Guidelines Phase1 Clinical Trials

Guidelines for phase 1
clinical trials
2012 edition
Foreword
The development of new and better medicines is vital for the public health. A key step in
medicines development is the transition from the laboratory to the human subject in a phase 1
clinical trial, when potential new medicines are given to humans for the first time. Phase 1 is the
gateway between scientific research and clinical medicine.
The phase 1 trial falls within the realm of experimental science, and requires a range of skills
and expertise of the highest standard. Confidence in the results depends upon the clarity and
understanding of the questions asked, and upon the quality of the trial designed to answer them.
However, the safety and well-being of the subjects whether they be healthy individuals or
patients must always have priority.
The translation of advances in the biological sciences into health benefits, via the development
of new medicines, is likely to occur at an increasing pace in the coming years. New medicines
will be based on progressively refined biological and biochemical insights. There may be no
prior experience in humans of many of the new types of medicine that advances in molecular
pharmacology should yield. The challenges for phase 1 trials include: finding methods to assess
the potency and effectiveness of these new medicines; sharing of safety information; calculation
of the starting dose; design of dose-escalation protocols; and, in the interests of the well-being
and safety of the subjects, ever-vigilant attention to risk reduction and risk management in the
conduct of the trial.
This 2012 edition of the ABPI Guidelines for Phase 1 Clinical Trials is science based, and is a
remarkably thorough and notably clear compilation of updated information and guidance on
best practice. It covers all of the key points, and warrants close reading and frequent reference
by those involved in the development, investigation and regulation of new medicines. As we
enter an era of high expectation in the provision of much-needed innovative medicines, the
ABPI is to be commended on the timely production of professional guidance that will underpin
the safe and effective conduct of future phase 1 trials.
Sir Gordon Duff
Florey Professor of Molecular Medicine, University of Sheffield
Chairman, UK Commission on Human Medicines
Preface
The first edition of these ABPI guidelines was published in 1970.1 They were revised in 19772
and 1988. The 1988 revision resulted in two sets of guidelines, one for procedures3 and another
for facilities.4 In 1986, the Royal College of Physicians (RCP) published a report on research in
healthy volunteers,5 which has never been revised. But the 1988 revision of the ABPI guidelines
took the RCP report into account.
These editions were written when many ABPI member companies had their own facilities
and used their own staff as a source of healthy volunteers. Nowadays, contract research
organisations (CROs) do most of the phase 1 trials in the UK,6 and many sponsors are from
countries outside the UK.
In 2007, the guidelines underwent a major revision. It took into account the many changes that
had taken place in the two decades since the 1988 edition. Numerous sections were updated
and expanded: premises, facilities equipment, staff emergency procedures and equipment,
pharmacy and laboratory, records and archiving, justification for studying healthy subjects,
recruitment and payment of subjects, frequency of volunteering, ethics committee, and
compensation. New sections were added to reflect the significant changes to the regulations
and the ways in which Phase 1 trials were being conducted.
The 2007 edition was extremely well received and became a useful guide not only to sponsors
and investigators but also to ethics committees and trial volunteers, read by people well beyond
the borders of the United Kingdom.
However, developments in the regulatory arena are moving at a fast pace and a considerable
amount of what previously constituted guidance has now become a legal requirement.
Moreover, an impressive range of guidance documents dealing with various aspects of
conducting clinical trials has been published by Health Authorities and other stakeholder
organisations around the world in recent years. Hence, many readers still feel the benefit from
a comprehensive, largely jargon-free document that outlines the framework within which
Phase 1 research is conducted and provides pointers for further, more in-depth reading. The
ABPI therefore decided to release an updated version of the 2007 edition.
In addition to recent regulatory changes, the new edition contains the latest ABPI guidance
on insurance and trial subject compensation. It also responds to the feedback received from
many stakeholders, several of which had commented that the guidelines had become overprescriptive in places, especially in the sections on premises and facilities. Thus, these sections
have been scaled down.
The new edition is in line with the references cited below:
Potential new medicines are called investigational medicinal products (IMPs).7
Clinical trials of an IMP that do not benefit subjects whether they be healthy subjects or
patients are called phase 1 or non-therapeutic trials.7
The premises where trials are conducted are called phase 1 units, or simply units.
People who take part in clinical trials are called subjects:7 healthy subjects when they are
truly healthy, and patients when they have the disease for which the IMP is being developed.
The discipline that underpins phase 1 trials is called clinical or human pharmacology.8, 9
Updated in 2014 by:

Arnold & Porter LLP on behalf of the ABPI
Updated and edited in 2012 on behalf of and with the ABPI Experimental Medicine Expert
Network by:
Oliver Schmidt
2007 edition written and compiled for the ABPI by:
Malcolm Boyce
Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI)
Acknowledgements:
We thank the many stakeholders from industry, regulators and professional organisations who
provided feedback in response to our consultation on the 2012 and 2014 revisions.
Table of Contents
1

Developing a new medicine

First-in-Human trial
Subsequent trials
7
8
8
Regulations
MHRA
CTA application
Protocol amendments
Inspections
Breaches of GCP or trial protocol
11
11
11
11
12
Risk assessment
All IMPs
Higher risk IMPs
Other factors
12
12
12
13
Risk management
Starting dose
Increasing the dose
Administration of doses
Facilities and staff
Procedures
Subjects
13
13
14
14
14
15
15
Safety record of Phase 1 trials
15
Protocol
16
Contracts
17
Trial subjects
Recruitment
Monitoring overexposure
Special populations
Payments
Obtaining informed consent
Screening
Timing of recruitment and screening
Identification
Informing the subjects General Practitioner
Safety
Follow-up
18
18
19
19
20
21
21
22
22
22
22
23
10

11

Research ethics committee

General
23
23
Pharmacy
Premises, facilities and equipment
Storage
Staff
23
23
23
24
4
12

Investigational medicinal products

Manufacture
Documents
Records
Supplying the investigator
Transport to the trial site
Accountability at the trial site
Recall
Retention of samples
Randomisation
Emergency unblinding
Quality management
24
24
24
25
25
25
25
25
25
25
25
26
13

Biotechnology products
General
Proteins and monoclonal antibodies
Gene therapy
Genetically modified micro-organisms
26
26
26
26
27
14

Radioactive substances
General
Microdose trials
Staff
Trial subjects
27
27
27
27
28
28
15 Non-investigational medicinal products
28
16

Qualified Person
Requirements
Responsibilities
Releasing IMP prepared by the pharmacy
Manufacture of IMP
29
29
29
29
30
17

Resuscitation procedures, equipment, medicines and training

General procedures
Resuscitation equipment and medicines
Antidote
Resuscitation training
30
30
31
31
31
18

Confidentiality
Sponsors
Trial subjects
Data Protection Act
Human Tissue Act
31
31
32
32
32
19

Compensation, indemnity and insurance

Compensation
Indemnity
Insurance
32
32
33
33
20 Pharmacovigilance
34
21

Pathology laboratory
General
Premises, facilities, equipment and procedures
Staff
35
35
35
35
22

Data management, statistics, report and publication

General
Data management
Statistics
Report and publication policy
Staff
35
35
36
36
36
37
23

Essential documents, trial master file and archiving

Trial master file
Quality of documents
Storage of documents
Duration of storage
Disposal of documents
37
37
37
37
37
38
24 Project management and monitoring
38
25

38
38
39
39
39
39
Quality management
Quality system
Quality control
Auditors
Audits
Sponsors auditors
26 Health and safety
40
27 References
41
28 Websites
44
45
47
48
50
52
61
Appendix 1: Qualifications relevant to Phase 1 trials

Appendix 2: Contents of the information and consent form
Appendix 3: Challenge agents
Appendix 4: Abbreviations
Appendix 5: Glossary of terms
Appendix 6: Consultation Responses
1: Developing a new medicine

The pharmaceutical industry is the main sponsor of medicines research in the UK. Sponsors
have to demonstrate the safety, quality and efficacy of a potential new medicine called an
investigational medicinal product (IMP) through a series of rigorous trials in humans in order
to obtain a licence, so that doctors can give the medicine to patients.
However, before an IMP can be given to humans, sponsors must first test it thoroughly in
animals. The main aims of these pre-clinical studies are:
to find out the effects of the IMP on body systems (pharmacodynamics)
to study the blood levels of the IMP, and how it is absorbed, distributed, metabolised and
eliminated after dosing (pharmacokinetics)
to find out if a range of doses of the IMP, up to many times higher than those intended for
use in humans, are toxic to animals10 and if so, to identify the target organs and the margin
of safety in terms of (a) the no-observed-adverse-effect dose level (NOAEL) relative to body
weight and (b) IMP exposure the concentration of IMP in the bloodstream over 24 hours
(toxicokinetics),11 and
to make a formulation of the IMP, such as a capsule or injection, suitable for early studies in
humans.
After the pre-clinical studies, there are four phases of trials in humans, which in practice often
overlap. Phases 1 to 3 are done before a licence is granted and Phase 4 is done after authorisation
to market the drug. The phases are different in terms of the number and types of subject studied,
and the questions asked. The numbers in the table are indicative only and can vary.
Phase
Number and type of subject
Questions
50200
healthy subjects (usually) or patients
who are not expected to benefit from
the IMP
Is the IMP safe in humans?

What does the body do to the IMP?
(pharmacokinetics)
What does the IMP do to the body?
(pharmacodynamics)
Might the IMP work in patients?
100400
patients with the target disease
Is the IMP safe in patients?

Does the IMP seem to work in
patients? (efficacy)
10005000
Is the IMP really safe in patients?

Does the IMP really work in patients?
many thousands or millions

Just how safe is the new medicine?

