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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

EMA Reflection Paper on GCP compliance in relation to Trial Master Files 22/02/2013

Posted by Shirley Hallam in Essential Documents, GCP audit.
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filesThe EMA (GCP Inspectors Working Group) has issued a draft reflection paper on the maintenance of Trial Master Files. The paper has been produced partly in response to difficulties encountered during inspection in obtaining full access to the TMF. Although fairly short (18 pages) there is a great deal of detail about management and retention of the TMF which has not been spelt out previously.

The definition of the Trial Master File given is helpful, reflecting its purpose rather than simply describing it: “A TMF is the collection of documentation that allows the conduct of the clinical trial, the integrity of the trial data and the compliance of the trial with GCP to be evaluated.” It is therefore necessary to include not just all essential documents as defined in the ICH GCP guideline (these are described as a minimum requirement), but also evidence of key decisions made. Documents generated from following internal procedures should be retained, as should those created during the trial that might help reviewers to reconstruct and evaluate it. The reflection paper also recommends the TMF should be “a stand-alone set of documentation that does not require additional explanation from the associated sponsor or site staff.”

There is acknowledgement that some documents (e.g. the Investigator’s Brochure) may be applicable to more than one clinical trial, and that documents may be held across a number of company departments. In this case, cross references may be held within the TMF, but care should be taken, particularly at archive, to ensure that these will remain unchanged, and where there is doubt then a copy should be placed in the TMF.

Particularly welcome is the consideration given to maintenance of oversight by sponsors who delegate all or part of the management of the trial to a CRO. The paper suggests there should be an agreement between the sponsor and CRO which includes:
• which party holds the official TMF (or which parts of the TMF each party holds when this is divided);
• the process for filing documentation in the TMF
• the access arrangements for both parties
• the structure and indexing of the TMF
• where an eTMF is being used, the details of the system
• lists of applicable procedures to be followed and training requirements
• documents that both parties must retain
• arrangements for managing correspondence
• how the TMF would be made available if either party was inspected
• arrangements for when the trial is completed
• arrangements for oversight of the quality control/quality assurance of the TMF by the sponsor

With regard to correspondence, the paper stresses the important of maintaining that from both parties. For example, if only approval letters are retained without applications, the audit trail is not complete. Different modalities for the retention of email are discussed.

There is discussion about eTMF, and a comment that “remote access to eTMF without the inspector visiting the site may assist in planning inspections and could, in future, potentially form part of the inspection.” Retention periods are covered, with increased stratification according to the lifetime of the product, with clinical study reports being kept for five years after the end of the period of marketing authorization.

The paper concludes with common inspection findings relating to the TMF, which include
• Inability to provide a full TMF (paper and electronic) for inspection purposes on request of the GCP inspectors.
• The paper TMF structure (poor indexing etc.) did not facilitate timely review to evaluate the conduct of the trial.
• The sponsor provided an “artificial TMF”, thus failed to provide adequate direct access and led to issues with documentation not being consistent with that of the official TMF.

Specific eTMF findings include:
• Staff that were put forward as “system users” for eTMF were also unable to locate documents requested by the inspector.
• Failure to fully document and perform effective QC checks on documents uploaded into eTMF. Discrepancies were seen, e.g. missing pages, incorrect documents, poor quality scans, undermining confidence in the eTMF
• Incorrect documents located in the TMF and eTMF
• Poor labelling of files
• activities (e.g. training, Project Team Meetings) were not filed.
• Inadequate equipment for the inspector to review the eTMF, e.g Lap tops with tiny screens.

Comments on the draft to the EMA are invited by 30 April 2013.

The RQA Quality Systems Workbook 13/11/2011

Posted by Shirley Hallam in Quality Management.
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Help is at hand for anyone embarking on developing a quality management system in research and development.

Over the last few months, the Research Quality Associate (RQA) Outreach Working Party has been developing this accessible and practical workbook. Download a copy here.

“A Quality System sets out the standards that you are working to, and how you are going to meet them. The system should define what people, actions and documents are going to be employed in order to carry out the work in a consistent manner, leaving evidence of what has happened. It may include manuals, handbooks, procedures, policies, records and templates. The terminology used is less important than the purpose and use of the documents. The fundamentals of a Quality System are the same regardless of what your work is. The same principles can be applied whether you are an academic research laboratory, a medical device manufacturer or a hospital clinical trials unit

“Understanding, interpreting and implementing a Quality System is a skill in its own right.

“The aim of this new Workbook is to provide tools and a practical approach to develop a Quality System that works for the user.

“The Workbook concentrates on the core, underlying principles of quality which are pivotal – explicitly or implicitly – to all quality management standards that impact on research and development.

“These principles are also fundamental to the conduct of efficient, reliable and credible scientific and clinical work and will help the user to design and implement a practical Quality System that works for their organisation to make it more productive and compliant.

“The workbook may also help users in the task of persuading others of the importance of such a system. It is aimed at the doers within the Outreach target audience who will either have been delegated the task or are volunteers who have seen the need for a Quality System.”  RQA OWP

The Work book is available to both RQA Members and non-members as a free download here.

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.

New Pathway for the Regulation and Governance of Health Research 11/01/2011

Posted by Shirley Hallam in Approvals, Regulatory.
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The Academy for Medical Sciences, chaired by Prof Michael Rawlins, has unveiled its recommendations for a streamlining the systems of approvals and governance for health research, including clinical trials. The main suggestion is the creation of a new Health Research Agency to rationalise the approvals required to conduct research.

The introduction of the report criticises the current barriers to research, specifically:

  • Delays and duplication in obtaining research permissions from NHS Trusts.
  • Complexity and inconsistency across the regulation pathway.
  • A lack of proportionality in the regulation of clinical trials.
  • Inappropriate constraints on access to patient data.
  • A healthcare culture that fails to fully support the value and benefits of health research.

The new Health Research Agency should have two major functions:

  • A National Research Governance Service that would eliminate inefficiency and support NHS Trusts and researchers by undertaking all NHS research governance checks just once.
  • A single system for ethical approvals. This system would encompass the responsibilities for both general ethical approval (the National Research Ethics Service), as well as specialist approvals and licenses

The report also calls for:

  • A reduction in the scope of the European Clinical Trials Directive, with risk based monitoring and a simplification of the requirements for drug safety reporting.
  • Greater access to patient data for research purposes.
  • The embedding of health research to be embedded into NHS leadership and governance processes, ensuring that within each Trust there is an executive director with specific responsibilities to promote health research.

Full Report: http://www.acmedsci.ac.uk/index.php?pid=47&prid=88

Quality Assurance in Good Clinical Practice 27/12/2010

Posted by Shirley Hallam in Uncategorized.
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Welcome to the new website of Hallam Pharma Consulting.

We provide quality assurance services in GCP, assisting pharma companies and non-commercial sponsors to achieve clinical research outcomes in a timely and efficient manner.