General information · Central ECG monitoring (SpaceLabs) on all 145 beds, using wall-mounted and mobile units. Continuous electronic and hard copy ECG recording, arrhythmia detection

Certificate no: GB99/50577

Hammersmith Medicines Research Limited Registered Office: Cumberland Avenue, London, NW10 7EW

Registered in England No 2779946

General information

Hammersmith Medicines Research

www.hmrlondon.com

00 44 20 8961 4130

[email protected]

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.cmi.edu.jm/&ei=S5B1VKTYBtCwsAS0uoK4AQ&bvm=bv.80642063,d.ZGU&psig=AFQjCNF-SlrvDO1Mwi_6s8wSg3cf_It_dA&ust=1417076746566640

mailto:[email protected]

HMR Information (revised June 2016) Page 2 of 36

CONTENTS

1 BACKGROUND INFORMATION 3

1.1 History 3

1.2 Location 3

1.3 What we do 3

1.4 Our facilities and staff 3

1.5 Facilities for volunteers 4

1.6 Our services 4

1.7 Recruitment of healthy and patient volunteers 5

1.8 Writing documents, and applying to the MHRA and ethics committee 6

1.9 Markets and customers 6

1.10 What’s special about us 7

2 SCOPE OF OUR WORK 8

2.1 Our trials 8

2.2 Biotechnology 9

2.3 Pharmacodynamic trials 9

2.4 Types of analysis of drug concentrations 12

2.5 Pharmacokinetic analysis 12

2.6 Special expertise 12

3 OTHER SERVICES 12

3.1 Quality 12

3.2 Data management, statistics and report writing 13

3.3 Pharmacy 13

3.4 Analytical laboratory 14

3.5 Analysis of drug concentrations 14

4 RESUSCITATION FACILITIES 14

APPENDIX 1 Maps to help you find us

APPENDIX 2 Organogram

APPENDIX 3 Curricula vitae of senior staff

APPENDIX 4 Countries we work for

APPENDIX 5 HMR leaflets


1 BACKGROUND INFORMATION

1.1 History We founded Hammersmith Medicines Research (HMR) in January 1993. At first, we were

based in the Department of Clinical Pharmacology, St Bartholomew’s Hospital, London,

EC1. In 1994, we moved to the Central Middlesex Hospital (CMH), London NW10. In

December 2008, we moved again, to our own new premises in Cumberland Avenue,

close to CMH.

1.2 Location HMR is: 2 min from 24/7 urgent care service and the ITU at Central Middlesex Hospital;

close to Park Royal (Piccadilly line) and Hanger Lane (Central line) tube stations; easily

accessible from/to A40, North Circular and M25; and 40 min from London Heathrow

airport. Maps are in Appendix 1.

1.3 What we do We specialise in phase 1 trials of investigational medicinal products (IMPs) for

pharmaceutical and biotechnology companies. We do about 25–30 each year. Since

1993, we have done over 730 trials of IMPs. About one third were trials of the very first

administration of an IMP to humans.

1.4 Our facilities and staff HMR is one of the largest phase1 units in Europe. Our spacious new premises have first-

class facilities for carrying out early trials of IMPs: 145 beds; central monitoring and ECG

telemetry; nurse stations; dedicated special procedure rooms – allergy, endoscopy, sleep;

separate outpatients facility; state-of-the-art laboratory; best-practice pharmacy; offices;

meeting rooms; document storage; equipment storage; training area; IT facilities and

server room; laundry; electronic fob control of all areas; temperature control throughout


the premises; designated rooms for monitors and auditors; industrial kitchen and contract

caterers to cook fresh food daily for volunteers and staff; on-site preparation of controlled

diets for volunteers; 100-seat restaurant for staff and visitors; and parking for 95 cars.

Floor plans are in Appendix 1.

We have over 200 staff – 8 physicians (including two very experienced principal

investigators who between them have done over 1,500 phase1 trials), 35 nurses, and 140

graduates or PhD. A staff organogram is in Appendix 2 and curricula vitae of senior staff

are in Appendix 3.

We can do most types of phase 1 trial. Nowadays many phase 1 trials are large, complex

and demanding, especially first-in-man trials. We have the facilities and experienced staff

to do such trials well and on time. We have an excellent track record in that respect.

1.5 Facilities for volunteers We have outstanding new facilities for the volunteers who take part in our trials:

restaurant-standard food cooked fresh every day; air-conditioned wards; separate toilets

and showers for men and women; computers with wireless internet access; widescreen

TVs, Sky and games consoles; range of DVDs, books, daily newspapers and board

games; large recreation and dining area; secure storage for belongings; and short walk

from underground stations.

1.6 Our services We can provide a full service for almost any kind of phase 1 trial – most of them in

healthy subjects but some in patients – and certain types of early phase 2 trial. Our

services include:

reviewing preclinical data, and the scientific and medical literature, then advising on a trial, or programme of trials, in humans;


writing an investigator’s brochure;

writing an IMP dossier;

writing a trial protocol;

preparing an application for a Clinical Trial Authorisation (CTA), to the Medicines and Healthcare products Regulatory Agency (MHRA);

developing methods of testing the effects of the IMP;

writing, designing and printing the CRF;

writing an information leaflet and consent form;

preparing the application to the ethics committee;

recruiting and screening volunteers;

doing the trial according to the protocol;

importing, preparing and/or repackaging, and releasing (by a Qualified Person – we have 4 of them) IMPs in our on-site pharmacy, in accordance with our MIA(IMP);

analysing blood, urine and other bodily fluids in our on-site laboratory;

arranging assays of IMPs;

monitoring and pharmacovigilance;

doing data management and statistical analysis;

doing pharmacokinetic analysis;

generating an integrated clinical, statistical and pharmacokinetic report; and

preparing abstracts and manuscripts for presentation and publication.

1.7 Recruitment of healthy and patient volunteers We recruit subjects from our large database (>30,000) of volunteers, from our website

(www.londontrials.com) for recruiting volunteers, and by ethics-committee-approved

advertisements in local or national newspapers and journals. In 2002, we set up an

http://www.londontrials.com/


internet-based system (www.TOPS.org.UK) – to prevent subjects from taking part in trials

too often – which we handed over to the UK Health Research Authority to run in 2013.

MHRA Supplementary Accreditation of a phase 1 unit, and ethics committee approval of a

study, are now both conditional on proper and regular use of TOPS.

We can recruit young subjects as well as postmenopausal women or elderly subjects.

We have panels of patients with conditions such as asthma, allergic rhinitis, herpes virus

infection, obesity, benign prostatic hypertrophy, diabetes, male erectile dysfunction, and

migraine. We liaise with physicians within the Central Middlesex Hospital, other hospitals

or patient support groups, to recruit patients for proof-of-principle trials.

1.8 Writing documents, and applying to the MHRA and ethics committee We can write all the documents required to start a study: protocol, case report forms,

investigator’s brochure, IMP dossier, MHRA application for a CTA, and ethics committee

application, including the information and consent form (ICF). Sponsors may choose to

write some of those documents, but we always write the ethics committee application and

ICF. Our clinical project managers and their line manager write documents, and our

senior physicians review them. We revise thoroughly all documents that we write, to

ensure that they are accurate and well written. Plain English Campaign has approved the

standard parts of our ICF. Also, ethics committees and sponsors compliment us on the

clarity of our writing.

We use various UK ethics committees. Which one we use for a specific study depends

on the sponsor’s timelines. But, we mainly use our local committee – London-Brent

Ethics Committee – which is based at Northwick Park Hospital.

1.9 Markets and customers We have done studies for companies of all sizes from many countries: Australia, Austria,

Belgium, Canada, China, Denmark, Finland, France, Germany, Holland, Hungary, Ireland,

Israel, Italy, Japan, Norway, South Korea, Spain, Sweden, Switzerland, UK and USA


(Appendix 4). We have worked for most of the big international pharmaceutical and

biotechnology companies. About one-third of our trials come from the UK, about one-

third from the rest of Europe, and one-third from countries outside Europe, mainly the

USA and Japan.

1.10 What’s special about us Some of the features that help distinguish us from other phase1 units are:

Phase 1 Supplementary Accreditation by the Medicines and Healthcare products

Regulatory Agency (MHRA). HMR was the first to get this accreditation (April 2008),

which recognises our ability to do trials of all types of IMPs – including ones that

affect the immune system and require review by the MHRA Expert Advisory Group –

and to manage acute medical emergencies.