(pharmacovigilance)
Does the medicine work in the real
world? (real world data collected to
demonstrate value)
How does the new medicine compare
with similar medic
Phases are also often subdivided. For instance, small-scale, exploratory efficacy studies in a
limited number of patients may be referred to as Phase 2a. In contrast, slightly larger trials
that test the efficacy of a compound at different doses (dose-range finding studies) might be
designated Phase 2b.
Phases 1 to 3 can take up to 10 years for a successful IMP. However, many IMPs are withdrawn
from development, mainly because:12
they are not well-tolerated or safe enough in humans, or
their pharmacokinetic or pharmacodynamic profile in humans is disappointing, or
they do not work or do not work well enough in patients with the target disease.
In a 10-year review of IMPs13, only 60% progressed from Phase 1 to 2, and a mere 11% became
a marketed product. Phase 1 trials can identify IMPs with potential for success as well as
excluding failures and thereby preventing unnecessary exposure of the IMP to many more
subjects.
The past decade has seen the introduction of exploratory studies that are performed prior
the traditional Phase 1 Single-Dose Escalation. These studies, which involve exposure of a
limited number of subjects to a much-reduced dose (also referred to as a micro-dose) of a novel
compound, are beyond the scope of these guidelines, which only cover conventional Phase 1
experimental studies. Guidance on this type of study can be obtained from the Food and Drug
Administration (FDA) as well as the European Medicines Agency.14, 15
While the categorisation of human drug development trials into distinct phases implies
chronology, in practice there can be considerable overlap. A range of Phase 1 studies is
performed when the IMP is already in a more advanced stage of development.
A Phase 1 study is defined as a non-therapeutic, exploratory trial in human subjects who may be
healthy or have a specific disease. In contrast to later phase studies, subjects can usually expect
no therapeutic benefit from a Phase 1 trial.
The primary parameters tested in Phase 1 studies (which can involve single or multiple doses of
the IMP) are:
Safety and tolerability
Pharmacokinetics
Pharmacodynamics
There is a range of distinct Phase 1 studies, each of which is designed to address a particular
question or set of questions:
First-in-Human trial
The first trial of an IMP in humans is usually a trial of single doses given in increasing
amounts. The aims are to assess the tolerability, safety, pharmacokinetics and, if possible, the
pharmacodynamic effects of the IMP, and to compare the results with those from the preclinical studies. Details about the conduct and design of these trials can be found in the ABPIs
First In Human Studies guidelines.16
Subsequent trials
After the First-in-Human trial, the next one is usually a trial of multiple ascending doses.
Examples of other Phase 1 trials are trials to assess:
the effects of potential influences, such as food, gender, age and genetic differences, on the
activity of the IMP
the relationship between dose or concentration of the IMP and the response for example,
by measuring biomarkers17 or using challenge agents (Section 18)
the possible interaction of the IMP with marketed medicines
the absorption, distribution, metabolism and elimination of a radiolabelled IMP
the bioavailability or bioequivalence of the IMP,18 and
the effect of the IMP on the QT interval of the electrocardiogram (ECG).19
There is an increasing tendency for sponsors to combine the first single-dose and multiple-dose
trials of an IMP, and even add a trial of the effect of food or age, so that the First-in-Human trial
is merely the first of a bundle of trials.
Some of these trials, such as the interaction trials and QT-interval trial, may be done during any
stage of development of an IMP. While it is customary to refer to pharmacokinetic studies as
Phase 1, it is not very helpful and might lead to confusions.
2: Regulations
In recent years, there have been many changes to the regulatory aspects of clinical trials. Most
changes stem from the introduction of Good Clinical Practice (GCP), Good Manufacturing
Practice (GMP) and the Clinical Trials Directive, which is based on GCP and GMP. The main
documents are:
International Conference on Harmonisation (ICH) Guideline for GCP20
European Union (EU) Clinical Trials Directive 2001/20/EC21
GMP for Medicinal Products. EudraLex Vol. 422, 23 and Annexes, especially Annexes 1,24 1325
and 1626
Directive 2003/94/EC on GMP for Medicinal Products and IMPs27
Directive 2005/28/EC on GCP28
Governance Arrangements for Research Ethics Committees (GAfREC)29
Standard Operating Procedures (SOP) for Research Ethics Committees (REC)30
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP),
July 2007. Guideline on strategies to identify and mitigate risks for first in human trials with
Investigational Medicinal Products (EMEA/CHMP/SWP/28367/07).31
The Clinical Trials Directive was implemented in the UK through the Clinical Trials
Regulations7 in May 2004 or Statutory Instrument (SI) 2004/1031. The SI has since been
amended on an annual basis. Its aims are:
to simplify and harmonise clinical trials across Europe
to give better protection to subjects who take part in clinical trials, and
to enforce by law the principles of GCP and GMP.
In addition to the Clinical Trials Directive, the European Commission has published a set of
guidelines covering a range of clinical trial aspects (EudraLex, Vol. 10).22 EudraLex is a 10-volume
body of regulations and guidelines governing medicinal products in the European Union.
The scope of the Clinical Trials Directive is wide; it covers all commercial and academic clinical
trials of IMP and marketed medicines, apart from trials of marketed medicines prescribed in the
usual way. The types of IMP are:
chemical entities
biotechnology products
cell therapy products
gene therapy products
plasma derived products
other extractive products
immunological products, such as vaccines, allergens and immune sera
herbal products
homeopathic products
radiopharmaceutical products.
In addition, a placebo, or a marketed product used or assembled in a way different from the
approved form, is an IMP when used as a comparator.
The impact of the Clinical Trials Directive on Phase 1 trials is as follows.
Trials of IMPs in healthy subjects are now regulated. They were excluded from the
Medicines Act 196832 because healthy subjects get no therapeutic benefit from an IMP. All
non-therapeutic trials of IMPs whether they involve healthy subjects or patients are now
called Phase 1 trials.7
Sponsors must apply to and receive approval from the Medicines and Healthcare products
Regulatory Agency (MHRA) for a Clinical Trial Authorisation (CTA), and for substantial
protocol/CTA amendments.
Investigators must apply to and receive approval from a REC (Section 13) for the protocol
and substantial amendments; the type of REC depends on whether the trial is in healthy
subjects (Type 1) or patients (Type 2 or 3). Previously, any REC could review a Phase 1 trial.
The MHRA and REC must respond to applicants within 30 and 60 days, respectively. (They
have longer for biological IMPs Section 16.) Both must respond to protocol amendments
within 35 days.
Whoever imports, manufactures, assembles or repackages IMPs must have a Manufacturers
Authorisation [MIA (IMP)] from the MHRA and must follow GMP, just like manufacturers
of marketed medicinal products.
Sponsors from third countries countries from outside the European Economic Area33
(EEA), such as Japan and USA must manufacture IMPs at least to EU standards. Also, they
must have a legal representative in the EU.
Sponsors must get a European Clinical Trials Database (EudraCT) number for all trials, and
send safety information to the MHRA and REC.
The MHRA must inspect sponsors, trial sites and other trial-related activities to check that
the Clinical Trials Directive is being followed.
The First-in-Human trial of TGN141234 has also had a big impact on Phase 1 trials. All subjects
who received it had severe adverse reactions. As a result, the UK Government set up the Expert
Scientific Group (ESG) to consider the transition from pre-clinical to First-in-Human Phase 1
trials, and the design of these trials, with specific reference to:
biological IMPs with a novel mechanism of action
IMPs with highly species-specific activity
IMPs that target the immune system.
The findings and recommendations of that group were published in a report in 2006 and have
influenced regulatory guidance on Phase 1 trials (Section 4).
10
3: MHRA
CTA application
The sponsor of a clinical trial of an IMP must submit a CTA application to the MHRA. There
is an algorithm for deciding if a trial requires a CTA.22 The MHRA must respond to a valid
application within 30 days (longer for certain biotechnology products Section 12).7 However,
applications for Phase 1 Healthy Volunteer Studies are usually assessed and processed within 14
days or fewer.6
The MHRA reviews trials of higher-risk IMPs (see Section 4) differently from trials of other
IMPs. They seek advice for First-in-Human trials of higher-risk IMPs from the Expert Advisory
Group of the Commission on Human Medicines (CHM) before approval can be given. Sponsors
can seek advice from the MHRA about whether their IMP is higher risk. First, they must submit
a summary of the nature of the IMP, its target or mechanism of action, and the relevance of the
animal model(s).
Protocol amendments
The MHRA reviews any substantial protocol amendments, and is allowed 35 days to do so. In
reality, the agency reviews Phase 1 protocols in a much shorter time-frame, typically within 14
days. Some amendments for Phase 1 trials need to be reviewed quickly to keep the study running
smoothly. However, the MHRA has no formal procedure for expedited review. Therefore,
whoever writes the protocol should try to allow for unforeseen findings and thereby avoid
protocol amendments.
Inspections
The MHRA can inspect any site involved in a clinical trial. The inspectors assess GCP and
GMP compliance separately. Inspections are compulsory, system- or trial-specific, and may be
announced or unannounced. Units should be prepared for an inspection at any time.
The inspector prepares for an inspection by reviewing the sponsors CTA application and
requesting and reviewing documents from the site, such as SOP, details of computer systems
critical for GCP, charts of how the staff are organised, and contracts.
During the visit, the inspector starts by meeting key staff, and then interviews selected staff,
inspects the facilities, and reviews relevant documents and records. The inspector gives verbal
feedback to staff at the end of the visit.
After the visit, the inspector writes and circulates a report (urgent action may be required before
this); requests and reviews the investigators or sites responses to the findings (which are graded
in the report); and makes conclusions and recommendations (this might include re-inspection or
enforcement action).
In 2007 the MHRA introduced a scheme of voluntary accreditation. Under this scheme, units
are inspected by the agency against sets of pre-defined standard or supplementary classification
criteria. The latter is required for units performing trials across the entire Phase 1 range,
including First-in-Human trials, with risk factors that would require a review by the Clinical
Trials Expert Advisory Group of the Commission on Human Medicines (CTEAG see above).
While the scheme is still voluntary, it has found widespread acceptance and Phase 1 units are
encouraged to apply for MHRA accreditation to demonstrate that they meet those criteria.
Detailed information about the scheme, including a Question & Answer document, can be found
on the MHRAs website.15
11
Breaches of GCP or trial protocol

The sponsor or delegate must notify the MHRA within seven days of any serious breach of GCP
or the protocol. A serious breach is one that is likely to affect to a significant degree:
the safety or physical or mental integrity of the subjects of the trial, or
the scientific value of the trial.
Sponsors and investigators should have a procedure in place to assess whether a deviation from
the protocol or a failure to comply with the principles of GCP constitutes a serious breach.
The sponsor has responsibility for assessing the impact of the breach on the scientific value
of the trial. The MHRA offers guidance on identifying and notifying serious breaches, and the
consequences.
4: Risk assessment
All IMPs
Subjects who volunteer for Phase 1 trials get no therapeutic benefit from the IMP, so the risk
of harming the subjects must be minimal.5 The risk must be fully assessed before each trial,
especially during the transition from pre-clinical studies to the First-in-Human trial, when
uncertainty about tolerability and safety of the IMP is usually at its highest. The sponsor must
have the pre-clinical data reviewed by people who have the appropriate technical, scientific and
clinical expertise. At least one reviewer should be independent of the project. Sponsors that do
not have the expertise themselves must use external advisers instead. All aspects of the IMP
such as its class, novelty, species specificity, mode of action, potency, dose- and concentrationresponse relationship for efficacy and toxicity, and route of administration must be taken into
account. Risk must be assessed on a case-by-case basis, and there is no simple formula. The
seriousness of possible adverse reactions and the probability of them happening must both be
considered.5
Higher risk IMPs
The ESG Report35 deemed some agents to have a higher potential for risk of harm to volunteers
during the first human exposures. The group provided examples of factors that should trigger
particular caution:

any agent that might cause severe disturbance of vital body systems
agents with agonistic or stimulatory action
novel agents or mechanisms of action for which there is no prior experience
species-specificity making pre-clinical risk assessment difficult or impossible
high potency, eg compared with a natural ligand
multifunctional agents, eg bivalent antibodies
cell-associated targets
targets that bypass normal control mechanisms
immune system targets, and
targets in systems with potential for large biological amplification in vivo.
The term higher risk means that the assessment of the IMP needs even greater care and
expertise than is usual; it does not mean that the risk to the subjects can be more than minimal.
The EMA Guideline on strategies to identify and mitigate risks for first in human trials with
Investigational Medicinal Products31 provides advice on risk factors to consider in FIH trials,
particularly but not exclusively around:
12
mode of action
nature of the target
relevance of animal models.
A copy of the risk factors listed in the guideline can also be found in the ABPI document First in
Human Studies: Points to Consider in Study Placement, Design and Conduct.16
Other factors
The risk assessment must also take into account other factors, such as the procedures and any
non-IMP (Section 17) used in the trial, and whether the trial should be done in healthy subjects
or patients.
5: Risk management
Before every Phase 1 trial, as well as assessing risk and justifying that assessment, there must be a
strategy for ensuring that any risk is minimal throughout the trial.
Should potential investigators be concerned about the level of risk of the IMP, the sponsor
must give them access to people with responsibility for the relevant pre-clinical work. Also, the
sponsors physician should liaise with the investigator. If investigators still have concerns about
pre-clinical data, they should consult an independent adviser.
Assessment and management of risks should be documented (eg through a risk management
plan). The strategy for managing risk should consider all aspects of the trial.
Starting dose
Previous ABPI guidelines2 suggested that the starting dose of an IMP should be a small fraction
not more than 10% of the predicted therapeutic dose.
The FDA Guidance36 method of calculating the safe starting dose in man follows a stepwise
process:
first, convert the NOAEL from the toxicology studies10 to a human equivalent dose (HED) on
the basis of body surface area
then, select HED from the most appropriate species
after that, apply a safety factor (10-fold) to give a Maximum Recommended Starting Dose
(MRSD)
finally, adjust the MRSD on the basis of the predicted pharmacological action of the IMP.
This method is simple and supported by a wealth of historical evidence. But the emphasis is on
selecting a dose with minimal risk of toxicity, based on the NOAEL, rather than selecting one
with minimal pharmacological activity in humans. Also, the focus is on the dose of the IMP
rather than exposure.11
Following the recommendations of the ESG report,35 the EMA Guideline on strategies to identify
and mitigate risks for first in human trials with Investigational Medicinal Products31 advises
the use of a different approach to calculate a safe starting dose for high-risk agents, based on
the minimal anticipated biological effect level (MABEL).37 This approach uses all relevant
information, taking into account: novelty; potency; mechanism of action; degree of speciesspecificity; dose-response data from human and animal cells in vitro; dose- and concentrationresponse data from animals in vivo; pharmacokinetic and pharmacodynamic modeling;
calculated target occupancy versus concentration; and concentration of the target or target cells
in humans in vivo.
13
If different methods give different estimates, the lowest value should be taken and a margin of
safety built into the actual starting dose. If the pre-clinical data are likely to be a poor guide to
responses in humans, the calculated starting dose should be reduced, and the dose increased in
smaller increments lest the dose-response curve be steep. A detailed discussion of the MABEL
can be found in a recent paper by Muller et al.37
Increasing the dose
In an ascending dose trial, the dose is often increased three- to five-fold at each increment at
the lower doses and smaller increments around the expected therapeutic range. Increases in
dose, and the amount, should be made only after carefully assessing all of the available data
from previous doses. Serial measurements of the IMP in blood during the trial allow increases
in dose to be guided by exposure to the IMP.11 As a general rule, the dose/toxicity or dose/effect
relation observed in non-clinical studies, depending on which is steeper, should guide the dose
increment between the two dose levels. The steeper the increase in the dose/toxicity or dose/
effect curves, the lower the dose increment that should be selected.38
The investigators and the sponsors physician, and the sponsors expert in pharmacokinetics,
if appropriate, should review all of the available data, including the pre-clinical data, before
deciding to increase the dose. Sponsors without a physician experienced in First-in-Human
studies should use an independent medical monitor. An intermediate dose should be given if
there are any concerns about tolerability and safety of the IMP or exceeding the NOAEL, but
only if the protocol (Section 7) allows. The basis of all decisions on increasing the dose must be
documented.
Administration of doses
The number of subjects dosed on any one occasion, and the interval between dosing individual
subjects and cohorts of subjects, will depend on the IMP, its route of administration, and the
type of trial. For example, only one subject should be given an active IMP at the very first
administration of a high-risk IMP. And if the route of administration is intravenous, the dose
should be given by slow infusion, perhaps over several hours, rather than by rapid injection,
unless there is a good reason for that method. The protocol should include details for the rate
and duration of infusion. In contrast, if the IMP is of low risk and the route of administration
is oral, cohorts of subjects can be dosed on the same occasion, and at short intervals, say every
510 minutes.
Facilities and staff
First-in-Human trials of an IMP are regarded as higher risk than later Phase 1 trials. However,
the risk during transition from pre-clinical studies to the very First-in-Human trial may be
no higher than it is during other transition trials, such as from single to multiple doses, from
young to elderly subjects, and from administration of the IMP alone to giving it with established
medicines during interaction trials. Sponsors must place their trials of an IMP especially
a First-in-Human trial and other transition trials with Phase 1 units, including their own,
whose staff, premises and facilities (Section 9) match the level of risk of the IMP. Furthermore,
investigators must not take on trials of an IMP for which they do not have adequate experience
or training (Section 10).
The investigator must assess the risk of harm, by reviewing the protocol, investigators brochure,
IMP dossier, CTA application (Section 12) and, as required by the Declaration of Helsinki,39 any
relevant medical and scientific literature. In addition, the investigator must weigh the foreseeable
risks and inconveniences against the expected benefits for the individual subject, and for future
subjects with the target disease. Finally, the investigator must explain and justify any risks in the
information leaflet for trial subjects (Section 11) and in the REC application (Section 13).
14
Appendix 1 of the MHRAs accreditation scheme document lists a range of standards relating to
facilities, staff and procedures that are expected to be met by clinical research units conducting
Phase 1 studies in the UK. These standards serve as guidance even for units that opt not to apply
for accreditation.
Procedures
Non-invasive trial procedures should be used whenever possible. If invasive procedures such
as an arterial cannula, a biopsy or an endoscopy are used, they must be done or supervised by
someone skilled in the procedure.
Subjects
The decision as to whether a Phase 1 trial should be conducted in healthy subjects or patients
should be made on a case-by-case basis. Compared with patients, healthy subjects are easier
to find, more robust, free of other medicines, more likely to respond uniformly, and better
at completing long and complex trials. Typically, healthy subjects tolerate IMPs better than
patients.42 On the other hand, for some IMPs, obese subjects or subjects with high serum
cholesterol may be more suitable than truly healthy subjects. Other IMPs such as cancer
therapy and most types of gene therapy (Section 12) should be given only to patients with
the target disease (Section 11). Pharmacokinetic and/or pharmacodynamic findings in healthy
subjects might have limited predictive value compared to the situation in patients.
6: Safety record of Phase 1 trials

