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  • Regulation of Clinical Products

    Nic Robinson Production Manager, EnteroBiotix

  • Regulatory Affairs • Regulatory affairs is a profession developed from the desire

    of governments to protect public health by controlling the safety and efficacy of products in areas including pharmaceuticals, veterinary medicines, medical devices, pesticides, agrochemicals, cosmetics and complementary medicines,

    • Professional Body – TOPRA (The Organisation for Professionals in Regulatory Affairs)

    • Described by one as science in a suit • Less laboratory based

  • Substances and Medicines • Paracelsus (1493-1541) • All substances are

    poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy (medicine)

  • Early Transfusion • On June 15, 1667, Dr. Jean-Baptiste

    Denys, personal physician to King Louis XIV, performed the first human blood transfusion. The patient was a 15 year old boy who had been treated by using leeches to suck out “the bad blood.”

    • His experiments with animal blood provoked controversy and in 1670 the procedure was banned in France.

    • Regulation by king, pope and parliament - Stopped progress for nearly 150 years

  • Landsteiner – Blood Groups • 1900 Landsteiner describes blood groups

  • Transfusion comes good • Blood transfusion is often cited as the major

    medical advancement of the First World War • 1919 Aberdeen surgeon Henry Gray gives talk to

    Rotary club describing his war experience • 1928 Staff of infirmary set up transfusion service

    and 6 years later 34 on donor panel and 32 transfusions that year.

    • 1988 European Blood Directive

  • Thalidomide • Thalidomide was first manufactured for the purpose of treating

    respiratory infections but was also used for morning sickness. • During clinical trial everything went well and as it was impossible

    to die from an overdose of the medicine, it was deemed safe, and it hit the shelves in 1956

    • In 1961 the link between Thalidomide, offspring and the occurring limb deformities was discovered.

    • Over 10,000 people paid the price

    • 2001 – Medicines Directive

  • Cellular Therapies • Development of Biologics • After initial rejection problems there were successful

    Bone Marrow transplants from 1968 • Many centres started peripheral blood stem cell

    transplants and cord transplants in the 1990s. • Quality of some of this work varied leading to the

    requirement for regulatory controls

    • 2004 – European Tissue and Cells Directive (EUTCD). • Mainly regulated by Human Tissue Authority

  • ATMP • An Advanced Therapeutic Medicinal Product is defined as either:

    (a) a gene therapy ‘medicinal product’ (b) a somatic cell therapy ‘medicinal product’ (c) a tissue engineered product – a product that:

    • contains cells or tissues that have either been subject to ‘substantial manipulation’

    • and • is presented as having properties for treating or preventing disease in human


    • MHRA is the competent authority • Specials Scheme - interpreted to mean the absence of a pharmaceutically

    equivalent and available licensed product

  • Historical Drivers • 1964 - The Declaration of Helsinki establishes Ethical principles for

    clinical research • 1965 - EU decides that Medicinal Products need to be authorised

    before being placed on the market and developed structured medicinal regulations. (UK Medicines Act, 1968)

    • 1989 – First Guidelines on GMP

    • 2001 – Medicines Directive • 2004 – EUTCD (UK – Human Tissue Quality and Safety Regs 2007) • 2007 – Regulation on ATMP

  • Why Regulate • To ensure quality, safety and efficacy of drug products in

    order to assure the continued protection of Public Health. • No drug product is completely safe or efficacious in all

    circumstances. • There is a moral and legal expectation that appropriate

    steps are taken to assure optimal quality, safety and efficacy by the producers.

    • Benefit versus Risk.

  • Standards

    • Regulation provides standards • Standards give specification and develop guidelines • Audit or inspection based around standards

  • Regulatory Compliance

    • Compliance means conforming to a rule, such as a specification, policy, standard or law.

    • Regulatory compliance describes the goal that organisations aspire to achieve in their efforts to ensure that they are aware of and take steps to comply with relevant laws, policies, and regulations

  • Officers

    • Regulatory affairs officers ensure that products such as cosmetics, pharmaceuticals, and veterinary medicines meet legislative requirements and standards.

    • Key duties of the job include: studying scientific and legal documents

    • Ensuring compliance with regulations

  • Role • Development – advice, dossier preparation – quality

    and clinical, product claims, clinical trial. • Licence approval – application / submission,

    compliance, ‘go-between’- business, quality, production, support functions.

    • Post licence – life cycle(drug) management, compliance with limitations, clinical trials, new angles of development

  • Associated roles • Quality control – checking against defined set

    of quality criteria • Quality Assurance - determining whether a product

    or service meets specified requirements. Ensures QMS

    • Regulatory Affairs - handle regulatory matters for companies

  • Business Aim

    • Get the product to market • Keep it safely there as long as possible • Balance business with regulatory and quality • Keep investors happy • Achieve best Manufactures Licence (MIA)

  • Clinical trial error

    • France clinical trial: One person brain-dead and five in hospital after drug testing 'accident' in Rennes

    • Dose should have been 1.25mg, but used up to 100mg. • Insufficient pre clinical data.

  • Medicines Directive • The requirements and procedures for marketing

    authorisation, as well as the rules for monitoring authorised products

    • Additionally, EU legislation provides for common rules for the conduct of clinical trials (to test the safety and efficacy of medicines under controlled conditions) in the EU.

  • Hierarchy of risk 1 A licensed UK medicine 2 An off-label use of a UK licensed medicine 3 An imported product licensed in the country of origin 4 A UK manufactured special made in MHRA- licensed facilities 5 An extemporaneously dispensed medicine 6 An imported product not licensed in the country of origin 7 A non-UK-made unlicensed medicine or food supplement

    Low risk

    Medium risk

    Higher risk

  • Regulated manufacturing centres • Moving technique from essentially research to

    licenced production. • Requires a Quality Management System(QMS). • Must work to GMP. • Inspection body checks compliance against current

    standards. • Generally a risk based approach.

  • Summary of trial regulations - linking the stages

    Marketing Authorisation Centralised licence


    CommercialClinical Trials Phase I, II, III

    Pre- clinical

    Clinical Trials National licence – CTA



    EUTCD/ Medicines Directive activities

    Procurement, donation,


    Unlicensed (hospital exemption, Specials)

    Grafts / transplants

    Processing, preservation, storage, distribution

    Cert of Quality & non-clinical


    GP GMP








  • MHRA view of GMP – Required for all medicinal product manufacture – Regulation:

    • Risk-based inspections – across all GxPs (GMP, GLP, GCP, GSP, GDP) – lab, clinical, storage, distribution.

    • GPvP - Pharmacovigilence – Quality Risk Management (QRM), ICH Q9, principles in Chapter 1

    • evaluation of risk to quality based on scientific knowledge and link to the protection of the patient

  • Guidelines • EudraLex - Volume 4 - Good Manufacturing Practice

    (GMP) guidelines • Contains guidance for the interpretation of the

    principles and guidelines. • Basis for MHRA standards. • Guidance on clinical trial – Investigational medicinal

    product (IMP)

  • General GMP issues – Facilities:

    • Tends to be focus of attention due to capital and running costs – Quality Systems:

    • Main elements: documentation, change control, validation, training, production, QC, batch release, self-inspection, quality incidents (deviations, complaints, recall)

    • may not be given full attention, focus is on facilities / equipment • ‘simple as you can, complex as you must’

    – Annex 13 requirements for IMPs: • Product Specification File • Validation is required for facilities and equipment • Process validation relaxation – focus on safety