MHRA Manufacturer’s Authorisation [MIA(IMP) No 15140] to import, assemble,

package and label non-sterile, sterile and radiopharmaceutical (pending) IMPs.

Again, HMR was the first phase 1 unit to get this licence (May 2004).

ISO 9001 quality management system.

Laboratory accreditation by the College of American Pathologists.

Pharmacy registration by the Royal Pharmaceutical Society.

Environment Agency licence to store and dispose of radioactivity.

Home Office licence to keep controlled drugs.

Resuscitation Council approval to train staff in immediate and basic life support.

Resuscitation Committee, Resuscitation Team (24/7 cover) and Resident Medical

Officer in compliance with Resuscitation (UK) Council guidelines.

Thorough knowledge and understanding of the regulations controlling phase 1 trials

in the EU: our staff are members of MHRA and National Research Ethics Service

committees, and revised the ABPI guidelines for phase1 trials.

University-based course in GCP training.

Sponsors who want to place or discuss new studies have direct access to a clinical

pharmacologist. We do not have a business development department.


1.11 Training All staff are trained according to their needs. In particular, ward staff are trained in Good

Clinical Practice (GCP) and pharmacy staff in Good Manufacturing Practice (GMP). We

have set up our own 18-month, university-based training course in GCP for ward staff.

Successful candidates receive a Certificate in Professional and Personal Development

(CPPD) for (GCP) from the University of West London.

2 SCOPE OF OUR WORK

2.1 Our trials First administration to man – single and repeat dose

Safety and tolerability

Pharmacokinetics

Pharmacodynamics – using established or new methods

Drug interactions – drug/drug; drug/food; drug/alcohol


Metabolic trials – 'cold' and radiolabelled

Microdosing

2.2 Biotechnology About 20% of our studies involve biotechnology (biological) IMPs. We have studied novel

proteins, peptides, cytokines, monoclonal antibodies, small interfering RNA, spiegelmers,

biosimilars, biobetters, and vaccines, including those made from genetically modified

micro-organisms. The UK Health & Safety Executive has approved our premises for trials

with genetically modified microorganisms, types 1 and 2.

2.3 Pharmacodynamic trials We have extensive experience of measuring actions of drugs:

2.3.1 Cardiovascular

Central ECG monitoring (SpaceLabs) on all 145 beds, using wall-mounted and mobile units. Continuous electronic and hard copy ECG recording, arrhythmia detection.

Telemetry (SpaceLabs): ECG monitoring of 16 channels throughout premises

12-lead ECG

High-speed, high-gain surface ECG

Manual overread of ECG

24-h ambulatory ECG (‘Holter’) monitoring

Ambulatory BP monitoring

Exercise ECG

Passive tilt testing

Systolic time intervals

Impedance cardiography

Doppler aortic velography

Laser Doppler flowmetry

Forearm blood flow

Hand venous reflex

Fingertip photoplethysmography

Catecholamine and prostanoid agonist/antagonist trials


2.3.2 Central nervous

Psychomotor testing

Coordination tests

Cognitive function assessment

Scopolamine model of dementia

5-HT1A receptor-mediated function tests

Positron emission tomography (with Imanova, Hammersmith Hospital)

Analgesia assessment o Dental pulp tester o Cold pressor test

Body sway

Saliva flow rate

EEG

fMRI (with Imanova or Institute of Psychiatry)

Polysomnography (analysis of recordings by the Department of Neuropsychopharmacology, Imperial College)

2.3.3 Dermatological

Transdermal bioavailability

Cutaneous irritancy and sensitisation

Extracellular fluid pharmacokinetics by suction blister

Local anaesthetic testing

Histamine, 5-HT or substance P intradermal tests

UV erythema challenge tests

Allergen tests

2.3.4 Gastro-intestinal

Upper (esophagogastroduodenoscopy) and lower GI endoscopy (flexible sigmoidoscopy and colonoscopy) by Kai Chan MD FRCS, who endoscopes regularly at Stoke Mandeville and Wycombe Hospitals, UK.

Ambulatory pH monitoring

Pentagastrin- or histamine-stimulated acid secretion

GI transit time

Intragastric drug infusion

Intrajejunal drug infusion

Faecal red blood cell loss using 51Cr-labelled red cells

Gastric emptying using 99mTc-labelled meal, with o Caesium iodide portable detector o Gamma camera

Gastric emptying using paracetamol kinetics

Gall bladder scintigraphy using 99mTc-HIDA (with Radiological Sciences Unit, Hammersmith Hospital)

HMR Information (revised April 2015) Page 11 of 36

2.3.5 Haematological

Bleeding time o Simplate o Ivy

Platelet aggregometry

Red blood cell deformability

PTA100

Coagulation trials

Cytokine assay

Assay of red and white blood cell precursors

Flow cytometry (FACS)

2.3.6 Ocular

Intraocular pressure by non-contact or applanation tonometry

Slit lamp examination

Ocular analgesia

Static pupillometry: photographic, twin hole, or infrared video methods

Dynamic pupillometry: infrared video

2.3.7 Renal

51Cr - EDTA method for glomerular filtration rate

125I - Hippuran method for effective renal plasma flow

Renin and angiotensin assay

Nephrotoxicity detection o Urinary transferrin, microalbumin

and 1-microglobulin o Urinary enzyme assay

2.3.8 Respiratory

Lung volumes by helium dilution

CO transfer factor

Peak expiratory flow rate

Vitalograph Gold Standard spirometry

Computer-assisted spirometry

Minute volume

Pulse oximetry on all beds

End-tidal pCO2

Transcutaneous pO2

Bronchoscopy, broncho-alveolar lavage and bronchial biopsy


Histamine, methacholine and AMP challenge

Allergen challenge

Exhaled NO

Sputum induction and cell count

Acoustic rhinometry

Body plethysmography

Oscillometry

2.4 Types of analysis of drug concentrations

Gas chromatography

HPLC

EMIT

LCMS-MS

Radioimmunoassay

Drugs of abuse

2.5 Pharmacokinetic analysis

WinNonlin

Derivation of all parameters

Kinetic modelling

2.6 Special expertise We have special expertise in some types of phase 1 trial, such as positron emission

tomography (PET); allergy; thorough QT; drug-drug interaction; flow cytometry; gastric

function; cardiovascular; ‘bridging’ studies in Japanese subjects; sleep; and radiolabelled.

For example, we have done over 40 PET and 40 allergy studies, mainly asthma. We

have separate leaflets for some of those types of trial (Appendix 5).

3 OTHER SERVICES

3.1 Quality We have had ISO 9001 accreditation for our quality management system since 1999. It’s

based on GCP, GMP and the EU Clinical Trials Directive, and comprises a quality manual,

22 quality system procedures, over 800 standard operating procedures, and many forms.

We audit all stages of our trials, from protocol design to trial report via MHRA and ethics

HMR Information (June 2016) Page 13 of 36

committee submissions and clinical work. We describe our quality services in a separate

brochure.

3.2 Data management, statistics and report writing We manage, analyse and report data generated within or outside the company. We use

ClinPlus, which is a SAS-based data management system, CDISC, ADAM and eCRF

(Medrio). SAS is our main software for statistical analyses. We prepare trial reports in

accord with ICH Guidelines and the client’s standard operating procedures. Our QA

function audits from source data to statistical output and trial report. We describe our data

management, statistics, and medical writing, in a separate brochure.

3.3 Pharmacy Our GMP-compliant pharmacy was designed, commissioned and operates in compliance

with MHRA best practice. We can import, prepare and/or repackage non-sterile and sterile

IMPs not only for our own phase1 trials but also for trials of other CROs and of academia.

We have a Manufacturer’s Authorisation for IMPs [MIA(IMP)], and 4 Qualified Persons to

release batches of IMP. We use a Technical Agreement with sponsors for whom we do

pharmacy work.

We can also prepare non-IMPs, such as AMP, methacholine and allergen as inhalation

challenge agents for asthma trials.

We have a separate radiopharmacy. Our premises are licensed for storing and disposing

of radioactivity, our Chief Medical Adviser has done over 40 phase 1 trials of radiolabelled

IMPs, including microdoses, and we have staff trained in radiopharmacy work. So, we

are capable of doing most types of phase 1 trial involving radiolabelled molecules.