Reviews of the safety of Phase 1 trials show that they have a good safety record.40 - 42 Overall,
the incidence of serious adverse events related to the IMP was about 0.02%. However,
some healthy subjects have died. A man died of cardiac arrest after taking an IMP in a
trial in Ireland in 1984. When he was screened for the trial, he did not declare that he had
recently been given a depot injection of an anti-psychotic medicine.43 A woman died after
receiving a high dose of lidocaine a widely used local anaesthetic to prevent discomfort
from endoscopy in a trial in the USA in 1996.44 She was discharged soon after the procedure
and died at home. Another woman with mild asthma died of lung damage after inhaling
hexamethonium in a trial in the USA in 2001.45 Hexamethonium is an old medicine given by
injection to treat conditions other than asthma and is now rarely, if ever, used. Lung toxicity
of hexamethonium was first reported many years ago.46
These cases show that established medicines as well as IMPs have the potential to harm subjects
in Phase 1 trials. Also, they highlight the need to:
contact the subjects General Practitioner (GP) to check the medical history (Section 11)
keep subjects overnight when necessary, and
review all the relevant scientific and medical literature before starting a clinical trial.
At one time, almost all IMPs were new chemical entities (NCE). Now, many are biological in
nature (Section 16). Many biological IMPs such as proteins,47 cytokines,48 and monoclonal
antibodies49, 50 have been tested safely in First-in-Human trials in healthy subjects or in patients.
However, compared with NCE, there is a paucity of data about their overall safety. Some reasons
why biological IMPs, especially monoclonal antibodies, should be seen as different from NCE are:
Proteins can cause anaphylactic or infusion reactions.
Even a single dose of a fully humanised protein can induce an immune response.51
There is a report of a delayed hypersensitivity reaction52 to re-challenge with a monoclonal
antibody after a long period of non-exposure.
15
Two monoclonal antibodies53, 54 in clinical use have caused progressive multifocal

leukoencephalopathy(PML), a rare and usually fatal infection of the brain and spinal cord
due to reactivation of a virus (JC polyoma) which most people carry. However, PML has
almost always occurred in patients with profound immune dysfunction.
TGN1412 a monoclonal antibody that differs from those in clinical use in that it activates
rather than blocks an immune response caused a cytokine storm and organ failure in all
six previously healthy subjects who received it in a First-in-Human trial.34
If the risk of giving a biological IMP to healthy subjects is more than minimal, patients with the
target disease might be studied instead (Section 11). However, the substitution of patients for
healthy volunteers must be carefully considered, especially if no potential benefit is expected
to arise from participation in the study. Their condition might make patients more susceptible
or less tolerant to unwanted effects from the investigational product. Also, the mass of tissue
being targeted by the IMP may be much increased in patients compared with healthy subjects.
A careful risk/ benefit analysis should be performed before deciding on the appropriate study
population. Properly validated biomarkers17 may help monitoring potential risks.
7: Protocol
A clinical trial must be scientifically sound and described in a clear, detailed protocol.22
Compared with the protocol for an IMP at later phases of development, the protocol for a Phase
1 trial should emphasise:
the pre-clinical information such as pharmacology and toxicology about the IMP
the assessment of risk of harm from the IMP, trial procedures and any non-IMP (Section 18),
the justification of that assessment, and how the risk will be kept minimal throughout the trial
the methods of deciding: the first dose; the maximum dose; the increases in dose; the route
of administration; the rate of administration of intravenous doses; the interval between
dosing individual subjects; and the number of subjects to be dosed on any one occasion; the
minimum set of data or subject numbers required for decision-making
any assessment of dose- or concentration-response relations
any pharmacy work needed to prepare doses of the IMP for administration (Sections 14 and 15)
stopping or withdrawal criteria.
Many Phase 1 trials, especially the early ones, cannot be completed without protocol
amendments. There are three types substantial, urgent and minor. An amendment is
substantial if it is likely to have a significant impact on:

the safety or physical or mental integrity of the trial subjects

the scientific value of the trial
the conduct or management of the trial, or
the quality or safety of any IMP used in the trial.
The sponsor decides whether an amendment is substantial, and whether a substantial

amendment requires MHRA and/or REC approval. Guidance on what constitutes a substantial
amendment can be found in CT1 Vol 10, as well as the SOP of the National Research Ethics
Service (NRES). The investigator and sponsor may implement a substantial amendment without
REC and MHRA approval, respectively, if the change is an urgent safety measure to protect the
trial subjects. However, the investigator and sponsor must notify the REC and MHRA within
three days afterwards by telephone first and then by a written report.
16
In order to cope with unexpected findings, and to prevent the need for protocol amendments, an
appropriate degree of flexibility should be built into the protocol. For example, there should be
scope to modify dose increments and frequency of blood sampling as safety and pharmacokinetic
data become available. Additionally, the investigators should be able to use their clinical
judgment to allow inclusion of subjects with minor out-of-range results of safety tests of blood
and urine, and minor variants of the ECG.
The need to increase efficiency in the drug development process has seen the introduction of
more flexible protocol designs (so-called adaptive designs), where progression within a given
study (eg subsequent doses in an ascending dose study) is not dictated by the protocol but by
the results of individual trial sections. In such a setting, the protocol would simply provide the
framework (eg minimum and maximum doses to be administered) but leave the exact dose at
any given step and the number of steps to be determined during the trial depending on interim
results, thus being adaptive to the findings during the trial.
8: Contracts
When entering into an agreement to conduct a trial, the sponsor must provide the investigator
with copies of: the protocol, up-to-date investigators brochure, IMP dossier, CTA application
and approval letter, indemnity, and insurance (Section 22), all of which the investigator must
review.
If the investigator agrees to do the trial, there must be a written, dated and signed trial-specific
contract between the sponsor and the investigator, and between the investigator and any
subcontractors, which sets out the obligations of the parties for trial-related tasks and for
financial matters. Examples of subcontractors are a laboratory and a commercial archivist. The
protocol may serve as the basis of a contract. In order to protect the trial subjects, contracts must
be in place before the start of the trial.
The contract between the sponsor and the investigator should state that the investigator agrees to:
start the trial only after it has been approved by the MHRA and REC
start and complete the trial in realistic times
undertake all the trial-related duties and functions allocated by the sponsor to the
investigator
carry out the trial according to the Clinical Trials Regulations and Amendments, GCP, GMP,
all relevant regulatory requirements, and the protocol agreed to by the sponsor and approved
by the MHRA and REC
comply with procedures for recording or reporting data
allow direct access, by the sponsors monitors and auditors, and by the MHRA and REC, to
the trial site, and to source documents, source data, and reports.
Also, the contract should include statements relating to:
confidentiality, publication policy, payments, reasons for non-payment, stopping the trial,
storing and destroying trial-related documents, any equipment provided by the sponsor, and
ownership of trial materials, records and results, and
the sponsor abiding by Section 22 of these ABPI guidelines about compensation for injury to
trial subjects and indemnity for the investigator.
Units that manufacture or import IMPs must have a technical agreement with the sponsor
(Section 15).
17
The sponsor may transfer any or all of their trial-related duties and functions to a CRO. The CRO
must have sound finances, so that they can meet their contractual obligations. Thus, in these
ABPI guidelines, what applies to the sponsor may also apply to a CRO. However, the sponsor
retains overall responsibility for the trial.
9: Trial subjects
Recruitment
Potential trial subjects may be recruited:
from a paper or electronic database of people who have indicated their willingness to take
part in a trial
by advertisements in a newspaper or magazine, or on a noticeboard in places such as a
university or hospital, or on the radio or television, or on a website
by word of mouth, or
by referral from another doctor.
All study-specific advertisements must be approved by a Research Ethics Committee The
Clinical Trials Directive guidance document on REC applications22 and the ABPI Medical
Commission Guideline55 give advice about advertising for subjects for clinical trials.
Advertisements should say that the trial involves research and that the advertisement has
been approved by a REC, and should give a contact name and phone number and some of the
selection criteria. In addition, advertisements may give the purpose of the trial, where it will
take place and the name of the company or institution carrying it out. However advertisements
must never over-stress payment, use REC or MHRA approval as an inducement, name and
promote the product, or claim that it is safe.
In contrast to study-specific advertisements, general advertising and screening procedures do
not need to be reviewed by an ethics committee. General screening constitutes non-invasive
procedures that are undertaken to evaluate a subjects eligibility to join a trial units volunteer
panel. Further guidance can be obtained from Section 4.55 of the Standard Operating Procedures
For Research Ethics Committees (of the United Kingdom).30
Whatever the method of recruitment, subjects must be recruited of their own free will. They
should not be made to feel obliged to take part in a trial, nor should they suffer in any way if they
do not take part. Additionally, they should be recruited only if they:
are capable of giving valid consent, and
have been fully and properly informed so that they understand:
- the nature and purpose of the trial
- any risks, either known or suspected, and any inconvenience, discomfort or pain that they
are likely to experience
- that they can withdraw at any time and without giving a reason
- that the investigator may withdraw them at any time if they do not follow the protocol or
if their health is at risk.
All units must keep records of subjects who take part in their trials and avoid excessive use of
any subject. The number of trials that a subject may take part in during any 12-month period will
depend on:
the types of IMP and their half-lives
the routes of administration of the IMP
18
the frequency and duration of exposure to the IMP

