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EU Clinical Trials Regulation 11/06/2014

Posted by Shirley Hallam in Approvals, Regulatory.
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Slide21The European Union Clinical Trials Regulation 536/2014 was published in the official EU Journal on 27th May 2014.  It will enter into force on 16th June 2014, and will be implemented either from 28th May 2016, or six months after the necessary portal and databases become fully functional, whichever is the later.

The latest version of the GCP Update course offered by Hallam Pharma Consulting is now available, and includes a detailed overview of the Regulation.  Central to the new Regulation is an effort to simplify the submission and notification.  The illustration from the course materials illustrates the submission and approval timelines for part 1 of the application process.

For further details of this and other training courses please contact Shirley Hallam.

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.

ABPI Phase I Guidelines 2012 Edition 05/09/2012

Posted by Shirley Hallam in Essential Documents, Regulatory.
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The Association of the British Pharmaceutical Industry has published new Guidelines for Phase I Clinical Trials, 2012 edition. At 63 pages, this is an informative and well written document, providing  not only a comprehensive overview of current requirements for phase I trials, but also historical background on the development of clinical research legislation in the UK. The introductory sections would make a good starting point for anyone interested in learning more about the drug development process.

On the whole the guidelines are derivative, referencing UK and European legislative requirements and guidance, and other recently published research. As might be expected post TGN1412 there are detailed sections on Risk Assessment (section 4) and Risk Management (section 5) in phase I research.

Section 8 Contracts goes beyond the definitions of essential documents in ICH E6, including the IMP dossier and CT application among the list if documents which must be supplied by the sponsor to the investigator before the trial begins.

There is clarification in section 9 that general (i.e. non study specific) recruitment advertising and non-invasive screening procedures do not require REC or MHRA approval. There is reference to the TOPS database for the prevention of over-exposure.  There are several mentions of the importance of communicating with the subject’s General Practitioner.  Subject payments should be based on the minimum hourly wage and should be increased for procedures requiring extra care on the part of the subject or involving more discomfort; however, payment must never be related to risk. There is guidance relating to payment for cancelled or prematurely terminated trials.

Phase I units should have a designated pharmacy area, carrying a stock of treatments for common adverse events and an antidote to the IMP, if one exists.

Particularly welcome in the guidelines is the specificity with regard to qualifications which key researchers might be expected to have – a concrete answer to the question “What is appropriate?” in the context of the much quoted ICH E6 principle that those conducting clinical research should be “appropriately qualified by education and experience”.  So Appendix 1 includes a list of possible post-graduate qualifications for medical researchers, while section 21 suggests that laboratory heads would be expected to have “a professional qualification such as FIBMS”

Red Tape Challenge – do we need so many regulations? 19/08/2011

Posted by Shirley Hallam in Regulatory.
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The UK government announced that it was going to review unnecessary legislation when it came to power in 2010.  In April 2011 the Red Tape Challenge website went live, inviting the public to comment on any areas where there were over burdensome or obsolete regulations.

 Because there have been many comments from businesses about enforcement, the consultation has now been extended to include Regulatory Enforcement.  The theme will run to mid-September. 

 Feedback is invited on the following:

  • How enforcement has placed an unnecessary burden on you or your business
  • Whether you have experienced overlap between different enforcement rganisations? If so how?
  • Your experiences of particularly overzealous enforcement that is beyond the remit of the regulation
  • Where you feel that you or your sector could manage compliance without intervention by enforcers
  • Where enforcement works well and is helpful.

 The MHRA has posted a link to the Red Tape Challenge website, and clearly is expecting to come within the scope of the review.

 Do you have thoughts on pharmaceutical legislation or the way in which is enforced by the MHRA?  Now is your chance to make them known: Red Tape Challenge website.

Revision of the Clinical Trials Directive 2001/20/EC 28/02/2011

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Following last year’s public consultation exercise to assess the functioning of the Clinical Trials Directive 2001/20/EC, the European Commission has issued a concept paper to assess the impact of proposed legislative changes.  The concept paper sets out a preliminary overview of potential changes to the directive, and invites responses on 18 specific consultation items.  Responses should be forwarded to the Commission by 13 May 2011 at the latest. 

The concept paper can be found at: http://ec.europa.eu/health/files/clinicaltrials/concept_paper_02-2011.pdf

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