3.4 Analytical laboratory We have an on-site, state-of-the-art, central laboratory, which is accredited by the College

of American Pathologists. The main features are: pneumatic sample transmission from

ward to laboratory; automated sample processing and storage (Beckman-Coulter robotic

system); walk-in 4°C and –20°C cold rooms; separate rooms for platelet function tests, cell

stimulation and separation, flow cytometry, and radioimmunoassay; safety pathology;

biomarkers; and laboratory management system (GLIMS). Also we have a stomacher,

oxidiser and liquid scintillation counter for radiolabelled studies, and uHPLC.

3.5 Analysis of drug concentrations We collaborate with the Analytical Unit, St George’s Hospital, London, a GLP-registered

laboratory with a full range of analytical methods for assay of drugs by the appropriate

method, such as HPLC or LC-MS/MS. Alternatively, we liaise with a laboratory of the

sponsor’s choice.

4 RESUSCITATION FACILITIES

We have full facilities for cardiopulmonary resuscitation, including cardiac defibrillation,

external pacing and airway intervention. We have set up our own Resuscitation

Committee, Resuscitation Team and Resident Medical Officer, in accordance with

Resuscitation (UK) Council guidelines. Team members each carry a pager, which when

activated identifies the precise location in the building of the emergency. Our physicians

are trained in advanced life support, and our nurses and some research technicians are

trained in immediate life support. Other ward staff are trained in basic life support. The

Resuscitation Team comprises 1 ALS-trained physician, 2 ILS-trained staff and 2 BLS-

trained staff, who are available 24/7. If necessary, we can transfer a patient by ambulance

to the Central Middlesex Hospital.


5 HMR ACHIEVEMENTS

1995: Rubicon Award for New Business of the Year

1998: The Queen’s Award for Export Achievement

1998: Member of the Association of the British Pharmaceutical Industry (ABPI)

1999: Rubicon Award for Growing Business of the Year

1999: ISO 9001 accreditation

1999: UK Fast Track 100 company (one of the 100 fastest growing UK companies)

2001: Corporate member Plain English Campaign

2002: The Queen’s Awards for Enterprise: International Trade

2002: Laboratory accreditation by the College of American Pathologists

2002: Setting up TOPS (The Over-volunteering Prevention System), a registered charity

2002: Setting up our university-based training course in GCP for ward staff

2002: Setting up MSc course in early drug development, Barts & London Medical Colleges

2003: Pharmacy registration by the Royal Pharmaceutical Society

2004: MHRA Manufacturer’s Authorisation for IMPs

2004: National Training Award for our GCP training course

2006: Setting up Trio Medicines Ltd to develop potential new medicines

2006: Giving evidence to the Expert Scientific Group enquiry into the TGN1412 disaster

2007: Revising the ABPI guidelines for phase 1 clinical trials

2008: MHRA Phase1 Supplementary Accreditation

2010: CIR Accreditation

2013: Handing over TOPS to the Health Research Authority

2014: HMR identified among ‘1000 Companies to inspire Britain’ by the London Stock

Exchange Group


Appendix 1

Map and floor plans


Location map

HMR floor plans

HMR floor plans

Ground:

outpatients, archive, reception

HMR floor plans


First south:

offices, meeting rooms

Second north:

restaurant, kitchen

Second south:

ward B

Third north:

pharmacy, laboratory

Third south:

ward A, clinical procedures

First north:

ward C


Appendix 2

Staff organograms


Laboratory

Executive Chairman

QP GMP

Compliance

Ward Teams

Technical

division

Facilities

Finance

Clinical

Resource

Management

Project

Management

Clinical

division

Ward

Management

Corporate

division

Human

Resources

Hotel Services

Quality AssurancePhysicians

Chief Medical Adviser

Projects

divisionCompliance

Director of

Pharmacy

Statistics & Data

Management

Special

Projects (TRIO)

Management

Accounts

Payroll

Training

Project Finance

PA to Chairman

Finance Director

and Company Secretary

Recruitment

and Screening

Equipment

PharmacokineticsContracts

Information

Technology

Pharmacy

Production Systems Validation

Monitoring

Enquiries

Divisional functions


Malcolm Boyce

Medical Director

Recruitment &

Screening Manager

2 Deputy Team

Leaders

Yellow

Team Leader

2 Senior Research

Physician & PIs

2 Research Physicians

2 Screening Physician

Sarah Boulton

Ward Manager

4 Research Nurses

9 Research

Technicians

2 Quality

Coordinators

Clinical Equipment

Specialist

6 Resident

Medical

Officers

Steve Warrington

Chief Medical Adviser

7 Recruitment &

Screening Associates

Japanese trials

15 Recruitment &

Screening Technicians

3 Bank Recruitment &

Screening Technicians

3 Quality Coordinators

Indigo

Team Leader

Orange

Team Leader &

Clinical Nurse

Specialist

Violet

Team Leader &

Clinical Nurse

Specialist

3 Night

Coordinators

Deputy Team

Leader

Deputy Team

Leader

2 Research Nurses

9 Research

Technicians


Deputy Team

Leader

4 Research Nurses

8 Research

Technicians


2 Research Nurses

9 Research

Technicians

1 Bank Research

Technician


Deputy Team

Leader

4 Research Nurses/

Bank Research Nurses

7 Research Associates

4 Research Technician


Deputy Team

Leader

Red

Team Leader Pink

Team Leader

Deputy Team

Leader

4 Research Nurses

8 Research

Technicians

2 Quality

Coordinators

Blue (Night)

Team Leader

1 Research

Nurse

Green Team Leader

Japanese

Recruitment Team

Leader & Sponsor

Liaison Manager

Medical PhysicistSenior Clinical Resources

Manager

Clinical Resources

Manager

Clinical division


Kate Darwin

Director of Scientific Services

Steve Warrington

Director of the HMR Laboratory

Juan Naveda

Director of Laboratory

Services

4 Senior

Biomedical

Scientists

Kirsten Heukelbach

Head of Pharmacy

Production

2 Senior Pharmacy

Technicians and Trio

Technicians

Trainee Pharmacy

Technician

Aseptic

Compounding

Technician

Pharmacy Assistant

Senior

Pharmacist

2 Student

Biomedical

Scientists

Radio-

pharmacy

Technician

4 Laboratory Assistants

Pharmacy

Team

Leader

8 Biomedical Scientists

External Consultant

Pharmacokineticist

Senior

Data Entry

Operator

Principal SAS

Programmer

Toni Mitchell

Director of Statistics &

Data Management

Data

Management

Team Leader

Senior Data Manager

2 Data Managers

4 Assistant Data

Managers

4 Trainee Data

Managers

SAS

Programmer

2 Assistant SAS

Programmers

Assistant Data

Analyst

Data Management

Deputy Team Leader

And EDC Coordinator

Senior

Statistician

Statistician

2 Assistant

Statisticians

Chief

Biomedical

Scientist

GLIMS

Administrator

Chemical

Hygiene

Officer

10

Bank Data Entry

Operators

Amanda Peter

Director of Pharmacy

Laboratory

Quality

Officer

Analytical

Chemist

Laboratory

Project

Manager

Technical division


Sarah Mole

Head of Clinical

Science

Lead Auditor

4 Quality

Research

Associates and

Trial Monitors

Trial Monitor

Quality Manager

and Trial Monitor

Supervisor

Senior

Archivist

Senior QA

Assistant

QA

Pharmacist

2 Senior Clinical

Project Managers

7 Clinical Project

Managers

Assistant Clinical

Project Manager

(Vacant)

Head of Quality

Services

Malcolm Boyce

Quality System Manager

Kate Darwin

Director of Scientific Services

Narendra Patel

Systems Validation

Manager and

GLIMS Specialist

Senior Principal

Scientist

Principal

Scientist

Clinical Project

Management

Team Leader

QPs

Kate Darwin

Director of

Scientific Services

TRIO Team

Leader

Amanda Peter

Director of

Pharmacy

Malcolm Boyce

Executive Chairman

Senior Principal

Scientist

Projects

Scientist

External

Systems Validation

Consultant

IT Validation

SpecialistMedical Science

Liaison

Sally Dowen

Head of Medical

Writing

Projects and compliance divisions


John Kirk

IT Manager

Kevin O’Brien

Financial Director

Accounts

Assistant

(Student

Placement) 2 Senior Support

Analysts

Trainee

Management

Accountant

James Gartside

Staff Training

Manager

Clinical

Nurse

Trainer

Stephen Smith

Director of Corporate

Services

Reception

Manager

Head of Hotel

Services

4 Housekeepers

1 Receptionist/

Administrator

Senior Projects

Manager

Financial

Administrator

Deputy Head of

Hotel Services

Projects

Manager

Payroll &

Pensions Officer

and Trainee

Accountant

Finance and corporate divisions


Appendix 3

Curricula vitae of senior staff

Curriculum vitae

Malcolm Boyce Executive Chairman


1. Qualifications

2007 FBPhS UK 2004 QP MHRA, London 2003 FRQA BARQA 2003 FCIPD London 2001 FCMI London 1999 FRCP RCP, London 1990 FFPM RCP, London 1988 MFPM RCP, London 1972 MRCP RCP, UK 1969 MB ChB Bristol University 1966 BSc Physiology Bristol University