the procedures involved, and
the total volume of blood taken from the subject.
Subjects must not:
take part in more than one trial at a time
receive more than 10 milliSievert of radioactivity (Section 17) in any 12-month period.
In general, subjects should not receive an IMP systemically less than three months after the
previous one. However, on occasions a shorter interval may be justified, especially when using
well-characterised, marketed drugs with a short half-life and little risk of carryover effects.
Monitoring overexposure
Trial subjects must provide proof of identity before they take part in a trial and should be
monitored and prevented from taking part in too many trials. The ways to ensure this are:
counselling the subject
including warnings in the information leaflet and consent form
for units to keep a register of their clinical trials and subjects who have taken part in them
keeping photographic evidence of a subjects identity should be considered
contacting the GP
being vigilant when screening trial subjects, eg look for evidence, such as needle marks on
the forearm and low blood counts, that the subject may have taken part in a trial recently,
and
using an internet-based central register called TOPS,56, 57 which is run by a registered charity
and used by most UK Phase 1 units.
REC applications must include information about procedures for checking simultaneous or
recent involvement of potential subjects in other trials.7
Special populations
Women
A woman capable of having a child should take part in a trial of an IMP only if:
the reproductive toxicology studies have been completed and the results raise no concern
against participation in clinical trials58 or there is a good reason why reproductive toxicology
studies are not needed
she is not pregnant, according to her menstrual history and a pregnancy test
she will not be at risk of becoming pregnant during and for a specified interval after the trial
she is warned about the potential risks to the developing child should she become pregnant,
and
she is tested for pregnancy during the trial, as appropriate.
Women using a hormonal contraceptive, such as the pill, should use an alternative method of
contraception until the possibility of an interaction with the IMP has been excluded.
Children
IMPs should be tested in healthy children only if the circumstances are exceptional and the
guidelines for trials in children are followed.59, 38
Elderly
Trials of IMPs in elderly subjects are justified if the product is intended for use in the elderly,
and especially if its effects and metabolism might differ from those in younger subjects.
19
Vulnerable subjects
Investigators must be wary of recruiting vulnerable trial subjects, such as the unemployed, or
employees of the company or students of the institution that is sponsoring or carrying out the
trial. Employees and students are, or may feel, vulnerable to pressure from someone who can
influence their careers. Should such subjects decide to take part in the trial, they must be dealt
with like other subjects in the trial, and not be allowed to let their normal work interfere with
the trial. The investigator should forewarn employees, in a written agreement, of the possible
implications of having their personal data processed at work by their colleagues. Employees
and students may need to get permission from their employer or institution beforehand. Some
sponsors bar use of employees from trials of IMPs.
Patients
All non-therapeutic trials of IMPs whether they involve healthy subjects or patients are now
called Phase 1 trials.7 The following are examples of Phase1 trials involving patients.
Subjects who are well but have a chronic, stable condition such as asthma, hayfever, type
2 diabetes or hypertension may be given single doses or short courses of an IMP from
which they do not benefit therapeutically. Such trials, especially if they include a challenge
agent (Section 18), can help decide whether or not to proceed to trials in larger numbers of
patients, who may benefit therapeutically.
The First-in-Human trial of a cytotoxic IMP to treat cancer is sometimes single-dose rising
in design, to assess the pharmacokinetics of the IMP. Such trials have to be done in patients.
Regulatory authorities usually want sponsors to do trials on the pharmacokinetics of an IMP
in patients with varying degrees of impaired kidney or liver function, and if necessary to
recommend adjustments to the dose in such patients. Such trials are difficult to do because of
slow patient recruitment and ethical concerns. For those reasons, they are usually done late
in the development of the IMP.
Payments
Many trials are demanding of the subject and involve long periods of residence, many visits
to the trial site, urine collections, and multiple blood tests and other procedures that cause
discomfort, as well as lifestyle restrictions. So it is right to pay subjects healthy subjects and
patients who volunteer for Phase 1 trials more than just any expenses that they incur.5 The
amount should be related to the duration of residence on the unit, the number and length
of visits, lifestyle restrictions, and the type and extent of the inconvenience and discomfort
involved. As a guide, payments should be based on the minimum hourly wage60 and should
be increased for procedures requiring extra care on the part of the subject or involving more
discomfort.5 Payment must never be related to risk.
Subjects who withdraw or are withdrawn even for medical reasons should not always be paid
the full amount. The investigator should decide the amount of payment depending on the
circumstances. Payment may be reduced, if a subject does not follow the protocol, or may be
increased, if the protocol is amended to allow further tests or visits.
If a trial is postponed or cancelled, subjects may be paid for setting aside time to do the trial.
Reserve subjects, who stand by in case someone drops out or are withdrawn from the trial
before first dosing, should be paid.
The policy on paying trial subjects, and the amount, must be stated in the subject information
leaflet and be approved by the REC.
20
Obtaining informed consent

The investigator or delegate must:
obtain the consent of subjects only after the REC has approved in writing the information
and consent form
fully inform potential trial subjects before they agree to take part in the trial
give the subjects oral and written information that is free of jargon and is easy to understand
give the subjects enough time and opportunity to ask questions about the trial, answer their
questions accurately and honestly, and ensure that they understand the answers
ensure that neither the investigator nor other staff coerce subjects to take part or continue to
take part in the trial
give the subjects, in writing and after approval of the REC, any new information that might
make them change their mind about taking part in the trial, and
ensure that the subjects, and who informs them, sign and date a consent form, and are given
a copy.
Details of the contents of the information and consent form are in Appendix 2. NRES has issued
guidelines61 for writing information and consent forms for clinical trials. The Plain English
Campaign62 gives advice about how to write medical documents for members of the public.
Screening
The investigator should judge trial subjects suitable on the basis of tests, such as:

a medical history and examination

medicines taken within a set period before the start of the trial
a 12-lead ECG
routine safety tests of blood and urine
tests for drugs of abuse such as alcohol, cannabinoids, cocaine, morphine, benzodiazepines,
barbiturates and amphetamines
tests for HIV, hepatitis B and hepatitis C
pregnancy tests in women capable of having a child and at risk of becoming pregnant
trial-specific tests, such as 24-hour ambulatory ECG, echocardiogram, lung function tests,
kidney function tests and genetic tests
for IMPs that affect the immune system: tests to exclude active or recent infections, such as
tuberculosis and genito-urinary infection, and willingness not to travel to countries for which
vaccinations are intended or that present a higher risk of infectious diseases during the
period that the IMP may be active, and
information from the General Practitioner.
Before subjects decide to have the tests for viruses and for drugs of abuse, the investigator must
explain to them what will happen if one of the tests turns out to be positive.
Healthy subjects often have minor out-of-range results of safety tests of blood and urine, and
minor variants of the ECG. For example, serum transaminases that are out-of-range,63 red blood
cells in the urine,64 and nodal rhythm of the ECG65 are common findings. Some monitors and
auditors regard these as deviations from the protocol of a trial in healthy subjects. However,
usually they have no clinical relevance and do not justify excluding subjects from a trial. A
physician should decide their clinical relevance, and the protocol should allow for use of clinical
judgement. If subjects are deemed unsuitable for a trial, they should be told why.
Investigators should ask potential trial subjects if they have taken part in a study in previous
months. In addition, they should look for evidence, such as needle marks on the forearm and low
blood counts, that the subject may have taken part in a trial recently.
21
Timing of recruitment and screening

Panel: Investigators can recruit and screen subjects at any time for a panel of subjects interested
in taking part in a Phase 1 trial, providing the REC has given written approval of the screening
protocol and the subjects have given written consent.
Specific trial: Investigators can start to recruit subjects for a specific trial after the REC has given
written approval. However, investigators must not screen subjects for a specific trial before
obtaining written approval of both the REC and MHRA, and of course the subjects.
If the investigator has REC approval for panel recruitment and screening, and if the sponsor
agrees, the investigator may transfer subjects and their data from a panel to a specific trial, but
only after the REC and MHRA have both given written approval for the specific trial and the
subject has given written consent for the specific trial. Before transferring subjects, investigators
must not carry out procedures that are not covered by the protocol for panel recruitment and
screening.
Identification
Subjects who are judged suitable at screening should be photographed to check their identity at
subsequent visits to the unit. Subjects who are resident in the Phase 1 unit should be fitted with
some form of identification, such as a wristband, with the subjects number and trial code. The
subjects identity must be checked before carrying out procedures, such as taking blood samples,
giving the trial IMP, or recording information in the case report form. The subjects number or
barcode should be used on all samples and results.
Informing the subjects General Practitioner
The investigator should ask potential trial subjects for permission to contact their General
Practitioner (GP). Subjects who do not have a GP or do not want their GP to be contacted should
be excluded from the trial unless there is a good reason to the contrary.
The investigator should inform the GP that their patients have agreed to take part in a trial and
should ask if their patients:
have or have had any relevant illnesses
are taking or have recently taken any medicines
have taken part in another clinical trial recently.
The investigator should ask the GP to reply in writing and may offer them payment for
responding. The investigator must be able to justify including in the trial a subject whose GP
does not give any information. Whether or not the GP responds, the investigator is ultimately
responsible for making sure that subjects are suitable for the trial before allowing them to take
part in it.
Safety
The investigator must assess the health of trial subjects throughout the trial and should
withdraw any subject whose health is at risk. The methods, which should be described in the
protocol (Section 7), include:

asking subjects about adverse events

medical examinations
measuring vital signs such as heart rate and blood pressure
routine safety tests of blood and urine
continuous monitoring of variables such as the ECG and pulse oximetry, and
trial-specific tests, such as lung function tests.
22
Follow-up
The investigator must follow up:
all subjects after their last dose of IMP, for a period depending on the IMP and the trial
subjects with adverse events, including clinically-relevant abnormal laboratory results, until
they have resolved or it is clear that they are resolving, and
subjects who withdraw or are withdrawn from a trial, as if they had completed it, providing
they agree.
10: Research Ethics Committee

General
Before starting a Phase 1 trial in healthy subjects or in patients, the investigator must obtain
written approval of a Research Ethics Committee (REC) recognised by the United Kingdom
Ethics Committee Authority (UKECA). Guidance on the process of applying for ethics approval,
types of RECs, communications with RECs during a clinical trial, and protocol amendments can
be found on the website of the National Research Ethics Service.
11: Pharmacy
All units should have a designated pharmacy area that is secure and accessible only to certain
staff. The type of premises, facilities and equipment should reflect the types of trial that the
investigator does for sponsors. For example, the investigator for a trial of an IMP that is packed
and labelled ready for administration to individual subjects will need only basic facilities to store
and dispense the IMP, and procedures to keep records of its receipt, use, disposal and retrieval.
However, an investigator who assumes some or all of the sponsors responsibilities for an IMP
will need to have the right premises, facilities, equipment and procedures, such as:
premises that are purpose-built or adapted for the purpose
the right environment, such as directional air-flow that is controlled for particles,
microbiological contamination and temperature, and is monitored appropriately
a designated storage area, with a quarantine area, for the IMP
the right equipment, such as a laminar flow cabinet to prepare sterile products
procedures to comply with GMP23 and the annexes, especially the current versions of annex
1,24 annex 13,25 and annex 1626
a rigorous quality management system, and
a Manufacturers Authorisation [MIA (IMP)]7 to manufacture, assemble or import IMPs,
including placebo and other comparators.
Storage
IMPs should be stored in designated areas under conditions and for times recommended by the
sponsor. Storage areas should:

23
have adequate space for different IMPs to be stored apart

be temperature-controlled and, if appropriate, humidity-monitored, with alarm controls
be protected from direct sunlight
be mapped to identify and avoid using hot and cold spots, if appropriate
be secure
be accessible only to authorised staff
have records for logging IMPs in and out.
The pharmacy should keep a stock of marketed medicines for managing common adverse
events such as headache and nausea and for managing medical emergencies other than
cardiopulmonary resuscitation (Section 20) such as convulsions and low blood sugar. The
sponsor should indicate whether an antidote to the IMP exists and ensure its supply. These
medicines must be readily available to clinical staff.
Staff
The pharmacy staff must be suitably qualified and experienced, and sufficient in number for the
type and amount of work that the pharmacy undertakes.
A registered pharmacist, ideally with manufacturing experience, should prepare or assemble the
IMP. A pharmacist may delegate work to pharmacy technicians or assistants, but must supervise
their work.
A physician or a pharmacist should have overall responsibility for IMPs and marketed
medicines, including emergency medicines.
Holders of an MIA (IMP) must:
allow the MHRA to inspect the premises at any reasonable time
have access to a qualified person
provide the qualified person with adequate facilities and staff.
Types of work
The work that the pharmacy might undertake, and for which GCP and GMP sets the standards,
includes: importing; packaging and labelling; randomisation; manufacture; batch release;
sampling and testing; blinding and emergency unblinding; retrieval; and disposal.
12: Investigational medicinal products

