question 32

What is the Caldicott principles?

Answer 32

These are principles set out to control the protection of patient data. Any collected data is protected under the Data Protection Act and Caldicott approval MUST be given for any study involving patient data. If patient identifiable information is going to be used, then it must be only be used when strictly necessary, and access to the PII is on a strictly need to know basis.

Question 33

What is IRAS?

Answer 33

IRAS stands for Integrated Research Application System. Ultimately, it is a web based system for obtaining approval for research applications.

Question 34

What regulatory bodies are included in the IRAS?

Answer 34

NHS R&D Approval, MHRA, NHS REC approval and some others. Approval will still be needed outside of these regulatory bodies, e.g. Caldicott approval, Human Tissue Act approval. Applications are sent to all the regulatory bodies in IRAS at the same time, not sequentially.