2. Present appointments

2012–present: Medical Director & Executive Chairman, HMR 1999–present: Manager, ISO 9001 Quality Management System, HMR 2004–present: Holder of Manufacturer’s Authorisation for IMPs, and Qualified Person

for IMPs, HMR 2006–present: Chief Executive of TRIO Medicines Limited, a wholly owned subsidiary

of HMR 1993–present: Honorary Senior Lecturer in Clinical Pharmacology, Department of

Clinical Pharmacology, St Bartholomew’s Hospital Medical College, London

3. Previous appointments

1969–1975: Various NHS/academic posts up to Senior Registrar/Lecturer in general medicine, psychiatry and paediatrics, Bath, Bristol and London hospitals

1975–1992: Clinical pharmacologist or pharmaceutical physician with Beecham (now GSK), SmithKline & French (now GSK), ICI (now AstraZeneca) and Marion Merrel Dow (now Aventis)

1993–2012: Managing and Clinical Director, HMR

4. Current teaching and training

Course organiser and teacher of MSc on early drug development, Queen Mary College. MSc in Pharmaceutical Medicine, University of Surrey: module on ethics committees, and MSc supervisor. Course organiser of the University of West London Certificate in Practical Clinical Pharmacology.

Curriculum vitae

Malcolm Boyce Executive Chairman


Senior Speciality Adviser on Higher Medical Training, Faculty of Pharmaceutical Medicine, Royal College of Physicians. BARQA tutor for courses on GCP, GMP and EU Clinical Trials Directive.

5. Experience of clinical trials

Coordinator or investigator for numerous clinical trials across all phases of drug development in Europe and the USA; principal investigator for over 700 phase 1 clinical trials.

6. Membership of committees

MHRA GCP Consultative Committee; NRES Phase 1 Advisory Group; Faculty of Pharmaceutical Medicine: Advisory Committee; Diploma/Certificate in Human Pharmacology; Member of the Founding Committee of the Faculty of Medical Leadership and Management; Chairman of the Clinical Pharmacology Special Interests Group of the Faculty of Pharmaceutical Medicine; The National Research Ethics Advisors’ Panel; London Research Ethics Committee, 1997–2007; Association for Human Pharmacology in the Pharmaceutical Industry, 2002–2012.

7. Learned societies

Member of 16 learned societies including: British Pharmacological Society American Association of Clinical Pharmacology and Therapeutics British Society of Allergy and Clinical Immunology British Association for Psychopharmacology

8. Publications and reports

Over 130 papers and articles on clinical pharmacology, drug development and research ethics. Numerous company reports and reviews. Various applications and expert reports for drug regulatory authorities in Europe and the USA.

Curriculum vitae

Steve Warrington Chief Medical Adviser


1. Qualifications 2004 QP Qualified Person 1991 FRCP Royal College of Physicians, London 1990 FFPM Royal College of Physicians, London 1990 FRCP Royal College of Physicians, Edinburgh 1984 MD Cambridge University 1974 MRCP (UK) Royal College of Physicians, London 1972 MA Cambridge University 1971 MB BChir Cambridge University 1968 BA (1st class) Cambridge University

2. Present appointment 2012–present Chief Medical Adviser, HMR 1987–present Honorary Senior Lecturer in Clinical Pharmacology St Bartholomew’s Hospital Medical College

3. Previous appointments 1993–2012 Medical Director, HMR 1981–1993 Medical Director, Charterhouse Clinical Research Unit 1977–1981 Lecturer in Clinical Pharmacology, St Bartholomew’s Hospital

Medical College, and Honorary Senior Registrar in General Medicine and Clinical Pharmacology, St Bartholomew’s Hospital

1975–1977 Research Fellow in Cardiology and Clinical Pharmacology St Bartholomew’s Hospital 1971–1975 Various NHS posts in general medicine and cardiology

4. Current teaching and training Course organiser and teacher of MSc on early drug development, Queen Mary College. Course organiser and teacher of the University of West London Certificate in Practical Clinical Pharmacology. Examiner for the Diploma in Pharmaceutical Medicine and the Diploma in Human Pharmacology, Faculty of Pharmaceutical Medicine, Royal College of Physicians. Teacher of courses on GCP and the EU Clinical Trials Directive.

5. Experience of clinical trials Principal investigator for over 1,000 phase 1 or phase 2 trials for pharmaceutical companies from many countries worldwide.

6. Membership of committees Clinical Section of the British Pharmacological Society

7. Publications and reports 151 original papers and reviews on general and cardiovascular clinical pharmacology. MD thesis on measuring cardiovascular effects of drugs by non-invasive methods. Numerous study reports.

Curriculum vitae

Atholl Johnston Pharmacokineticist


1. Qualifications

1999 MSc in Applied Statistics, Sheffield Hallam University, Sheffield, UK

1998 Membership of the Royal College of Pathologists

1993 PhD Pharmacology, University of London, Medical College of St Bartholomew’s Hospital, London, UK

1975 BSc honours, 2.1, Biochemistry (Toxicology), University of Surrey, Guildford, Surrey, UK

2. Present appointment

1998–present Professor since 2002, Senior Lecturer previously Clinical Pharmacology, St Bartholomew’s and Royal London School of Medicine and Dentistry

1993–present Consultant Pharmacokineticist and Statistician, HMR

3. Previous appointments

1993–1998 Senior Research Fellow Clinical Pharmacology, St Bartholomew’s and Royal London School of Medicine and Dentistry

1985–1993 Research Fellow Clinical Pharmacology, St Bartholomew’s and Royal London School of Medicine and Dentistry

1977–1985 Research Assistant to Dr John Hamer Clinical Pharmacology, St Bartholomew’s and Royal London School of Medicine and Dentistry

1975–1977 Toxicologist Department of Forensic Medicine & Toxicology, Charing Cross Medical School, London

4. Learned Societies and Publications

Membership of 12 learned societies including the British Pharmacological Society, and Society of Pharmaceutical Medicine. Over 170 papers and reviews in peer-reviewed journals, mainly on pharmacokinetic aspects of clinical pharmacology.

Curriculum vitae

Amanda Peter Director of Pharmacy


1. Qualifications 1980–1984 BPharm (Pharmacy Degree)

University of the Witwatersrand, South Africa 1998–2003 MSc Medicine

University of the Witwatersrand, South Africa 2000–2001 Overseas Pharmacist Transfer Exams

Sunderland University Aug 2001 MRPharmS (2053143) 2003–2004 GradDipLaw (Eng) equivalent to LLB

University of Westminster London 2004 Transitional QP (42217)

2. Present appointment 2013–present Director of Pharmacy

3. Previous appointments 2004–2012 Associate Director of Regulatory Affairs

& Pharmaceutical Sciences and QP Quintiles Drug Research Unit London

2003–2004 Clinical Trials Bank Pharmacist Quintiles Drug Research Unit

2002–2003 Clinical/Manufacturing Pharmacist (Oncology Clinical Trials) Mount Vernon and London Bridge Hospitals

2000–2002 Boots the Chemist Oxford Street London

1997–2000 Regulatory Affairs Manager/Managing Director Apotex Pharmaceutical Company SA

Curriculum vitae

Toni Mitchell Director of Statistics and

Data Management


1. Qualifications 2009 Professional Diploma in Management, with Merit

Open University 1996 Chartered Statistician

Royal Statistical Society 1990–1991 MSc Statistics with Applications in Medicine

University of Southampton 1987–1990 BSc Chemistry and Mathematics, First Class

Hull University

2. Present appointment 2013–present Director of Statistics and Data Management

3. Previous appointments 2010–2013 Head of Statistics & Data Management, HMR 2006–2010 Director, Business Analysis & Development

GlaxoSmithKline, Harlow 1998–2006 Manager, Clinical Pharmacology Statistics & Data Management

GlaxoSmithKline, Harlow 1996–1998 Senior Statistician

Glaxo Wellcome, Greenford 1996 Biostatistician, HMR 1991–1996 Statistician/Senior Statistician