Manufacture
Whoever imports, manufactures, assembles or repackages IMPs must apply for and get a
Manufacturers Authorisation [MIA (IMP)]7 from the MHRA and must follow GMP. Many of
the pharmacy tasks that Phase 1 units do for sponsors need an MIA (IMP). Some examples are:
re-packing bulk capsules or tablets into unit-dose containers, and randomising and labelling
them
weighing bulk material directly into capsules
preparing, under aseptic conditions, a formulation for parenteral use
receiving labelled unit-dose containers from a third country.
During the early stages of development of an IMP, the manufacturing process may change as the
sponsor learns more about the product. So the sponsors early formulations of an IMP may be
primitive and require finishing work by the Phase 1 unit before they are ready for administration
to the trial subjects.
Documents
Pharmacies that manufacture or prepare IMPs must have written instructions and records for
their manufacturing processes. It should be possible to trace the history of each batch and any
changes introduced during IMP development.
24
Records
The pharmacy should keep records of manufacture, preparation, packaging, quality control,
batch release, storage conditions, and shipping of an IMP.
Supplying the investigator
The sponsor should not supply the investigator with an IMP before:

the CTA application is approved in writing

the REC application is approved in writing
the IMP has been certified by the sponsor
the code-break is in place
the technical agreement between sponsor and investigator is in place.
However, the sponsor may release the IMP to the qualified person (Section 19) of the Phase 1
unit, providing he or she quarantines it until the above conditions have been met.
Transport to the trial site
The sponsor should pack the IMP properly and ensure that storage requirements are met during
transport to the investigator. If the IMP is transported cold or frozen, temperature loggers
should be added to the container.
Accountability at the trial site
The investigator, pharmacist or other delegate should keep records of each stage of the handling
and use of an IMP, such as:

receiving it and assessing its condition on arrival, and notifying the findings to the sponsor
dispensing or manufacturing it
giving each subject the dose or doses specified by the protocol
returning unused product to the sponsor or delegate, or destroying it, as instructed by the
sponsor
keeping an inventory
reconciling all the IMP received from the sponsor.
These records should include the dates, quantities, batch numbers, expiry dates and the unique
code numbers assigned to the IMP and to the trial subjects.
Recall
The unit must have a system for retrieving the IMP promptly at any time.
Retention of samples
Manufacturers or importers of the IMP must retain samples of each batch of bulk product,
and of the packaging components used for each finished batch, for at least two years after
the trial. Pharmacies may not be able to meet those requirements if they manufacture only
small quantities or individual doses of an IMP, or if the finished product is unstable. In those
circumstances, the MHRA may agree to other sampling conditions, which should be described
in the protocol or the CTA application.
Randomisation
There should be written procedures as appropriate for generation, distribution, handling and
retention of any randomisation code used for packaging an IMP.
Emergency unblinding
The investigator or delegate must have a written procedure for rapidly identifying a blinded
IMP in an emergency. The procedure must be secure, readily available at all times during the
trial, and not allow breaks of the blinding to go undetected.
25
Quality management
Manufacturing and dispensing IMPs is more complex than manufacturing and dispensing
marketed products due to:

production processes that are often not validated

the lack of fixed routines
the increased risk of contamination, including cross-contamination
the need for blinding and randomisation in most trials.
Therefore, units must have robust quality control and quality assurance procedures for
manufacturing and dispensing IMPs. The people responsible for manufacturing and dispensing
should be independent of those responsible for quality management.
13: Biotechnology products

General
Examples of biotechnology IMPs (also called biological IMPs) are: recombinant proteins,
hormones, cytokines, monoclonal antibodies, genetically modified micro-organisms (GMM) and
gene therapy. They are regulated differently from other IMPs, as follows.
They need different pre-clinical studies to support clinical trials.66
The Clinical Trials Directive allows the MHRA and REC an extra 30 days to review trials of
gene therapy, somatic cell therapy or GMM. It allows another 90 days to consult others.
Clinical trials of gene therapy need approval of the Gene Therapy Advisory Committee
(GTAC)67 in addition to the MHRA and REC.
Clinical trials of live GMM must follow the Health and Safety Executive regulations
controlling contained use of GMM.68 Guidance on risk assessment and containment is
available from www.hse.gov.uk.
The MHRA handles trials of higher risk biological IMPs differently from trials of other IMPs
(Section 12).
Proteins and monoclonal antibodies
Units must have the appropriate experience (Section 6), facilities (Section 9), and staff
(Section 10) to do trials of these types of IMPs. The investigator must be capable of managing
immune reactions, including anaphylactic reactions.69 Proteins often have long half-lives, and
are designed for infrequent dosing regimens in patients. Thus, depending on the molecules
characteristics, there should be enough follow-up of subjects three months or even longer to
obtain a full pharmacokinetic profile and to allow reliable assessment of the immune response.
Gene therapy
Gene therapy is the deliberate introduction of genetic material into human somatic cells for
therapeutic, prophylactic or diagnostic purposes. Examples include genetically modified viral
vectors and naked DNA injection. GTAC has issued guidelines for applications for gene therapy
trials,67 and expects the investigator to have:

a substantial multidisciplinary team of researchers

suitable clinical and laboratory facilities
on-site support, such as infection-control measures
a proven track-record of high-grade clinical research.
Investigators who are unsure if an IMP is gene therapy, or if it is appropriate to give it to healthy
subjects, should seek advice from GTAC. GTAC has approved certain non-therapeutic trials of
gene therapy in healthy subjects.
26

Some GMM, such as vaccines containing genetically modified viruses intended to raise a
prophylactic immune response to the wild virus, can be given to healthy subjects. GTAC does
not normally wish to review such trials.
14: Radioactive substances

General
Radioactive substances contain a radioactive isotope. Examples of radioactive substances that
may be given to healthy subjects are:
radiolabelled IMPs usually with 14C but also 3H, 99mTC and other isotopes to assess their
absorption, metabolism, elimination and gastrointestinal transit as well as the performance of
individual product formulations
imaging agents such as receptor ligands labelled with 11C or 18F for PET (positron emission
tomography) scans, and ligands labelled with 99mTc for SPECT (single photon emission
computed tomography) scans to produce images of organs such as the brain or heart
biological products such as red blood cells labelled with 51Cr or proteins labelled with 131I
to assess their life span
radiolabelled products with which to assess the effect of an IMP on normal function, such as
51
Cr-EDTA to assess renal function, and 99mTc to assess cardiac function.
Administration of radioactive substances is governed by the Medicines (Administration
of Radioactive Substances) Act (MARS)70 and the Ionising Radiation (Medical Exposure)
Regulations (IRMER).71 Clinical trials of radioactive substances must follow the Ionising
Radiations Regulations72 and must be approved by the Administration of Radioactive Substances
Advisory Committee (ARSAC) before they can start. ARSAC decides if the radiation exposure
that the trial subjects are to receive is within acceptable limits. ARSAC guidelines73 state that
the radiation dose should be as low as reasonably practical in healthy subjects, and should not
exceed
10 milliSievert annually.
A hospital department of nuclear medicine may have a licence to use a radionuclide, such as
99m
Tc, for routine diagnostic purposes in patients. However, a clinical trial involving 99mTc in
healthy subjects still needs ARSAC approval.
Microdose trials
A single microdose of a radiolabelled IMP can be used to obtain early information about its
pharmacokinetic or receptor-selectivity profile by means of PET imaging or AMS (accelerator
mass spectrometry)74 or other very sensitive analytical techniques. A microdose is defined as less
than one hundredth of the predicted pharmacological dose but not exceeding 100 micrograms.75,
76
Because the risk of harm from a microdose is much lower than a pharmacological dose, fewer
or different pre-clinical studies are required to support a microdose trial. Also, a very low dose
(less than 1 microSievert) of radiation does not need ARSAC approval.73
The premises must be located, constructed and maintained to suit the operations to be carried
out in them, and must be registered by the Environmental Agency under the Radioactive
Substances Act77 to keep, use and dispose of radioactive materials. Sites that manufacture
radiopharmaceutical products must comply with specific GMP guidelines78 as well as standard
GMP guidelines. When making an ARSAC application for a trial, investigators must provide
evidence of the suitability of:
27
the equipment to undertake the procedure involved

the working areas and related equipment
the staff to supervise, dose and nurse the trial subjects.
For example, a trial of a radiolabelled IMP to assess its absorption and metabolism needs
only facilities to collect specimens of the subjects blood, urine and faeces, a suitable counter
to measure radiation, for safety purposes, and access to a laboratory scintillation counter to
measure radioactivity in the specimens. In contrast, a trial involving an imaging agent, such as a
ligand labelled with 11C or 18F for PET scans, needs much more sophisticated resources, including
access to a cyclotron unit to make the ligand, and a PET scanner to measure binding to the
receptor site.
Staff
The investigator must hold a certificate from ARSAC to administer or supervise the
administration of radioactive substances. Applicants for certificates are normally of consultant
status and supply information on their training and experience as well as on the services
such as departments of radiopharmacy and medical physics that support them. Other staff
should be suitably qualified and experienced. There must be a Radiation Protection Supervisor
whose work must be supervised by the area Radiation Protection Adviser. Trials of radioactive
substances usually need the collaboration of several groups of experienced researchers.
Trial subjects
When selecting healthy subjects for trials of radioactive substances,73 the investigator should:

study subjects over 50 years old, unless younger subjects can be justified
study as few subjects as possible
exclude women capable of having a child
not expose subjects to more radiation than necessary
exclude subjects exposed to radiation during their work
exclude classified radiation workers
exclude subjects who have received more than 10 milliSievert of radioactivity in the past 12
months.
15: Non-investigational medicinal products

Non-investigational medicinal products (non-IMPs) are often used during Phase 1 trials:
to induce a physiological or pharmacological response to assess the activities of an IMP
(in which case they are often called challenge agents), or
as support or escape medication for preventative, diagnostic or therapeutic reasons.
Under these circumstances, they do not fall within the definition of an IMP25 and investigators
who prepare them do not need a Manufacturers Authorisation for an IMP (MIA (IMP)). Nor
does a trial of a non-IMP by itself require a CTA.
An algorithm defining what does and does not constitute a NIMP can be found on the MHRAs
website.79 The site also contains a file with mock examples of NIMPs. Further guidance on the
requirements for and the use of NIMPs can be found in the European Unions Guidance on
Investigational Medicinal Products (IMPs) and Other Medicinal Products used in Clinical Trials,
Volume 10, Chapter 5.22
The ABPI maintains an online register for the purpose of sharing adverse event data associated
with NIMPs in Phase 1 clinical trials (www.nimps.org/).
28
16: Qualified Person

Requirements
Units with a pharmacy that manufactures, assembles or imports IMPs, including placebo and
other comparators, must have an MIA (IMP) on which a qualified person (QP) must be named.
A QP is someone who meets the permanent provisions of Directive 2001/83/EC80 or is someone
who met the eligibility criteria during the transitional period7 after implementation of the
Clinical Trials Directive. People who achieved QP status during the transitional period should
make sure that their job description accurately reflects the duties of a QP80 and that they keep up
to date with GMP.
Responsibilities
The QP must make sure that:
each batch of IMP that is made within the EU meets the requirements of GMP and the CTA
for an IMP made in a third country, each batch meets the requirements at least equivalent to
those in the EU, and the CTA requirements
for a comparator from a third country, if documents are not available to show that it was
made in accordance with EU GMP, that it has had all the analyses, tests or checks necessary
to confirm its quality in accordance with the CTA.
The scope of the work of the QP will depend on what the sponsor delegates to the unit. For
example, a unit might receive, store and account only for an IMP made in the EU, and a QP need
not be involved. On the other hand, a unit might import the IMP from a third country, obtain
evidence that it was made according to GMP, store it, manufacture or assemble batches of it,
release it, and account for it, and the services of a QP would be essential.
In an industrial setting, a single QP cannot usually be closely involved with every stage of
manufacture, so the QP who certifies a finished product batch may have to rely on the advice
and decisions of others. Before doing so, the QP must ensure that the advice is well founded. If
another QP confirms compliance with GMP, he or she must do so in writing and state exactly
what is being confirmed. The arrangements should be set out in the technical agreement.
Releasing IMP prepared by the pharmacy
It is the role of the QP to release batches of IMP. The manufacture and release of IMP for Phase
1 trials differs from that of marketed products. Marketed products are usually made in large
batches during continuous sessions of work, and a QP releases each batch before it is marketed.
Although a Phase 1 unit may prepare an IMP in one continuous session, it is more usual to
prepare an IMP for small groups of subjects or just one subject at a time, and perhaps at unsocial
hours. The time between preparing the IMP and giving it to the trial subjects may be a few hours
or even minutes. It is not clear what constitutes a batch of an IMP. It is also not practical to have
a QP available at all times. Therefore, units should devise a written procedure for releasing IMP
and be prepared to justify it during inspection for an MIA (IMP). The QP may have to release
some batches retrospectively. However, that should happen only on exception and stated in the
CTA application.
When deciding whether to accept an IMP prepared in the pharmacy for use in a clinical trial, the
QP should take into account, as appropriate:
CTA application
randomisation code
protocol and amendments
29
pharmacy instructions
pharmacy SOP
details of any deviations from procedures and action taken
production records
results of QC testing
certificate of analysis
certificate of compliance with GMP
stability data
inspection of finished product
environmental monitoring records
validation, calibration, servicing and maintenance records
findings of any audits
IMP accountability and storage records.
Manufacture of IMP
European Union or European Economic Area
If an IMP is manufactured in EU countries, an MIA (IMP) is required as part of the CTA
application, to show that the IMP has been made to GMP standards. The same applies to an IMP
made in the European Economic Area (EEA). The sponsor provides evidence of compliance
with GMP, and a QP signs off each batch.
Third country: importing an IMP
If an IMP is manufactured in a third country (outside the EU or EEA), the QP named on the
MIA (IMP) who authorises importation must certify that the IMP has been made to GMP
standards. The QP must submit a declaration available on www.mhra.gov.uk as part of the
CTA application.
The EU has negotiated a Mutual Recognition Agreement (MRA)33 with some countries, and
equivalent GMP standards apply to those countries. The latest news of MRA is available on the
website.33
17: Resuscitation procedures, equipment, medicines and training

