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An Introduction to Good Clinical Practice 17/01/2014

Posted by Shirley Hallam in Approvals, Essential Documents, Ethics, Training.
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trainingShirley Hallam writes: 

I have just completed the background notes for my 2014 Introduction to GCP training course.  The training is available as a half day course and is suitable for research staff at companies and research sites.  GCP refresher training is also available.  Please contact me if you would like further information.

New Readers Start Here…

Good Clinical Practice (GCP) is a set of principles, requirements and standards which govern the conduct of clinical research.  Its purpose is to protect people who take part in clinical trials, and to make sure that trials are conducted in accordance with sound scientific principles producing reliable data.

For research involving medication or medical devices, GCP is underpinned by European and UK legislation.  For other research involving NHS patients, GCP provides a helpful framework for researchers to consider in designing projects with arrangements that are proportionate to risk, producing evidence-based results.

 A History of Good Clinical Practice

The first half of the 20th century saw many developments in production of medicines which were largely unrestricted.  After World War II, the “Doctor’s Trial” at Nuremburg castigated unethical research which had been conducted on concentration camp inmates, and framed a set of ethical principles for research conduct in the Nuremburg code. The principles focused on the protection of research subjects, who should consent to taking part and be free to withdraw, and the need for experiments to be conducted in accordance with sound scientific principles, avoiding unnecessary suffering and prioritizing the rights of participants.

The World Medical Assembly (WMA) was formed in 1947.  In 1964 the WMA published the Declaration of Helsinki. It developed the Nuremburg Code by placing a set of responsibilities on physicians conducting research on human subjects, including the requirement for research to be reviewed by an independent Ethics Committee.  Although the Declaration of Helsinki is not in itself a legal requirement, it has had lasting influence because it is often referred to in legislation, and it is frequently reviewed and revised to remain relevant, most recently at Fortaleza, Brazil in 2013.

Within Europe, the first guideline on GCP was published in 1991.  In 1997, the International Conference on Harmonisation (ICH) published a GCP guideline with the aim of standardizing pharmaceutical research across major drug markets (Europe, USA and Japan).  The primary aim was to increase the acceptability of research data used in submissions for drug licenses, to prevent the need for repeating the same research in different territories.

Although it has been superseded to some extent by the legislation which followed, “ICH-GCP” remains the most significant document in the conduct of clinical trials of medicinal products today.  This is because it is relatively brief and easy to follow.  It sets out the responsibilities of ethics committee, investigators (physicians and research teams) and sponsors in a clear and pragmatic way.  Compliance with ICH-GCP largely guarantees fulfillment of the majority of legislation which has followed.

Current Legislation

In the UK, the first drug research law was passed in 2004.  Statutory Instrument 2004/1031 Medicines for Human Use (Clinical Trials) Regulations incorporated into UK law the European Directive 2001/20/EC which was passed three years earlier.  There have since been one more European Directive (2005/28/EC, the “GCP Directive”) and a handful of amendments to the UK statutory instrument (see Useful Links and Further Reading below).

Although produced with the intention of harmonizing clinical research across Europe, the method by which European directives are adopted into national law has resulted in a number of the Member States adding in local requirements.  Therefore at present there is not a single research standard across Europe.  In response to this problem, the European Commission is currently developing a Clinical Research Regulation.  Regulations are more powerful than Directives, in that they must be implemented as written and do not require incorporation into national law.  The Regulation is expected to take effect in 2016, and is currently available in draft.

The Research Governance Framework applies to all research conducted in health and social care settings. The principles it contains can be applied in a risk proportionate way to research projects. It sets out clear responsibilities for all stake holders involved in research, including participants, health care teams, investigators, sponsors and funders.

A core standard for health care organisations is that they have systems to ensure the principles and requirements of GCP are consistently applied.  The systems usually take the form of Standard Operating Procedures (SOPs) tailored to the needs and activities of the organisation.

Principles of Good Clinical Practice

From amendment 2006/1928 to the UK Statutory Instrument: Medicines for Human Use (Clinical Trials) Regulations.

  1. The rights, safety and well-being of the trial subjects shall prevail over the interests of science and society.
  2. Each individual involved in conducting a trial shall be qualified by education, training and experience to perform his 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. The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist.
  12. 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.
  13. 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.
  14. Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to the clinical trial.

Approvals

In order for a clinical trial to go ahead, it must have approval from the following organisations:

  • Regulatory authority (drug and device trials).  In the UK, the competent authority for issuing regulatory approval is the Medicines and Healthcare Products Regulatory Agency (MHRA).
  • Ethics committee approval.  This is required for all research involving:
    • NHS patients/service users (including potential participants recruited by the patient or user’s past or present treatment and NHS patients treated under contracts with private sector institutions)
    • Potential participants identified because of their status as relatives/carers of patients and users of the NHS
    • Access to data, organs or other bodily material of past and present NHS patients
    • Foetal material and IVF involving NHS patients
    • Recently dead in NHS premises
    • Use of/access to NHS premises or facilities
    • NHS staff – recruited due to their professional role
    • Healthy volunteers where a drug or device is being tested within the NHS.