Fisons Pharmaceuticals, Loughborough

4. Training 2011 Introduction to Phoenix WinNonlin v6.2

Pharsight, London 2009 CDISC Overview

GlaxoSmithKline, Harlow 2007 R&D Enhance Lean Sigma Expert

GlaxoSmithKline, Harlow 2004–05 Via Leadership Programme

GlaxoSmithKline, North Mymms 1998 Designing Bioequivalence Studies to Reflect Latest Regulatory Trends

ECPI, London 1998 Optimising the Role of Population Pharmacokinetics in Drug

Development. ECPI, London 1998 Good Clinical Practice

Glaxo Wellcome, Greenford

Curriculum vitae

Toni Mitchell Director of Statistics and

Data Management


1997 Categorical Data Analysis Glaxo Wellcome, Greenford

1996 Bioavailability and Bioequivalence Studies PSI, London

1994 Introduction to Pharmacokinetics Rostrum, London

1993 Random Effects Analysis of Clinical Trials Using PROC MIXED in SAS, University of Edinburgh, Edinburgh

1992 Using SAS in the Pharmaceutical Industry Statistical Services Centre, Reading

1992 Introduction to SAS & Statistics in SAS SPS, Loughborough

Curriculum vitae

Kate Darwin Director of Scientific Services

HMR Information (revised April 2015) Page 33 of 36

1. Qualifications 1992–1996 DPhil Medical Microbiology

Oxford University Department of Paediatrics 1988–1992 BA (Hons) in Biochemistry 2:1

University College, Oxford

2. Present appointment 2014–present: Director of Scientific Services, HMR

3. Previous appointments 2005–2013: Director of Clinical Science, HMR 2000–2005: Head of Quality Services and Medical Writing, HMR 1998–2000: Quality System Administrator and Medical Writer, HMR 1996–1998: Post-doctoral Research Assistant

Department of Academic Paediatrics, Imperial College, London

4. Experience of clinical trials and quality systems Key role in designing, writing, reviewing, implementing and maintaining the ISO 9001-compliant quality system of HMR, which has over 800 standard operating procedures, and has been assessed annually since 1999 without any critical findings. Coordinated expansion of system to include analytical laboratory in 2002 and GMP-compliant pharmacy in 2004. Organised and took part in major review of the system in line with EU Clinical Trials Directive. Managed a team of 6 auditors, 7 quality control officers and an archivist. Ensured compliance with GCP, GMP, EU Clinical Trials Directive and ISO 9001 at all stages of early phase clinical trials, from protocol design to data management, reporting and archiving. Oversaw audits of systems, facilities, subcontractors and validation of computerised systems. Participated in over 60 audits by the pharmaceutical industry, and MHRA inspections for GCP and GMP: no critical findings. From 2005 to present, head of Projects Division responsible for project management, protocols and amendments, information and consent forms, ethics and CTA applications, and clinical study reports. Managing templates, and ensuring compliance of company documents with regulatory requirements. Ensuring procedures are compatible with the NRES standard operating procedures and GAfREC. From 2014 to present, head of Technical Division responsible for the laboratory, pharmacy, data management and statistics.

5. Membership MRQA, MICR

6. Publications and reports Chapter on GCP in The Textbook of Pharmaceutical Medicine. 11 publications on microbiology and clinical pharmacology. Numerous clinical trial reports, and reports on company performance for ISO 9001 management review.


Appendix 4

Countries we work for


Phase I–II studies (n=730) done during 1993–2016*

17%

6%

12%

5%

21%

17%

5%

6%

21%

12%

38%

1%

38%

12%

* Up to June 2016


Appendix 5

HMR leaflets


Allergy studies

Advances in the understanding of the pathophysiology of the immune response have led to the discovery of many new molecules that need testing in patients with allergic disease. We have tested over 40 such molecules, in patients with either asthma or rhinitis. We have a large database of such patients and substantial experience of research procedures, such as:

wheal and flare response;

nasal challenge and washings;

nasal and respiratory peak flow rate;

acoustic rhinometry;

exhaled nitric oxide;

several types of spirometry;

bronchio-alveolar lavage and bronchial biopsy;

sputum induction by hypertonic saline inhalation;

bronchial challenge with allergen, AMP, histamine or methacholine;

sputum and nasal washings, processed for cells, proteins and cytokines;

lung function tests, such as transfer factor by CO single-breath method, total lung capacity by helium dilution and flow loops, body plethysmography, oscillometry; and

flow cytometry of whole blood for specific cell populations. We have tested a wide range of new molecules, including:

IL-5 monoclonal antibody;

recombitant IL-12;

antisense: adenosine A1 receptors;

integrin VLA-4 (41) antagonists;

leukotriene antagonist;

PDE4 antagonists;

‘soft’ steroids;

mast cell stabiliser;

IL-4 antagonist;

mast-cell tryptase / trypsin antagonist; and

5-lipoxygenase-activating protein inhibitor (FLAP inhibitor)

kinase inhibitors

Montelukast inhibits the early and late responses to allergen inhalation in mild to moderate asthma (mean & SD; n=13)

Time (h) after challenge

placebo

FEV1 (L)

montelukast

We can provide a full service from design through to report writing for a ‘proof-of-principle’ study of most types of new molecule in patients with asthma or rhinitis. Our track record shows that we can complete these demanding and complex studies to a high standard and on time. We have close links with other units with whom we collaborate on large studies.

Some of our publications

1. Bryan S, O’Connor B, Matti S, Leckie M, Kananbar V, Khan J, Warrington S, Renzetti L, Rames A, Bock J,

Boyce M, Hansel T, Holgate S, Barnes P. Effects of recombinant human interleukin-12 on eosinophils, airway

hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356: 21492153.

2. Carey W, Warrington S, Boyce M, Luria X. Inhibition of the histamine wheal by ebastine compared with cetirizine,

fexofenadine and loratidine at steady state. Drugs Exp Clin. Res 2002; 28: 243–247.

3. Erin E, Leaker B, Zacharasiewicz A, Higgins L, Jose P, Williams T, Boyce M, de Boer P, Durham S, Barnes P,

Hansel T. Single-dose topical corticosteroid inhibits IL-5 and IL-13 levels in nasal lavage following grass pollen

challenge. Allergy 2005; 60: 15241529.

4. Norris V, Choong L, Tan D, Corden Z, Boyce M, Arshad H, Holgate S, O’Connor B, Millet S, Miller B, Rohatagi S,

Kirkesselli S. Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with

asthma. J Allergy Clin Immunol 2005; 116: 761767.

For more information, contact:

Malcolm Boyce Hammersmith Medicines Research [email protected] Cumberland Avenue 020 8961 4130 London NW10 7EW



Bridging studies

Since 1993, we’ve done many studies in healthy Caucasians for Japanese companies, large and small. Since 2002, we’ve also done ‘bridging’ studies in healthy Japanese subjects, to compare results with those from Caucasians. We’ve even done three studies to compare Caucasians, Japanese, Koreans and Chinese.

About 65,000 Japanese people live in the UK. That’s enough to enable us to do bridging studies in a timely manner. The largest Japanese community in London is close to HMR. Our volunteers have Japanese parents and grandparents, and have lived outside Japan for less than 5 years.

Our dedicated team of 20 bilingual Japanese nurses and support staff have substantial experience of bridging studies. They recruit suitable subjects, translate trial documents and help do the studies. We’ve done 25 bridging studies including:

bioequivalence studies of new products not yet marketed in Japan;

studies that can’t be done in Japan, such as a study of an opioid;

‘add-on’ cohorts of Japanese subjects in large, complex, first-in-man single- and repeat-dose trials in Caucasians;

studies of biological products, including monoclonal antibodies and siRNA;

studies in Japanese poor and extensive metabolisers; and

PET studies in Japanese subjects.

Those studies have helped sponsors satisfy Japanese regulatory authority requirements.

Central monitoring and ECG

telemetry on all beds


We have spacious new premises with 145 beds, 24-h resuscitation team, CAP-accredited laboratory, GMP pharmacy and radiopharmacy with aseptic suites, and MHRA Supplementary Accreditation. There are separate facilities with TV room, computer games, DVDs, comics and books for Japanese bridging studies.

References

1. ICH 5. Guideline on ethnic factors in acceptance of foreign data. 1997

2. Kodama Y, Saito K, Ono S et al. Human pharmacology studies with biomarkers for new drug applications in Japan. Drugs R D 2005; 6: 21–34.