There must be procedures, equipment, medicines and trained staff to deal with any medical
emergency that might arise during a trial, as follows.
General procedures
Trial subjects must:
have a call button by their bed and in places such as toilets and showers, to call trial staff
be given the information and consent form and an appointment card with the names and
telephone numbers of the trial physicians, so that the subject (or another doctor who might
see the subject) can call the on-call physician or a trial physician at any time.
Trial staff must have access to:
medical cover throughout the trial
an on-call doctor who they can contact by telephone at any time
the sponsors medical monitor or defined delegates whom they can contact by telephone
at any time. A cascade of contactable personnel on the sponsors side should be available to
the investigator site this can be added to the study protocol or be detailed in a separate
document
30
a procedure to report serious adverse events

the randomisation code, should a subject have a severe adverse event
an alarm system, to call for assistance in case of a medical emergency
continuous monitoring of vital signs, such as ECG and pulse oximetry
procedures for dealing with the most likely medical emergencies,71 such as profound syncope,
hypotension, anaphylaxis and cardiopulmonary arrest
a procedure to transfer a trial subject to hospital (see below).
Resuscitation equipment and medicines
In each of the main clinical areas of the premises, there must be a resuscitation trolley with
equipment and medicines that can be moved quickly to where they are needed in a medical
emergency. Each trolley should have the same equipment and medicines, which must be
checked at least weekly and after use, and records of the checks must be kept. The main items on
each trolley should be:

a defibrillator with an ECG monitor (both mains and battery operated)

suction apparatus
an oxygen cylinder and flowmeter
oropharyngeal airways and face masks
a self-inflating bag
a laryngoscope and endotracheal tubes or laryngeal mask/alternative supraglottic airway
device
consumables such as intravenous cannulae and fluid infusion sets
emergency medicines, including intravenous fluids
a transcutaneous cardiac pacer (one should be enough for the whole premises).
The website (www.resus.org.uk/pages/eqipIHAR.htm) of the Resuscitation Council (UK) has a
full list of recommended equipment and medicines.
Antidote
If there is an antidote to the IMP being tested, it must be readily available at all times. The same
applies to NIMPs.
Resuscitation training
Physicians, nurses and other staff who help to care for trial subjects must all be trained and hold
a valid certificate in basic (BLS), immediate (ILS), or advanced life support (ALS) procedures, as
appropriate.69 For example, all physicians must be trained and hold a valid certificate in ALS or ILS.
The medical director or another doctor with clinical expertise in resuscitation should set and
maintain standards of training and assessment of the units staff, and ensure that competence
is maintained by regular refresher training. Appropriately trained people, such as doctors and
resuscitation training officers, should do the training and assessment.
Further guidance on training requirements for clinical staff and medical cover can be found in
Appendix 1 of the MHRAs Phase 1 Accreditation Scheme Document.15
18: Confidentiality
Sponsors
Sponsors expect investigators to keep confidential any commercially-sensitive information, such
as the protocol, investigators brochure, IMP dossier, and CRF. Trial subjects who ask to see the
protocol should be allowed to do so, but not be allowed to keep a copy.
31
A statement about confidentiality is normally included in the trial protocol or contract. So when
trial-related documents are not in use, trial staff must store them in a secure place with access
limited to authorised people the trial staff, the sponsors monitors and auditors, the REC, and
the MHRA and other regulatory authorities. An investigator who undertakes trials for different
sponsors should keep the trials apart while they are in progress on the unit. In addition, the
monitors and auditors of different sponsors should have separate spaces in which to work
during site visits.
Trial subjects
The investigator should give each trial subject a unique identifier to conceal the subjects identity
when recording and reporting trial related data. However, the investigator must identify the
subject when contacting the subjects GP.
If employees or students of the company or institution that is sponsoring or carrying out the
trial wish to take part in it, the investigator should forewarn them of the possible implications of
having their personal data processed at work by their colleagues.
Data Protection Act
The Data Protection Act81 covers the processing of personal data, whether written or electronic,
of trial subjects. The investigator should comply by:
entering on a national register details of all the classifications of data held, the subjects and
the recipients
obtaining the subjects consent for their personal data to be processed
using personal data only for the purposes set out in the protocol and the information and
consent form
making sure that personal data are relevant to the trial, accurate, not excessive and kept for
no longer than necessary
keeping paper and electronic documents in lockable offices, archives or storage cabinets, and
allowing access only to authorised people
making sure that personal data stored on computers are secure so that only authorised
people can change or delete them
telling subjects in the information and consent form that they may see information about
themselves on request
not transferring personal data outside the EU without adequate protection.
Human Tissue Act
Investigators must have informed consent from the trial subjects and approval from the REC to
take any samples of tissue. Consent may be sought for long-term storage and future research as
well as for use in the specific trial. Under the Human Tissue Act,82 REC approval makes it lawful
to store and use the samples for the specific trial only. Sponsors who continue to store samples
after the trial has ended either for their own research or to distribute to other researchers are
acting as a tissue bank, and must obtain a storage licence from the Human Tissue Authority.82
19: Compensation, indemnity and insurance

Compensation
For many years the ABPI has required that special provisions should apply to the provision of
compensation to volunteers involved in healthy volunteer studies and patient studies that are
sponsored by industry. However, different compensation provisions have applied to healthy
volunteer studies and to patient studies. The applicable guidelines are now contained in a
composite guidance document of 2014 entitled ABPI Guidelines on compensation for injury
32
resulting from participation in sponsored clinical research. This describes the provisions
applicable to most Phase I studies and, separately, the provisions applicable to Phase II-IV
studies.
As is noted at Section 5 of these guidelines, the expression Phase 1 studies may straddle
both studies in healthy volunteers and studies in patients, depending primarily upon the
characteristics of the medicine under research and whether it is only appropriate to administer
it to patients with the target disease. The same compensation provisions now apply to all
Phase I research subjects, regardless of whether they are healthy volunteers or patient
volunteers suffering from the target disease under research, provided such volunteers have no
prospect of direct personal therapeutic benefit as a result of participation in the research in
question. The prospect of therapeutic benefit is seen as critical. Patient volunteers in oncology
or other studies at Phase I who may reasonably expect to receive therapeutic benefit would
not be affected by this change of policy. Such studies would continue to be governed by the
principles of the Phase II-IV Clinical Trial Guidelines.
The nature of the compensation policy should be clear from the information and consent form,
and subjects should be invited to seek explanation of any aspect of the undertaking that is not
clear to them.
Subjects may make a claim directly to the sponsor or through the investigator. The sponsor
should involve the investigator in any discussions with trial subjects about their right to
compensation.
The Volunteers personal insurance policies
Appendix 2 to this guidance describes the matters required by ICH GCP and legislation of the
European Union to be included in the subject information or consent form. In addition the
implications of the volunteers decision to participate in the study for any insurance cover that
the volunteer may already have or may happen to be negotiating at the time, should be drawn
to the volunteers attention. Some insurers treat participation in clinical studies as a material
fact which should be mentioned when making any proposal for health-related insurance.
Accordingly, participation in the study should be disclosed if the volunteer is in the process
of seeking or renewing any such insurance. Volunteers should also check that participation
does not affect any existing policies they hold. The Association of British Insurers has issued
guidance on this subject entitled Clinical Research trials and insurance (2011).
Indemnity
Before the start of a commercially sponsored Phase 1 trial, the sponsor must indemnify
the investigator against any loss incurred by the investigator (including the cost of legal
representation) as a result of claims arising from the trial, except to the extent that such claims
arise from the negligence of the investigator for which the investigator remains responsible.
Insurance in respect of Sponsors insurance
In relation to the sponsors obligation to comply with the above compensation policy, the
sponsor must ensure that insurance or indemnity is in place to cover its liability and that of the
investigator.
The Phase 1 unit must have insurance to cover claims for negligence, or must provide evidence
of financial resources to meet any such claim. Also, physicians involved with the trial must
have insurance - such as that offered by a medical defence organisation - that will respond to
any negligence claim. Nurses must hold professional indemnity insurance: for example, that
which is provided by membership of the Royal College of Nursing.
33
The sponsor and investigator must be able to satisfy the REC and MHRA that subjects who
take part in a Phase 1 trial are adequately protected against injury. In addition, the sponsor
and investigator should do everything possible to ensure that a subject who is involved in a
compensation claim is dealt with sympathetically and quickly.
Detailed guidance of 2011 entitled Insurance and Compensation in the event of injury in
Phase 1 clinical trials was developed by a cross-sector group convened by ABPI83. Published
alongside the guidance in June 2012 is a template Statement of Insurance Cover developed by
NRES, to give clinical trial sponsors a consistent document to provide to the ethics committee.
The statement will be incorporated into the standard application for Phase 1 clinical trials
within the Integrated Research Application System for health and social care research in the
UK84.
20: Pharmacovigilance
Although the sponsor has overall responsibility for monitoring the safety of its IMP, the
investigator and sponsor should work together to help the sponsor meet their obligations.
The investigator must:
record all adverse events (AE), including abnormal laboratory results, as instructed in the
protocol
report to the sponsor, within the time frame identified in the protocol, all serious adverse
events (SAE), except those identified as exempt in the protocol or investigators brochure
provide follow-up reports of SAEs, and any other information requested, within the time
frame identified in the protocol.
The sponsor must:
report to the MHRA:
- suspected unexpected serious adverse reactions (SUSARs) that occur in the trial and are
associated with any IMP used in the trial
- SUSARs that are associated with any IMP used in the trial and that the sponsor learns
about from other sources, for example, a SUSAR that occurs in another trial.
report to the REC:
- SUSARs that occur in the trial at a site in the UK and are associated with any IMP used in
the trial30
- SUSARs that are associated with use of any of the IMP in the UK (for example a SUSAR in
another trial), if the IMP is not marketed in the EU.
report to the investigator(s):
- SUSARs, as they occur, without unblinding the investigator.
Where a trial is conducted in more than one site/country or different trial with the same IMP is
undertaken elsewhere, the sponsors reporting duties extend to all other involved investigators,
ethics committees, and health authorities.
Sponsors must report fatal or life-threatening SUSARs to the MHRA and REC within seven
days, and provide further information within another eight days, and report all other SUSARs
within 15 days.
Sponsors may delegate their responsibilities to the investigator, providing the investigator is not
unblinded in the process.
34
21: Pathology laboratory

General
All units should have access to a pathology laboratory for assays of blood, urine and other body
fluids. Some units may have their own laboratory, whereas others may use a subcontractor.
The laboratory should have external accreditation, such as Good Laboratory Practice85 (GLP),
College of American Pathologists86 (CAP), Clinical Pathology Accreditation87 (CPA) or ISO 17025.
It should be inspected regularly and participate in continual improvement schemes, such as
NEQAS.88
Premises, facilities, equipment and procedures
The pathology laboratory should:

be purpose-built or adapted for the purpose

have automated equipment for routine haematology, biochemistry and serology tests
have procedures for analyser calibration and quality control
regularly maintain all the equipment, including point-of-care equipment
have a procedure for transporting samples safely and quickly from clinical areas to the
laboratory
have written procedures for all assays, and validate the assays
have a stock control procedure to make sure that reagents and consumables are used within
their expiry dates
keep records, including source documents and final reports
have a procedure for authorising and releasing results
have a procedure for flagging and notifying medical staff of abnormal results
have a laboratory information management system, and validate and backup the system
provide protective clothing and safety equipment for staff
have a central alarm system for all fridges and freezers
have an internal audit programme.
Staff
The number and type of laboratory staff will depend on the workload, the complexity of the
work, and the extent to which the equipment is automated and computerised.
Laboratories usually have a head of department, with a professional qualification such as
FIBMS, who is responsible for the scientific and technical work, staff management and training,
and administration.
There should be enough trained and competent staff to ensure a good service for specimen
turnaround times, completion of acute work on the day of its receipt, and arrangements for
urgent specimens. All staff must follow the laboratorys SOP and the Institute of Biomedical
Science guidelines,89 and receive GCP training.
22: Data management, statistics, report and publication