There are a number of Ethics Committees throughout the country, with applications submitted centrally through the National Research Ethics Service (NRES), part of the Health Research Authority (HRA).  Applications are sent on line using the Integrated Research Application System (IRAS).

  • Institutional approval – For trials involving NHS patients, approval must also be sought from NHS management.  The application is also made via the IRAS system.

Research Responsibilities

GCP outlines responsibilities for each party involved in conducting a clinical trial.

Ethics Committee

  • Reviews relevant background information, trial protocol and drug information, where applicable
  • Considers the qualifications and suitability of investigators
  • Provides a written opinion on the research project
  • Reviews ongoing projects annually
  • Acts particularly on behalf of the trial participant by careful review of information to be provided to participants, methods of recruitment, compensation, confidentiality arrangements, and any special provisions for vulnerable participants including children and persons of reduced mental capacity
  • Has written procedures and maintains records of decisions.

Investigator

  • Qualified by education, training and experience
  • Familiar with the drug or other research
  • Permits monitoring by the sponsor, and inspection by regulatory authorities
  • Maintains a list of appropriately qualified persons to whom significantly trial-related duties have been delegated
  • Has adequate resources to conduct the trial
  • Responsible for all trial related medical decisions, and the overall medical welfare of the participant
  • Reports and communication with the Ethics Committee
  • Complies with the protocol
  • Has oversight of the trial medication.  This may be delegated to a pharmacist, but the investigator has overall responsibility.
  • Obtains informed consent from participants
  • Reports safety concerns promptly to the sponsor
  • Reports at the end of trial to the Ethics Committee

Other Researchers

  • Ensure that they follow the current version of the agreed protocol
  • Help to ensure that participants receive appropriate care while involved in research
  • Report any adverse drug reactions or other adverse events
  • Protect the integrity and confidentiality of clinical and other records and data generated by the research;
  • Report any failures or suspected misconduct through the appropriate systems.

Sponsor (some of the following responsibilities may be delegated in writing to Contract Research Organisations and the Chief Investigator)

  • Quality assurance and quality control
  • Appoints a medical expert to oversee the research
  • Trial management, data handling and record keeping
  • Selection of investigators
  • Compensation to participants and investigators
  • Finance
  • Reports and communication with the regulatory authorities
  • Manufactures, labels and supplies research medication
  • Maintains records
  • Reports safety issues to the regulatory authorities
  • Monitors and audits research trials

Fund holder

  • Ensures proper use of funds
  • Assures the quality of a study, by establishing that the research proposal is worthwhile, of high scientific quality, and represents good value for money.
  • Oversees independent expert review
  • Provides assistance to any enquiry, audit or investigation related to the funded work.

Informed consent and protection of participants

Consent to take part in a clinical trial must be freely given by participants after they have been fully informed about the trial and had the opportunity to ask questions.  They are also free to withdraw from the trial at any time without having to provide an explanation, and without any impact on the level of clinical care they receive.

The quality of the information and the way in which it is provided are both taken into account by the Ethics Committee review. Participants should be given enough time to read the information, and an opportunity to ask questions.

The ICH GCP guideline details twenty elements which should be included in information provided to participants.  These include:

  • Disclosure that the trial involves research, and an overview of which aspects are experimental
  • The purpose of the trial
  • Trial treatments, and an explanation of randomization and the chance of being assigned to a particular treatment
  • Risks and benefits of the treatment and trial assessments
  • Alternative treatments
  • Payments and expenses
  • Confirmation the entering the trial is voluntary, and that participants may refuse to take part, or may withdraw, with no impact on their subsequent clinical care
  • Confirmation of confidentiality, the publication policy, and information about who might have access to the participant’s medical records
  • The expected duration of the trial and the number taking part
  • Foreseeable circumstances under which the trial might be terminated
  • Who to contact in case of emergency

There are also provisions for research involving children, and people who are unable to consent on their own behalf.  Research can only be done in these circumstances where there is no other way of obtaining the information.  Legal representatives may be assigned to act on participant’s behalf, and any particular arrangements must be reviewed and approved in advance by an Ethics Committee.

Adverse event reporting

Many trials involve an evaluation of the effectiveness and also the safety of one or more possible treatments.  Information is collated, analysed, and reported at the end of the trial.  However, if serious safety concerns arise, it is important that these are reported as soon as possible, as there may be consequences for other trial participants.