3. Chow S, Shao J, Hu O. Assessing sensitivity and similarity in bridging studies. J Biopharmaceutical Statistics 2002; 12: 385-400.

4. Lister N, Warrington S, Boyce M et al. The pharmacokinetics, safety and tolerability of ascending doses of sublingual fentanyl (KW-2246) in Japanese subjects, with and without naltrexone. J Clin Pharmacol 2011; 51: 1195–1204.

5. Small D et al. Pharmacokinetics and pharmacodynamics of prasugrel in healthy Japanese, Chinese, Korean and Caucasian subjects. Eur J Clin Pharmacol 2010; 66: 127–135.

6. Toublanc N, Okagaki T, Boyce M, Chan R, Mugitani A, Watanabe S, Yamamoto K, Yoshida K, Andreas JO. Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration. Eur J Drug Metab Pharmacokinet 2014; Oct 5. [Epub ahead of print]

The percentage share by country of our

>660 phase 1 trials since 1993

To discuss your needs, please contact:

Malcolm Boyce, Managing Director [email protected] or

Ryo Ashizawa, Liaison Manager [email protected]

020 8961 4130

Hammersmith Medicines Research Cumberland Avenue London NW10 7EW UK

http://www.ncbi.nlm.nih.gov/pubmed?term=Toublanc%20N%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Okagaki%20T%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Boyce%20M%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Chan%20R%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Mugitani%20A%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Watanabe%20S%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Yamamoto%20K%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Yoshida%20K%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Andreas%20JO%5BAuthor%5D&cauthor=true&cauthor_uid=25283522

http://www.ncbi.nlm.nih.gov/pubmed?term=Andreas%20JO%5BAuthor%5D&cauthor=true&cauthor_uid=25283522




Hammersmith Medicines Research (HMR) and P1vital collaborate on early phase clinical studies. The outstanding phase 1 experience and facilities of HMR together with the unique CNS experimental medicine expertise and capabilities of P1vital provide a comprehensive solution for early assessment of the safety and potential efficacy of novel CNS compounds.

Central nervous system drugs

Since 1993, HMR has done over 730 phase 1 studies, over 200 of which involved compounds with central nervous system (CNS) activity. Many of the studies were first-in-man. We have experience of a wide range of procedures to assess novel CNS compounds, such as: psychomotor tests;

coordination tests;

sleep and polysomnography

ataxiameter;

body sway;

erythrocyte cholinesterase activity;

cognitive function assessment, using a computerised system, such as CDR and Cogstate;

scopolamine model of dementia;

saliva flow rate;

pain models;

saccadic eye movements;

critical flicker fusion frequency threshold;

digit span;

EEG, with interpretation by consultant neurologist;

PET, with Imanova, Hammersmith Hospital;

SPECT, with UC Hospital;

fMRI, with Imanova, Hammersmith Hospital or Institute of Psychiatry, King’s College Hospital;

clinical questionnaires, eg POMS, CSSRS, AIMS, Simpson-Angus, Barnes ARS, TFEQIII, BDI and HRS;

EEG electrodes

EEG

MRI scan

and …working together on CNS studies


Dose-related inhibition of red-cell cholinesterase in healthy men

(reference 4)

0 4 8 12 16-30

-20

-10

0

10

20

30

40

50

60

70

PL1X2X2.5X3X

44 64 84 104 12424

Time after 1st dose (h), Days 1-6

% in

hibi

tion

simple and choice reaction times;

visual analogue rating scales;

tyramine challenge tests, to assess MAO-B inhibition; and

5-HT1A-receptor mediated function tests.

Types of molecule Types of molecule that we’ve studied

include:

dopamine receptor antagonists;

cannabinoid-1 receptor inverse agonists;

MAO-B inhibitors;

anti-convulsants;

anti-psychotics;

anti-depressants;

cholinesterase inhibitors;

histamine H3-receptor antagonists;

histamine H1-receptor antagonists;

5-HT1A receptor agonists;

benzodiazepine analogues; and

GABA inverse agonists.

Collaboration with P1vital P1vital provides a unique range of products and services in CNS experimental medicine to enable client companies to more effectively manage their risk and investment in CNS drug development. The P1vital team has extensive expertise in all aspects of CNS drug discovery and development. This enables P1vital to offer their clients customised experimental medicine solutions including:

Consultancy and study delivery services to enable clients to assess the clinical efficacy of their early phase CNS development compounds;

P1vital® Oxford Emotional Test Battery (ETB), a product that can be used to assess antidepressant efficacy from Phase 1 MAD studies in healthy volunteers to Phase 2 POC studies in patients.

P1vital has an expanding portfolio of efficacy biomarkers for anxiety, depression, schizophrenia, cognitive disorders and obesity including: Depression: P1vital® Oxford ETB;


Depression: pharmacological fMRI;

Anxiety: CO2 inhalation;

Schizophrenia: pharmacological fMRI;

Schizophrenia: bi-conditional learning;

Schizophrenia: eye tracking;

Cognitive disorders: Arena & Platform fMRI tasks;

Obesity: universal eating monitor.

P1vital is expanding its portfolio of validated CNS efficacy biomarkers through a pre-competitive consortium agreement with AstraZeneca, GlaxoSmithKline, Lundbeck, Organon (a subsidiary of Merck) and Pfizer. P1vital has established collaborations with internationally renowned opinion leaders in psychiatry, neuroscience and obesity, linked through a network of university hospitals and clinical research facilities within the UK. Through its network of key opinion leaders P1vital provides:

Translational tools for making more rapid and effective decisions in Phase 1 and Phase 2 clinical development of drugs for CNS disorders and obesity;

Innovative clinical science in collaboration with its university research teams;

Synergy through combining CNS drug discovery and development expertise with the strong clinical science base in the UK;

Expertise in clinical project and quality management to recognised industry and regulatory standards.


Malcolm Boyce, Managing Director [email protected]

020 8961 4130


Cumberland Avenue

London NW10 7EW UK


Some HMR and P1vital publications

1. Addy C, Li S, Warrington S et al. Safety, tolerability, pharmacokinetics and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J Clin Pharm 2008; 48: 418–427.

2. Norris V, Baisley KJ, Calder N, van Troostenburg AR, Warrington SJ. Assessment of the Accusway Plus system in measuring the effect of lorazepam on body sway in healthy volunteers. Int J Pharm Med 2005; 19: 233–238.

3. Clarke A, Johnson ES, Mallard N, Corn TH, Johnston A, Boyce M, Warrington S, MacMahon DG. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transmission 2003; 110: 1257–1271.

4. Johnson N, Cattoni M, Warrington S, Boyce M. Tolerability and pharmacodynamic effects of repeated doses of ganstigmine, a new cholinesterase inhibitor, in healthy men. British Journal of Clinical Pharmacology 2000; 49: 492P–493P.

5. Harmer CJ, Cowen PJ, Goodwin GM. Efficacy markers in depression. J Psychopharmacol 2010; Jun 8. [Epub ahead of print].

6. Harmer CJ, de Bodinat C, Dawson GR, Dourish CT, Waldenmaier L, Adams S, Cowen PJ, Goodwin GM. Agomelatine facilitates positive vs negative affective processing in healthy volunteer models. J Psychopharmacol 2010; Jul 21. [Epub ahead of print].

7. Harmer CJ, O’Sullivan U, Favaron E, Massey-Chase R, Ayres R, Reinecke A, Goodwin GM, Cowen PJ. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am J Psychiatry 2009; 166: 1178–1184.

8. Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ. Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study. Br J Psychiatry 2007; 90: 531–532.

9. Halford JCG, Boyland EJ, Cooper SJ, Dovey TM, Huda MSB, Dourish CT, Dawson GR, Wilding, JPH. The effects of sibutramine on the microstructure of eating behaviour and energy expenditure in obese women. J Psychopharmacol 2010; 24: 99–109.

10. Antonova E, Parslow D, Brammer M, Simmons A, Williams S, Dawson GR, Morris RG. Scopolamine disrupts hippocampal activity during allocentric spatial memory in humans: an fMRI study using a virtual reality analogue of the Morris Water Maze. J Psychopharmacol 2010; Sep 7. [Epub ahead of print].