General
Sponsors may do their own data management and statistics on trial data or may subcontract it to
a unit with the right facilities and staff. Whoever does it, the credibility of the numerical results
of the trial depends on the quality and validity of the methods and software used.
35
Data management
Data management includes data entry, storage, verification, correction and retrieval. Data
managers should:
have computer systems that are:
- validated, secure and allow only authorised access to the data, and
- contain an internal audit trail, so that all changes to the data are documented and that
entered data are not deleted
back up each trial database
test the database setup and verification checks for each trial with dummy data before any
trial data are entered
enter the data twice, or once with 100% check of data
keep records of all queries and their resolution
have a formal procedure for locking and unlocking the database.
Data released to Data Monitoring Committees/Data Safety Monitoring Boards for the purpose
of making dose escalation decisions should undergo quality control and be kept in the Trial
Master File.
Statistics
There should be a statistical analysis plan (SAP) for each trial.90 The analysis plan could either be
a stand-alone document or be integrated into the protocol. A statistician should:
write and sign off on the analysis plans before the trial data is available and before any
analysis has started
describe in the protocol or SAP the hypotheses being tested and how conclusions will be
drawn, the analyses that will be done, the procedures for dealing with missing data and
avoiding bias, and the selection of subjects to be included in the analyses
put sample tables and listings in the SAP, to show how data will be presented
include any planned interim analyses in the SAP
describe and justify in the trial report any deviations from the SAP
ensure all steps of the data management, reporting and analysis process have fully validated
procedures to avoid the potential for errors. These procedures would normally be included
in a companys Standard Operating Procedures library.
The Report of the Royal Statistical Society91 gives guidance about the statistical aspects of Firstin-Human trials.
Report and publication policy
Whether the trial is completed or stopped prematurely, the sponsor should ensure that an
end-of-trial report is prepared from the data and is given to the investigator, for comments and
signature. The report should be based on the ICH Guideline for Clinical Study Reports92 and has
to be submitted to the MHRA within one year of the end of the trial.
The trial findings should be published,35 as an electronic and/or paper document, within
a reasonable time after the end of the trial. The sponsor and investigator should agree the
publication policy in the protocol or contract, before the start of the trial. The sponsor must be
allowed enough time to obtain any patent protection. Either party may prepare a manuscript
for publication in a peer-reviewed journal. Each party should allow the other at least 30 days to
comment before any results are submitted for publication. Authorship should reflect work done
by both parties, in accordance with recognised principles of scientific collaboration.
36
Staff
The statistician, data managers and data entry staff should be suitably qualified and experienced.
Data managers should be life science graduates or of similar status. Pharmacokinetic data should
be interpreted by an expert in pharmacokinetics.
23: Essential documents, trial master file and archiving

Trial master file
The investigator must keep a trial master file22 of essential documents that:
allow MHRA inspectors to assess how the trial was done, and the quality of the data
show whether the trial followed the relevant EU Directives, including the Clinical Trials
Directive, GCP Directive, and GMP Directive.
Essential documents should be:
generated and be on file before the trial starts
added to the files during the trial, to show that any new information is documented as it
becomes available
in the file after the end of the trial.
Quality of documents
Essential and supporting documents:
should be complete, legible, genuine, traceable to a specific trial, and readily available to the
sponsor and MHRA upon request
should not be altered without permission and creation of an audit trail, particularly if the
documents are stored on electronic, magnetic, optical or similar media
may be copied or transferred to other media for archiving, if the method has been validated
to ensure that information will not be lost or altered and if the copies or transfers are
certified for accuracy and completeness
should be readily available in printed form, if stored on media that require processing.
Storage of documents
A specific person, an archivist, should store trial documents. The archivist should:
have enough dedicated space that is suitable to store documents from all current trials on site
and to store documents from all completed trials either on-site or off-site in a commercial
archive
have storage facilities that are secure and adequately protected from fire, flood, pests,
extremes of temperature and humidity, and unauthorised access
inform the sponsor about the arrangements for storing documents, and about any changes to
the arrangements
notify the sponsor if the investigator becomes unable to store trial documents, so that the
sponsor can arrange for them to be stored elsewhere.
Duration of storage
Essential and supporting documents, including the trial subjects records, must be archived until
at least five years after the end of the trial. Access to documents must be restricted to the people
with responsibility for archiving:
37
until at least two years after the last approval of a marketing application in the EU and until
there are no pending or intended marketing applications in the EU or
until at least two years after stopping the development of the IMP or
for a longer period, if required by the MHRA or the sponsor.
Disposal of documents
The investigator must not destroy any essential documents without the sponsors permission.
The reasons should be recorded and the records kept for five or more years. Sponsors should
inform the Phase 1 unit when the retention period is over.
24: Project management and monitoring

Some sponsors allocate to every Phase 1 trial a project manager, to manage the administrative
aspects of the trial, and a monitor, to carry out the traditional duties of a monitor.20 Other
sponsors may have one person do both jobs. The project manager and monitor should be life
science graduates or of similar status. They should be trained in GCP, the relevant aspects of
GMP and monitoring, as appropriate.
Phase 1 trials have special features, as follows. Nowadays, commercial CROs conduct most Phase
1 trials.6 The trials start and usually end on schedule, especially if the trial subjects are healthy
volunteers. Beds, staff and resources for the trial are booked, and subjects set aside time to take
part. So any delay causes problems and many people are inconvenienced. In a Phase 1 trial, many
data are collected from few subjects. Unforeseen findings often need protocol amendments to
keep a trial running. A unit with an MIA (IMP) may have to manufacture, assemble or import
the IMP.
Hence, Phase 1 trials need more input from the sponsor. For example, the project manager and/
or monitor should:
know the pre-clinical data and be able to deal with any concerns that the investigators might
have about the risk assessment, by arranging for them to discuss their concerns with the
sponsors physician or pre-clinical staff
assist the investigator in obtaining from the sponsor in good time any documents required to
support applications to the REC or MHRA
ensure that all the trial documents and the IMP are delivered in good time for the trial to
start on schedule
monitor the trial for GMP compliance if the unit manufactures, assembles or imports the
IMP as well as for GCP compliance
schedule monitoring visits for key days of the trial, such as when the IMP is first
administered, the dose is increased and a non-IMP is administered
get the sponsor to provide the investigator in good time with any pharmacokinetic data that
are needed before the dose can be increased in a dose-rising trial, and
participate in and document, if appropriate, any discussions between the sponsor and the
investigator before the dose is increased, and ensure that the protocol is followed.
25: Quality management

Quality system
The sponsor is ultimately responsible for the quality and the integrity of the trial data. However,
all units should have their own system, such as ISO 9001, for quality control and quality
assurance, which the staff must follow. The scope of the system and the number and types of
38
staff who operate it will depend on the size of the unit and the sort of work carried out. All units
should have written, authorised procedures and should:

keep a current version of each procedure at each point of use

remove obsolete versions from circulation, but keep copies for reference
review the procedures regularly
inform relevant staff of any changes to procedures or of any new ones, and train those staff, if
necessary, and
keep records that make it possible to trace which version of a procedure was current at any
given time.
Quality control
Trial staff should check each stage of the trial to ensure that the regulations are being followed
and that the data generated are correct.
Auditors
Auditors should:
be life science graduates or of similar status
be trained in auditing
be independent of whatever they audit if a unit does not have its own independent auditor,
the sponsor or a subcontractor may conduct the audit
regularly audit the quality system
audit the validation of computerised systems
regularly audit the facilities, and frequently-used subcontractors such as laboratories, against
the relevant sections of these ABPI guidelines
know the details of the units quality system and of Directives such as 2001/20/EC, the
guidance documents, GCP, GMP, GAfREC and SOP of NRES, MHRA regulations, and other
relevant documents
check whatever tasks have been delegated to the investigator by the sponsor against those
documents as well as the protocol, and
devise and follow an audit plan based on the type and complexity of the trial, the number of
subjects and any problems encountered.
Audits
A full clinical trial audit should include:

the CTA and REC applications

the trial documents protocol, information and consent form, blank CRF, and the trial report
the trial procedures
the presence, completeness and accuracy of essential documents in the trial master file
the case report forms and source documents
the trial database and statistical analysis
a written report of the audit findings for the investigator and other relevant staff, and
an audit certificate for the trial master file.
Sponsors auditors
The sponsors auditors should audit the units facilities or systems or a specific trial, as necessary.
39
26: Health and safety

Units must have a health and safety at work policy,93 and policies or procedures for the relevant
parts of the legislation, including:

safety in the workplace

personal protective equipment
equipment and electrical safety, and
control of substances hazardous to health (COSHH).94
Units should follow the guidelines of the Advisory Committee for Dangerous Pathogens for
containment level 2 as a minimum.95 All staff at risk of contact with body fluids should be
vaccinated against hepatitis B. In addition, there must be a policy to prevent and manage
needlestick injuries.96
Units that prepare and serve food must follow the Food Safety Regulations.97 Kitchens and areas
where food is served must be kept clean and disinfected. Food must be prepared and stored
hygienically, and served at the right temperature.
40
27: References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
41
The report on medical experiments in staff volunteers. ABPI, 1970.

Guidelines for preclinical and clinical testing of new medicinal products. Parts 1 & 2. ABPI,
1977.
Guidelines for medical experiments in non-patient volunteers. ABPI, 1988.
Guidelines for facilities for non-patient volunteer studies. ABPI, 1988.
Research on healthy volunteers. Journal of the Royal College of Physicians 1986; 20.
Calder N et al. UK Phase 1 units: an AHPPI survey. British Journal of Clinical
Pharmacology 2003; 56: 7679.
The Medicines for Human Use (Clinical Trials) Regulations. May 2004. SI 2004, No. 1031.
Amendments: Aug 2006. SI 2006, No. 1928 and Dec 2006. SI 2006, No 2984.
Clinical pharmacology and therapeutics. Royal College of Physicians, 1999.
Higher medical training in pharmaceutical medicine. Joint Committee on HMT, 2002.
Non-clinical safety studies for clinical trials. CPMP/ICH/286/95.
Toxicokinetics and exposure in toxicology studies. CPMP/ICH/384/95.
Pharmaceutical innovation. British Journal of Clinical Pharmacology 1988; 25: 387396.
Kola I, Landis J. Can the industry reduce attrition rates? Nature Reviews Drug Discovery
2004; 3: 711.
Exploratory IND studies. FDA, Jan 2006
MHRA Phase 1 Accreditation Scheme, Final Version 1, 16th November 2007 (http://www.
mhra.gov.uk/Howweregulate/Medicines/Medicinesregulatorynews/CON2033112)
First In Human Studies: Points to Consider in Study Placement, Design and Conduct. ABPI
2011 (http://www.abpi.org.uk)
Lesko L, Atkinson A. Use of biomarkers and surrogate endpoints in drug development.
Annual Review of Pharmacology and Toxicology 2001; 41: 347366
Bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98.
Shah R. QT interval in drug development. British Journal of Clinical Pharmacology 2002;
54: 188202.
ICH Guideline for GCP. CPMP/ICH/135/95.
EU Clinical Trials Directive 2001/20/EC.
Eudralex Volume 10. Rules governing medicinal products in the EU. Clinical Trials, July 2006.
Eudralex Volume 4. Medicinal Products for Human and Veterinary Use.
Sterile medicinal products. Annex 1 to GMP, 2003.
Application of GMP to IMP. Annex 13 to GMP, 2003 (http://ec.europa.eu/health/files/
eudralex/vol-4/2009_06_annex13.pdf).
QP certification and batch release. Annex 16 to GMP, 2002.
Directive 2003/94/EC. GMP guidelines for medicinal products and IMP.
Directive 2005/28/EC. Good clinical practice.
Governance Arrangements for NHS Research Ethics Committees. Jul 2001.
Standard Operating Procedures for Research Ethics Committees. Version 4.1. May 2010
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP).
July 2007. Guideline on strategies to identify and mitigate risks for first in human trials with
Investigational Medicinal Products. [EMEA/CHMP/SWP/28367/07] (www.ema.europa.eu).
Medicines Act, 1968. TSO.
Mutual Recognition Agreements. www.ec.europa.eu/enterprise/pharmaceuticals/mra/
index_a.htm
Suntharalingam G et al. Cytokine storm in a Phase 1 trial of the anti-CD28 monoclonal
antibody TGN1412. New England Journal of Medicine 2006; 355: 4555.
Expert scientific group on Phase 1 clinical trials. TSO. Nov 2006..
Estimating the safe starting dose for healthy volunteers. FDA, 2005.
37 Muller PY et al. The minimum anticipated biological effect level (MABEL) for selection
of first human dose in clinical trials with monoclonal antibodies. Current Opinion in
Biotechnology 2009; 20: 722-729
38 Clinical Investigation of Medicinal Products in the Pediatric Population. ICH topic E11,
2000 (www.ich.org/)
39 Declaration of Helsinki. World Medical Association, 1996.
40 Sibille M et al. Is Phase 1 still safe? Br J Clin Pharmacol 2006; 62: 502503.
41 Orme M et al. Healthy volunteer studies in Great Britain. British Journal of Clinical
Pharmacology 1989; 27: 125133.
42 Kumagi et al. Serious adverse events in healthy volunteer studies in Japan. Clinical
Pharmacology & Therapeutics 2006; 79: P71.
43 Darragh A et al. Sudden death of a volunteer. Lancet 1985; 1: 9394.
44 Trigg et al. Death of a healthy volunteer. International Journal of Pharmaceutical Medicine
1998; 12: 151153.
45 Anon. 1966 and all that: when is a literature search done? Lancet 2001; 358: 646.
46 Steinbrook R. Protecting research subjects. New England Journal of Medicine 2002; 346:
716720.
47 Marshall E et al. Effects of human macrophage inflammatory protein: Phase 1 study in
cancer patients and healthy volunteers. European Journal of Cancer 1998; 34: 10231029.
48 Watts M et al. Effects of glycosylated and non-glycosylated G-CSF in healthy volunteers.
British Journal of Haematology 1997; 98: 474479.
49 Reilly S et al. Dose-escalation study of tefibazumab in healthy volunteers. Antimicrobial
Agents and Chemotherapy 2005; 49: 959962.
50 Line B et al. Fanolesomab, a murine anti-CD15 IgM monoclonal antibody, in normal
volunteers. Nuclear Medicine Communications 2004; 25: 807811.
51 Porter S. Immune response to recombinant human proteins. Journal of Pharmaceutical
Sciences 2001; 90: 111.
52 Hanauer S et al. Delayed hypersensitivity to infliximab. Gastroenterology 1999; 116: A731.
53 Yousry T et al. Natalizumab and PML. NEJM 2006; 354: 924933.
54 Itoh K et al. Rituximab and PML. Arthritis & Rheumatism 2006; 54: 10201025.
55 Guideline on advertising for clinical trials. ABPI
56 Boyce M et al. TOPS. British Journal of Clinical Pharmacology 2003; 55: 418P.
57 Tubel J, Hammond K. Why the UK needs a clinical trial register. Good Clinical Practice
Journal 2002; Nov p 3
58 Guidance on reproductive toxicology: CPMP/ICH/386/95
59 Guidelines for the ethical conduct of research in children. Archives of Diseases in
Childhood 2000; 82: 177-182
60 Dickert N, Grady C. Whats the price of a research subject? New England Journal of
Medicine 1999; 341: 198202.
61 Guidance for researchers. Patient information sheets and consent forms. COREC. Dec 2006
62 Plain English Campaign. www.plainenglish.co.uk
63 Rosenzweig P et al. Transaminase elevation on placebo during Phase 1 trials. British
Journal of Clinical Pharmacology 1999; 48: 19-23
64 Malmstrom P-U. Abandon testing for microscopic haematuria? British Medical Journal
2003; 326: 813-815
65 Stinson et al. 24-h ECG in healthy volunteers. British Journal of Clinical Pharmacology
1995; 39: 651-656
66 Pre-clinical safety of biotechnology-derived products. CPMP/ICH/302/95.
67 GTAC guidance on applications for gene therapy research. DH, 2000
68 GMO (Contained Use) Regulations. HSE, 2000
69 Resuscitation Council (UK). Guidelines, 2005
70 Medicines (Administration of Radioactive Substances) Act. SI 1995. No. 2147.
71 Ionising Radiation (Medical Exposure) Regulations. SI 2000. No. 1059
42
72 Ionising Radiations Regulations1999. SI 3232. HMSO