A Serious Adverse Event is an untoward medical occurrence which:

  • Results in death
  • Is life threatening
  • Requires hospitalization, or prolongation of existing hospitalization
  • Results in persistent or significant disability
  • Leads to a congenital abnormality or birth defect

Such events must be reported immediately to the trial sponsor and, if they have not previously been associated with the treatment, the sponsor must report them to the regulatory authorities.

Documentation

The maintenance of clear and comprehensive records is a key requirement of GCP.  The ICH-GCP guideline includes a list of “essential documents” which provides a useful starting point for ensuring that all the necessary evidence is retained.  In the case of trials involving medication, all documents and participant records must be kept in a secure location for a minimum of five years, and should be available for inspection by the MHRA at any time.

Useful links and further reading

Guideline for Good Clinical Practice (ICH-GCP)  http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf

Declaration of Helsinki http://www.wma.net/en/30publications/10policies/b3/

European Clinical Trials Directive 2001 http://www.eortc.be/services/doc/clinical-eu-directive-04-april-01.pdf

European Good Clinical Practice Directive 2005 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:091:0013:0019:en:PDF

Proposed European Clinical Research Regulation  http://ec.europa.eu/health/files/clinicaltrials/2012_07/proposal/2012_07_proposal_en.pdf

UK Medicines for Human Use Regulations 2004 http://www.legislation.gov.uk/uksi/2004/1031/contents/made

and amendments:
http://www.legislation.gov.uk/uksi/2006/1928/made
http://www.legislation.gov.uk/uksi/2006/2984/made
http://www.legislation.gov.uk/uksi/2008/941/made
http://www.legislation.gov.uk/uksi/2009/1164/made

Research Governance Framework for Health and Social Care https://www.gov.uk/government/publications/research-governance-framework-for-health-and-social-care-second-edition

Clinical Trials Toolkit http://www.ct-toolkit.ac.uk/

Medicines and Healthcare Products Regulatory Agency http://www.mhra.gov.uk/

Health Research Authority http://www.hra.nhs.uk/

Integrated Research Application System https://www.myresearchproject.org.uk/

© Shirley Hallam 2014

MHRA revises Phase I Accreditation Scheme 27/11/2013

Posted by Shirley Hallam in Approvals, Ethics.
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MHRAThe MHRA has updated the Phase I Clinical Trials Accreditation Scheme.  The voluntary scheme, which was introduced in the aftermath of the Te Genero incident in 2006, is designed to promote “best practice” procedures encompassing the highest standards for avoiding harm to trial participants and for handling medical emergencies.

The revision to the scheme puts in place a single level of accreditation, which has been extended to include academic units and patient volunteer trials.

Units that are not accredited are not excluded from conducting Phase I clinical trials, since the scheme is voluntary. However, sponsors are advised to take the absence of accreditation into account when considering the trial site and to consider conducting their own site inspection.

Declaration of Helsinki 2013 21/10/2013

Posted by Shirley Hallam in Ethics.
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WMAThe World Medical Assembly has published a new version of the Declaration of Helsinki. The 2013 version, formally ratified at the WMA meeting in Fortaleza, Brazil, includes:

  • requirement for risk assessment – physician must have confidence that risks can be adequately managed
  • where a relationship of dependence exists between the physician and a potential trial participant, informed consent must be sought by an appropriately qualified individual who is completely independent of this relationship
  • clarification on the use of placebo: only when no proven intervention exists or the use of placebo is necessary to determine the efficacy or safety of an intervention, and  patients will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention
  • clarification on post-trial provisions:  In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial
  • clarification on registration and publication:  trials must be registered in a publicly accessible database before recruitment of the first subject; and researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research
  • provisions for the use of unproven interventions to offer hope of saving life, re-establishing health or alleviating suffering.

The full text is available from the World Medical Assembly website.

The Immortal Life of Henrietta Lacks (HeLa) 01/04/2011

Posted by Shirley Hallam in Ethics.
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Henrietta Lacks was a black woman from Virginia who died in 1951 of cervical cancer at the age of 31.  A tissue sample of her tumour was taken and cultured in the laboratory of Johns Hopkins Hospital, where it became the original source of the immortal HeLa cell line. 

In “The Immortal Life of Henrietta Lacks”, science writer Rebecca Skloot has painstakingly researched both Henrietta’s life and the scientific discoveries arising from the development of the first immortal cell line.  Written without sentiment or sensationalism, the contrasts are stark: a multimillion dollar industry based on research at the frontiers of the scientific understanding of pathology and genetics, originating from a poor black tobacco farmer, whose family have remained in relative poverty.

The book raises important questions of ethics in research, informed consent, and ownership of samples and genetic code.  Although these topics are familiar territory, I found that reading the book made me consider them afresh, from the perspective of both research subject and scientist.  There are no easy answers, and just as HeLa cells continue to multiply, the story doesn’t have a neat ending.  But it is a timely reminder of the importance of communication and engagement between scientists and the public; and in this Rebecca Skloot is a great role model.