Regulation of Clinical Products

Nic RobinsonProduction 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

beings

• 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 been1.25mg, 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.

https://ec.europa.eu/health/human-use/clinical-trials_en

Hierarchy of risk1 A licensed UK medicine2 An off-label use of a UK licensed medicine3 An imported product licensed in the country of origin4 A UK manufactured special made in MHRA-licensed facilities5 An extemporaneously dispensed medicine6 An imported product not licensed in the country of origin7 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 AuthorisationCentralised licence

EMEA

CommercialClinical TrialsPhase I, II, III

Pre-clinical

Clinical TrialsNational licence – CTA

MHRA

Dossier

EUTCD/Medicines Directiveactivities

Procurement, donation,

testing

Unlicensed (hospital exemption, Specials)

Grafts / transplants

Processing, preservation, storage, distribution

Cert of Quality & non-clinical

EMEA

GP GMP

GMP

GMP GPvPGCP(GLP)

(GDP)

GDP

Dossier

GPvP

Dossier

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-critical step(s)

Initial experience HTA and stem cells

• Initial MHRA / HTA inspections• Facility• Storage• Autoclaves and sterility• Process simulation• Cleaning• Learnt from feedback

New CTL bank - Aims

• Develop Cytotoxic T cells as ATMP• Undertaken through SNBTS with grant from MRC.• Wanted cell bank compliant with current regulations /

GMP• Establish on a cost-recovery basis• Set up from 25 HLA-typed donors (from New Zealand)• Treat patients and also enable further safety/efficacy

studies and clinical trials

Bollard, Rooney, Heslop Nature Reviews Oncology Sept 2012

40GyWeekly stimulation with rIL-2+LCLs

4-6 weeks 6-8 weeks6-8.106 cells

Development Phase• Basic theory• Methodology• Possible changes to original trial material• Funding• Project plan• Regulatory requirements• Potential problems• Time frame• Market - treatment

GMP compliance problems• Source of PBMC/MNC.• Source of B958• Source of FCS• Cleanroom• Labelling• Audit trail • Import / export• Infusion of cells – Pharmacovigilence

Particular problems• Lack of specific science.• Selected HLA typed donations • Preferentially blood group ‘O’. • New Zealand law on liability (none)• Links to initial donation (tracking and traceability)• Risk assessment for EBV (Marmoset based master cell bank)• TSE risk from Bovine serum albumin• HLA matching or least mis-match with patients

Validation

Treatment• Male patient - Started 8/10/2012• Weekly infusions of 2.2 x 10*6/Kg • Each infusion was diluted 50%

with 5% albumin and given as bolus

• Patient attended as outpatient• Steady improvement in

physiological signs between infusions – improved concentration and vision

• MRI scan showed mass became non detectable by December 2012

EBV DNA

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

07/09

/2012

8/10//

12

22/10

/2012

25/10

/2012

01/11

/2012

Date

EBV

DNA

(cop

ies

/ml)

EBV DNA

Chart2

07/09/2012

8/10//12

22/10/2012

25/10/2012

01/11/2012

EBV DNA

Date

EBV DNA (copies /ml)

8400

4600

2900

1300

815

Sheet1

DateEBV DNAEBV log

9/7/1284004.1

8/10//1246003.6

10/22/1229003.4

10/25/1213002.9

11/1/128153.1

Sheet1

EBV DNA

Date

EBV DNA (copies /ml)

Sheet2

Sheet3

Br J Haematol. 2014 Nov; 167(3): 402–410Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease

21 months post licence 11 patients had received CTL.8 went into complete remission2 died of disease1 partial response but fatal infection

Licenced Phase

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232001/

Medicinal Products

• The MHRA definition of a medicinal product in The Human Medicines Regulations defines a “medicinal product” as:

• “Any substance or combination of substances presented as having properties for treating or preventing disease in human beings;

• Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis”.

Faecal Microbiota

• Medicines Directive applies to medicinal products either prepared industrially or manufactured by a method involving an industrial process

• Products that are not so produced are not subject to the requirements of the Medicines Directive.

• Faecal Microbiota product is subject to a level processing which would be regarded to be ‘industrially produced’, either by virtue of the batch sizes, the extent of processing and potential use includes supply between legal entities.

• Subject to MHRA inspection

Unlicensed products: Specials

• Company met MHRA and advised to take Specials route.• Manufacturer’s Specials – available for all pharmaceuticals

to supply special clinical need unmet by a licensed product.• Medicinal products to meet special (clinical) need of

patients in response to a bone fide unsolicited order.

– Site inspected for GMP compliance,

– Obtained an ‘MS’ licence.

– Now target IMP

Development• Quality/regulatory advisor and production manager

with appropriate experience.• Background science• Regulatory basis for validation processes• Validation master plan and process validation. • Quality Management System (QMS)• Start process development – lab space, SOP, SLA,

reagents, process optimisation, labels, stability, staff, training etc……….

Regulatory Queries• Facility - environment• Process• Glycerol / cryoprotectant• Donor screening• Traceability• Labelling• Advertising with Specials

Environment• Grade A environment.• Grade D background

The Process

Label Regulation

• Faecal Microbiota (FM250)WARNING - This product may contain infectious agentEnteroBiotix FM250: G2312xx xxxxxxx Split No:xx250ml per bottle contains 50g dose start material (Expiry date:dd/mm/yy)Strength n x109 cfu/ml for lower GI delivery to be used as directed.Contains 10% Glycerol. Store at -80°C (+/- 10°C).

Name of Medical Professional:

Patient Surname:Patient Forename:Patient Date of Birth:EnteroBiotix Ltd, Aberdeen, AB25 2ZW. Tel 01224 690373MHRA Site Code : MS 49464

F112

Labelling - Traceability

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

What do we want to achieve• Wanted a product that

helped patient quality of life• Wanted the personal

satisfaction• Want to make a difference• The company to develop

• Thank you for listening• Interested in being a donor

–donors@enterobiotix.com

Regulation of Clinical ProductsRegulatory AffairsSubstances and MedicinesEarly TransfusionLandsteiner – Blood GroupsTransfusion comes goodThalidomideCellular TherapiesATMPHistorical DriversWhy RegulateStandardsRegulatory ComplianceOfficersRoleAssociated rolesBusiness AimClinical trial errorMedicines DirectiveHierarchy of riskRegulated manufacturing centresSummary of trial regulations - linking the stagesMHRA view of GMPGuidelinesGeneral GMP issuesInitial experience HTA and stem cellsNew CTL bank - AimsSlide Number 28Development PhaseGMP compliance problemsParticular problemsValidationTreatmentSlide Number 34Medicinal ProductsFaecal MicrobiotaUnlicensed products: Specials�DevelopmentRegulatory QueriesEnvironmentSlide Number 41Label RegulationLabelling - TraceabilityRoleWhat do we want to achieveSlide Number 46