Examples of our studies

0 2 4 6 8 10 12 14 16 18 20 22 24

0.0

0.2

0.4

0.6

0.8

1.0

R-warfarin + placeboR-Warfarin + felodipineS-warfarin + placeboS-warfarin + felodipine

Time after dosing, hPl

asm

a w

arfa

rin

conc

entr

atio

n,

g/m

L

No effect of felodipine for 14 days on mean steady state plasma S- and R-warfarin in 18 healthy men. Warfarin dose adjusted to maintain INR 1.4–1.6 (Clin Pharmacol Ther 1993; 54:381–387)

0 4 8 12 16 20 24

0.0

0.5

1.0

1.5

2.0

2.5

3.0

triazolam + drug Xtriazolam

Time after dosing, h

Plas

ma

tria

zola

m c

once

ntra

tion,

ng/

mL

Large increase in plasma triazolam after a single 0.125 mg dose, alone or after pre-treatment with drug X (a new antimicrobial) daily for 6 days, in 10 healthy men (unpublished)

0 25 100 150

-5

0

5

10

15

TAK-013 Dose, mg6ßO

HC

ortis

ol:C

ortis

ol R

atio

Day

11

- Day

1

Dose-dependent increase in urinary 6-ß-OH cortisol:cortisol ratio after 11 days’ dosing with TAK-013 in healthy women (n=9 per dose) consistent with CYP3A4 induction (Fertility and Sterility 2002;78: S281)

Drug-drug interactions

All new drugs must be assessed in man in vitro and in vivo for their potential to interact with established drugs. In recent years, regulatory authorities have withdrawn several drugs such as terfenadine, astemizole and cisapride from the market, mainly because of the risk of interaction with other drugs.

We have done many studies in healthy subjects to assess the potential of new and established drugs to interact with:

drugs with a narrow therapeutic window, such as digoxin, warfarin and aminophylline;

oral contraceptives;

anticonvulsants, such as phenytoin and carbamazepine;

inhibitors of the most important P450 enzyme CYP3A4 such as ketoconazole, erythromycin, and grapefruit juice; and

a ‘cocktail’ of drugs to test for effects on cytochrome P450 enzymes, selected from 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1, and acetylation.

For more information, contact: Malcolm Boyce Managing Director [email protected]

020 8961 4130 Hammersmith Medicines Research

Cumberland Avenue

London NW10 7EW

England



We can provide a full service design, subject selection by phenotyping or genotyping, exclusion diets, drug assays, pharmacokinetics, statistical analysis, and report for the well-designed interaction studies that regulatory authorities expect when they are considering an application to market a new drug.

Interaction between drug and subject

68% of our European subjects are poor metabolisers of debrisoquine because of genetic polymorphism for CYP2D6. That can make a big difference to the dose that they need.

References

1. Drug metabolism/interaction studies in vivo. Study design, data analysis, dosing and labelling. FDA; Nov 1999.

2. Investigation of drug interactions. CPMP/EWP/560/95; June 1998.

3. Ethnic factors in acceptability of foreign clinical data. CPMP/ICH/289/95; Sept 1998.

4. Grind M, Murphy M, Warrington S, Åberg J. Method for studying drug-warfarin interactions. Clin Pharmacol and Ther 1993; 54: 381–387.

5. Johnston A, Holt D, Lee T, Clark E, Dunn K, Boyce M. Urinary 6-OH cortisol / cortisol ratio as a marker of CYP3A4 activity. Br J Clin Pharmacol 2003; 55: 440.

6. Boyce M, Clark E, Johnston A et al. TAK-013, a new non-peptide gonadotropin-releasing hormone antagonist, in healthy women. Fertility and Sterility 2002; 78: S281S282.

7. Frye et al. Pittsburgh cocktail. Clin Pharmacol Ther 1997; 62: 365376.

A survey showing the big increase in drug-drug interaction studies in man for all new molecules approved by the FDA from 1987 to 1997 (Clin Pharmacol Ther 2000; 68: 280–285)

98

193

117

540

0

100

200

300

400

500

600

1987-1991 1992-1997

Num

ber

New molecular entities

Drug-drug interactions

Dose requirement for nortriptyline in patients with different CYP2D6 phenotypes

Poor metabolisers = debrisoquine urinary metabolic ratio of >12.6 (dashed line). Meyer. Lancet 2000; 356: 1667–1671


Flow cytometry

Flow cytometry identifies and counts specific populations of cells. First, the cells are labelled with a fluorescent dye, and a monoclonal antibody. Then, the flow cytometer uses lasers, to generate fluorescence, and filters and detectors to measure forward and side scatter, as the cells flow past the light beam.

Many of the potential new medicines being developed by pharma and biotech companies are targeted at specific populations of cells. Flow cytometry can assess the pharmacodynamic effects of those medicines in phase 1 studies.

We have substantial experience of phase 1 studies using flow cytometry to measure:

changes in shape of eosinophils, neutrophils or monocytes;

platelet activation, using PAC-1 and CD62 markers;

reticulated platelets;

platelet VASP activation;

lymphocyte subsets, using monoclonal antibodies to various cell surface antigens; or

CD11b expression on neutrophils.

We use a Becton-Dickinson FACSCalibur, 4-colour, dual-laser, flow cytometer with autoloader. Our IMag Cell Separation System augments the power of our flow cytometer, by enriching and depleting specific cell populations.

Flow cytometry. Left-hand plot shows CD8 expression by peripheral blood (PB) lymphocytes. 38% of events fall between the marker boundaries, and are therefore regarded as CD8+ve. The centre plot depicts the relationship between CD8 and the T-cell marker CD3. The CD8+ve population contains two CD3-defined sub-populations (CD3+ve and CD3–ve); the CD3-ve fraction (lower right quadrant) expresses CD8 at a lower intensity than the CD3+ve fraction (upper right quadrant). The right-hand plot shows a population of CD34+ve ‘stem cells’ plotted against side scatter.

By collaborating with sponsors, our trained staff can transfer flow cytometry technology from pre-clinical research to phase 1.


Malcolm Boyce Managing Director [email protected] 020 8961 4130 or

Juan Naveda Director of Laboratory Services [email protected] 020 8963 2899 Hammersmith Medicines Research Cumberland Avenue London NW10 7EW England

References

1. H Shapiro. Practical flow cytometry. Fourth edition, 2003. Wiley-Liss.

2. In’t Veen J et al. CD11b and L-selectin expression on eosinophils in blood and induced sputum of patients with asthma compared with normal subjects. Clin Exp Allergy 1998; 28: 606615.

3. Brends et al. Expression of CD35 and CD11b on circulating neutrophils and eosinophils from allergic asthmatic children. Clin Exp Allergy 1993; 23: 926933.




Imanova, Hammersmith Hospital

Imanova, on the Hammersmith Hospital site, uses a cyclotron to label the ligand, which is then given to a subject lying in a PET scanner. The photons escape from the body and are detected by the scanner, giving a dynamic, 3-D image that reflects quantitatively the distribution of the radionuclide in the body over time.

Because the radionuclides have such short half-lives, the cyclotron and PET scanner must be close to each other, and the subject must be given the radioligand soon after it has been made.

…working together on PET studies

Positron emission tomography (PET) is a 3-D imaging technique that can be used to study the distribution, receptor occupancy and pharmacodynamic effects of a radiolabelled ligand (agonist or antagonist) in man. The main uses of PET for drug development are:

selecting a lead candidate; predicting the dose and interval; proof-of-principle; and predicting disease.

PET uses radionuclides such as 11C and 18F that emit positrons and have very short half-lives. On emission, a positron collides with an electron in an atom in the surrounding tissues after travelling only a few tenths of a millimetre. The positron and electron destroy each other, giving off two photons at 180 to each other.

and

Dose dependent occupancy of central dopamine D2 receptors by

the novel neuroleptic CP-88,059-01(n=1 per dose)

Bench et al. Psychopharmacol 1993; 112: 308

0

0.5

1

1.5

2

2.5

3

0 20 40 60 80 100Dose (mg)

Bin

ding

Pot

entia

l

Only specialised centres have the resources to do PET studies. HMR has used the imaging facilities on the Hammersmith Hospital site since 1993 to provide a PET service to the pharmaceutical industry.

HMR recruits the subjects, does the clinical work and runs the study. Imanova prepares the radioligand, does the PET scans, and analyses and interprets the results. We have done almost 50 studies in healthy subjects or patients, to assess new drugs acting at targets such as dopamine D2, adenosineA2A, benzodiazepine, MAO, neurotropin, NK1 and GABA receptors. We have studied drugs to treat conditions such as schizophrenia, Parkinson’s, Alzheimer’s and depression.

Case study

Using PET, and 11C-raclopride as the ligand, HMR and the imaging centre at Hammersmith Hospital studied two groups of healthy subjects (only eight per group) to predict the dose1 and dose-interval2 of a new neuroleptic, CP-88,059-01 (ziprasidone), for trials in patients. Ziprasidone has since been marketed (Geodon; Pfizer) at the doses (2040 mg) and dose-interval (twice daily) that we predicted.

Some of our references 1. Bench C, Lammertsma A, Dolan R, Grasby P, Warrington S, Gunn K, Cuddigan M, Turton D, Osman S,

Frackowiak R. Dose-dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: study using PET and 11C-raclopride. Psychopharmacology 1993; 112: 308–314.

2. Bench C, Lammertsma A, Grasby P, Dolan R, Warrington S, Boyce M, Gunn K, Brannick L, Frackowiak R. The time course of occupancy of striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by PET. Psychopharmacology 1996; 124: 141–147.

3. Brooks D et al. An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers. Clinical Neuropharmacology 2010; 33: 55–60.


Dr Malcolm Boyce Hammersmith Medicines Research Managing Director Cumberland Avenue [email protected] London NW10 7EW 020 8961 4130 England

Dopamine in the brain: 11C-raclopride

Baseline increasing dose of ziprasidone

Predicted dose in patients



Torsade de pointes – note QT prolongation

Thorough QT studies

Some people are born with prolonged QT interval, but others

have prolonged QT interval thrust upon them – by medicines that affect cardiac repolarisation. QT prolongation predisposes to a disorganised heart rhythm called torsade de

pointes, which can degenerate into ventricular fibrillation and death. In the last decade or so, several valuable drugs have been withdrawn from the market, or have had their use greatly restricted, because they can prolong QT interval and are associated with a risk of sudden death. Examples include prenylamine, terfenadine, astemizole, cisapride and sertindole.

Regulatory authorities now expect to see a thorough QT study of a new medicine a rigorous assessment of its potential to prolong QT interval – even if preclinical work shows no sign of

any problem. At HMR, we have successfully completed many definitive studies of the potential of new medicines to cause QT prolongation. We use industry-standard MAC5000 ECG machines to record high quality digital 12-lead ECGs, which can be coded and analysed ‘blind’ by the sponsor’s choice of specialist contractor, anywhere in the world. We capture the 24-h ambulatory ECG (Holter) using the ELA SyneFlash system, which records continuous 12-lead ECG. SyneFlash allows continuous beat-to-beat automated measurement of QT interval and hourly estimation of mean QT, with immediate online analysis of relationships between QT and RR intervals. In our definitive QT studies, we use repeat-dose regimens to achieve steady state. We can include a positive control, such as moxifloxacin, or a CYP3A4 inhibitor, such as ketoconazole. We maximise safety by keeping the subjects resident in our wards: our 16-channel Spacelabs ECG telemetry system allows us to monitor them continuously throughout the research facility. We have done many QT studies of new and existing medicines.

Our track record shows that we can give sponsors the thorough QT study data that the regulators demand – safely, securely, and to strict timelines. To discuss your needs, contact:

Malcolm Boyce Managing Director

[email protected]

020 8961 4130

Hammersmith Medicines Research Cumberland Avenue London NW10 7EW England



References 1. The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products.

CPMP/986/96 2. Haverkamp W, Breithardt G, Camm AJ et al. The potential for QT prolongation and pro-arrhythmia by non-

anti-arrhythmic drugs: clinical and regulatory implications. Cardiovasc Res 2000; 47: 219–233.

3. Boyce M, Dunn K, Warrington S. Hemodynamic and electrocardiographic effects of almotriptan in healthy volunteers. J Cardiovasc Pharmacol 2001; 37: 280289.

4. Malik M, Hnatkova K, Ford J et al. Near-thorough QT study as part of a first-in-man study. J Clin Pharmacol 2008; 48: 1146-1157.

5. Boyce M, Kerstens R, Beyens G, Vandeplassche L, Ausma J. Cardiovascular safety of prucalopride in healthy subjects: results from a randomized, double-blind, placebo-controlled, cross-over trial. 16th United Gastroenterology Week, 18-22 October 2008, Vienna. Poster PO892.

6. Boyce MJ, Baisley KJ, Warrington SJ. Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study. Br J Clin Pharmacol 2012; 73: 411–421.

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Floor plan of our sleep unit and adjacent facilities

Embla PSG equipment

Sleep studies We have 2 sleep units, each with 4 bedrooms – some with an en-suite toilet and shower; others (see right) with facilities close by. Other features include:

high-level sound-proofing, with acoustic boards, acoustic tiles and 10 cm thick fibre insulation;

no windows;

an entrance lobby, to maintain sound- and light-proofing when entering the room;

remote-controlled air-conditioning, and ventilation;

electrical trunking with separate channels for mains and low-voltage cables;

shielding of all mains cables, and wooden beds, to prevent electromagnetic interference;

infra-red light, and video camera;

controlled light for <5 lux waking environment;

microphone;

external port for remote intravenous blood sampling; and

Embla N7000 polysomnography system (PSG) with: EEG, EOG, ECG and EMG electrodes and leads; and oximeter, respiratory effort, body position, nasal cannula, thermistor and snoring sensors

We have 4 acquisition PCs. Each one is protected by an Uninterruptable Power Supply (UPS), and stores data on mirrored RAID hard drives. We copy the data across the network to our file server, which we back up every night. Then we copy it again to a review PC where we process it before copying the final version to external media (eg CD/DVD) or sending it to a sponsor across the internet (eg WWW/FTP).

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We validate PSG equipment in accordance with 21 CFR part 11. We have trained staff and links with academic units experienced in sleep research.

We work according to AASM-recommended technical standards, to produce data acceptable for peer-reviewed publication and regulatory approval.

We can:

assist with study design; and

provide onsite data analysis for interim results and final reports.

In addition to the sleep unit, we have:

extensive experience in phase 1 studies of novel CNS compounds, including first-in-man studies;

extensive experience of other CNS procedures, such as psychomotor tests, coordination tests, and cognitive function;

MIA(IMP) to manufacture sterile and non-sterile products; and

MHRA Phase 1 Supplementary Accreditation.


Malcolm Boyce, Medical Director [email protected]

020 8961 4130

Hammersmith Medicines Research Cumberland Avenue London NW10 7EW UK

REM

S4 –slow wave-deep sleep

EEG recording

Electrode placement for PSG

Clinical trials using radiolabelled products

Flexible, efficient, high quality service

State-of-the-art facilities

Licensed on-site aseptic radiopharmacy

ADME (mass balance)

Light label

Probe studies

PET


www.hmrlondon.com

For all enquiries, please contact: Dr Malcolm Boyce, Managing Director Phone: 020 8961 4130 Email: [email protected]

http://www.hmrlondon.com/


Since 1993, Hammersmith Medicines Research (HMR) has supplied industry-leading services for early phase clinical trials. We have extensive experience in administration of radionuclides.

Radiopharmacy

On-site radiopharmacy with aseptic suite

Licensed to manufacture capsules, and sterile or non-sterile solutions and suspensions

QC of specific activity by LSC

Secure IMP storage, with continuous environmental monitoring & integrated alarm

Wards

Separate wards for conventional and ‘light label’ doses of radionuclide

Urine/faecal collection & processing suites

Laboratory

Dedicated area for processing radioactive samples

Homogenisation & oxidation of faecal samples

LSC

Supporting services

Excellent recruitment & retention of volunteers

Dedicated project manager & clinical team

Regulatory & ethics applications & advice

Full data management, statistics & medical writing capabilities

Japanese-speaking ward staff for bridging studies

Our collaborators

PET: Imanova, a state-of-the-art unit at Hammersmith Hospital

API synthesis to GMP: Selcia

Accelerator mass spectrometry: Xceleron

Contacts

Malcolm Boyce, Managing Director [email protected]

HMR enquiries team [email protected]

Websites

www.hmrlondon.com

www.selcia.com

www.imanova.co.uk www.xceleron.com

Hammersmith Medicines Research Cumberland Avenue London NW10 7EW Tel: +44 (0)20 8961 4130



http://www.hmrlondon.com/

http://www.selcia.com/

http://www.imanova.co.uk/

http://www.xceleron.com/

Documents

General information · Central ECG monitoring (SpaceLabs) on all 145 beds, using wall-mounted and mobile units. Continuous electronic and hard copy ECG recording, arrhythmia detection