73 Guidance on Clinical Administration of Radiopharmaceuticals. ARSAC, 2006
74 Lappin G, Garner R. AMS and PET in human microdosing of development drugs. Nature
Reviews Drug Discovery 2003; 2: 233240
75 Position Paper On Non-Clinical Safety Studies To Support Clinical Trials With A Single
Microdose . CPMP/SWP2599/02/Rev 1, 2004
76 Exploratory IND studies. FDA, Jan 2006
77 Radiation Substances Act 1993, as amended by the Environmental Act, 1995
78 GMP for radiopharmaceutical products. WHO Technical Report 908, 2003
79 www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/ Clinicaltrials/
IsaclinicaltrialauthorisationCTArequired/CON071375
80 QP in the pharmaceutical industry. Royal Pharmaceutical Society, 2004
81 Data Protection Act: protection and use of patient information. DH, 1998
82 Human Tissue Act. TSO. 2004
83 www.abpi.org.uk/our-work/library/guidelines/Pages/clinical-trials-insurance.aspx
84 www.nres.nhs.uk/nres-publications/news/insurance-for-phase-1-trials/
85 GLP regulations, 1999. SI 1999 No. 3106
86 College of American Pathologists Accreditation Programme
87 Clinical Pathology Accreditation (UK) Ltd
88 UK External Quality Assessment Service (UK NEQAS).
89 Code of conduct for biomedical science laboratories. IBMS, 1996
90 Statistical principles for clinical trials. ICH topic E9, 1998.
91 Statistical issues in first-in-man trials. Royal Statistical Society. March 2007
92 ICH Guideline for the Structure and Function of Clinical Study Reports, 1995
93 Health and Safety at Work Regulations. SI 1999. No. 3242.
94 Control of Substance Hazardous to Health. HSE, 2002.
95 Advisory Committee on Dangerous Pathogens. TSO. 2003.
96 Tan L et al. Preventing needlestick injuries. Archives of Internal Medicine 2001; 61:
929936.
97 Food Safety Regulations. SI 1995. No.1763.
43
28: Websites
Acts of Parliament and Statutory Instruments
www.hmso.gov.uk
Health and Safety Executive

www.hse.gov.uk
Administration of Radioactive Substances

Advisory Committee (ARSAC)
www.arsac.org.uk
ICH Guideline for Good Clinical Practice

www.emea.europa.eu/docs/
en_GB/document_library/Scientific_
guideline/2009/09/WC500002874.pdf
Association of the British Pharmaceutical

Industry (ABPI)
www.abpi.org.uk
Ionising Radiations Regulations

www.hmso.gov.uk/si/si1999/19993232.htm
Association for Human Pharmacology in the

Pharmaceutical Industry (AHPPI)
www.ahppi.org.uk
Medicines and Healthcare products

Regulatory Authority (MHRA)
www.mhra.gov.uk
UK BioIndustry Association (BIA)

www.bioindustry.org/home/
National Research Ethics Service (formerly

COREC)
www.nres.nhs.uk/
Clinical Pathology Accreditation, UK (CPA)

www.cpa-uk.co.uk
College of American Pathologists (CAP)
www.cap.org/apps/cap.portal

Data Protection Act
www.legislation.hmso.gov.uk/acts.htm
Declaration of Helsinki
www.wma.net/en/30publications/10policies/
b3/index.html
EudraCT database
https://eudract.ema.europa.eu/
European Commission: implementing texts
for Directive 2001/20/EC
http://ec.europa.eu/health/human-use/
clinical-trials/index_en.htm
NIMP Safety Register

www.nimps.org
Resuscitation Council (UK)
www.resus.org.uk
The Stationery Office
www.official-publications.co.uk
The Medicines for Human Use (Clinical
Trials) Regulations
www.hmso.gov.uk/si/si2004/20041031.htm
The Overvolunteering Prevention System
(TOPS)
www.tops.org.uk
Gene Therapy Advisory Committee (GTAC)

www.dh.gov.uk/ab/GTAC/index.htm
Governance Arrangements for NHS Research
Ethics Committees
www.dh.gov.uk/en/Publicationsandstatistics/
Publications/PublicationsPolicyAndGuidance/
DH_126474
44
Appendix 1: Qualifications relevant to Phase 1 trials

Diploma in Pharmaceutical Medicine
The primary qualification for pharmaceutical physicians is the Dip Pharm Med, awarded by the
Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians. (www.fpm.org.uk/
trainingexams/exams/dippharmmed). It can be obtained:
by sitting an examination the University of Wales runs a course geared to the examination
(www.cardiff.ac.uk/phrmy/degreeprogrammes/postgraduate/
pharmaceuticalmedicine); or
as part of the MSc course in Pharmaceutical Medicine or Clinical Pharmacology (www.
surrey.ac.uk/fhms/study/Postgraduate/) run by the University of Surrey.
Diploma in Human Pharmacology
Developed by the Faculty of Pharmaceutical Medicine (FPM), the Diploma and Certificate in
Human Pharmacology (DHP and CHP) have been structured specifically to fit the needs of all
with an interest in exploratory drug development.
Diploma Programme
The DHP is a two year programme of structured training for doctors to attain and demonstrate
competence to serve as a Principal Investigator for exploratory studies of Investigational
Medicinal Products (IMPs) in man. It is anticipated that the DHP will become the primary
qualification for PIs.
Certificate Programme
The CHP is a 1-year part-time programme for doctors and scientists to attain and demonstrate a
comprehensive knowledge of all aspects (design, monitoring, analysis, reporting, safety, ethics,
regulation and law) of exploratory studies of IMPs in man.
These integrated training programmes address the requirements of Principal Investigators (PIs)
and all scientists involved in Phase 1 studies, whether based in CROs, pharmaceutical companies,
universities or regulatory authorities. Information on the DHP and CHP programmes and exams
can be found at: www.fpm.org.uk. Details and dates of the accredited compulsory Diploma and
Certificate courses provided by Kings College London can be found at: www.pharm-med.kcl.
ac.uk/fpm.html.
MSc
The modular MSc in Clinical Pharmacology run by the University of Surrey is tailored to
physicians, nurses and life science graduates working in the pharmaceutical industry. Barts the
London School of Medicine and Dentistry , part of the Queen Mary University of London, runs
an MSc course in early drug development (www.mds.qmul.ac.uk).
The Universities of Aberdeen (www.abdn.ac.uk) and Glasgow (www.gla.ac.uk) run MSc
courses in Clinical Pharmacology.
The European Centre of Pharmaceutical Medicine in Basel awards a Diploma in Pharmaceutical
Medicine (www.ecpm.ch], as does the Claude Bernard University of Lyon (www.univ-lyon1.fr).
The Universities of Glamorgan (www.glam.ac.uk/courses) and Liverpool John Moores (www.
livjm.ac.uk)run MSc courses in subjects allied to clinical pharmacology.
45
Higher Medical Training

Clinical pharmacology is a core component of the modular training courses (www.fpm.org.uk)
for Higher Medical Training that lead to accreditation in Pharmaceutical Medicine by the Faculty
of Pharmaceutical Medicine.
Physicians employed in academic and hospital clinical pharmacology units can train for
accreditation in clinical pharmacology. In addition, there is a joint ABPI and NHS scheme for
clinical pharmacology training.
46
Appendix 2: Contents of the information and consent form

According to ICH GCP14, the subject information and consent form should state or explain:

that the trial is research

the purpose of the trial
the IMP, and the chance of getting the active one
the trial procedures
what the subject must do
what is experimental and what is standard
the possible risks or discomforts
the possible benefits
the alternative treatments, if any
the compensation and treatment available to the subject, if harmed
how much the subject will be paid for completing all or only part of the trial
what expenses will be paid to the subject for taking part in the trial
that taking part is voluntary, and that the subject may withdraw at any time without giving
reasons and without penalty or loss of benefits
that the trial monitors and auditors as well as the MHRA and other regulatory authorities
worldwide may see the subjects medical records
that the subjects records will be kept confidential
that if the results of the trial are published, it will not be possible to identify individual
subjects
that subjects will be informed immediately about anything new that may cause them to
change their mind about taking part in the trial
who subjects should contact if they want more information about the trial, or if they want to
know their rights, or if they think they have been harmed by taking part in the trial
the reasons why the trial might be stopped
how long it will take the subject to finish the trial, and
how many subjects will take part in it.
According to the Clinical Trials Directive guidance document on REC applications,16 the
information leaflet should also inform trial subjects about:

the names and addresses of the researchers

any conflicts of interest
that the trial has been approved by a REC
the subjects right to privacy and protection of personal data
the subjects right to get new information and to correct errors
the subjects right to withdraw consent, that no new data will be added to the database, and
that all stored samples traceable to them can be destroyed, if they so wish
the subjects right to be told of any new analysis of data that can be traced to them, and
the plans for follow-up.
47
Appendix 3: Challenge agents

Some examples of challenge agents and their uses**
Challenge agent
Activity
Route of administration
allergens
allergy
skin prick or inhalation (asthma

only); to assess anti-allergy activity
AMP
transmitter release
inhalation; to assess anti-allergy

effect
capsaicin
villanoid receptor agonist
inhalation; stimulates cough reflex
histamine
H1- & H2-agonis
skin prick; to assess anti-allergy

activity
hyoscine
muscarinic antagonist
sc; dementia model
ipecac
causes nausea and vomiting
oral; to assess anti-emetic activity

via 5-HT3 or NK1 receptor
inhibition
isoprenaline
-receptor agonist
iv; to assess blocking activity
norepinephrine
- & -receptor agonist
iv; to assess blocking activity
methacholine
muscarinic receptor agonist
inhalation; to assess airway

responsiveness
substance P
NK-receptor agonist
skin prick; to assess NK blocking

activity
serotonin
5-HT agonist
iv, to assess blocking activity
tyramine
norepinephrine release
oral or iv; to assess MAO-B

selectivity
P450 probes*
P450 phenotypes
oral; to assess potential for

interactions with establi
* There are various probes, including cocktails,77-79 to assess the activity of cytochrome P450
enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1, and N-acetyltransferase-2.
** More details of challenge agents (or non-IMP) will be put on the MHRA website (Section 31).
48
Examples of radioactive isotopes for PET or SPECT scans
PET
radioisotope
half-life (min)
radioisotope
Rb
99m
123
10
111
20
201
Ga
68
133
111
82
15
13
11
68
18
49
SPECT
half-life (min)
Tc
13
In
67
Tl
73
Xe
126
Appendix 4: Abbreviations
ABPI
AHPPI
ALS
AMS
AREC
ARSAC
BIA
BLS
CAP
CHM
COSHH
CPA
CPD
CRF
CRO
CTA
DCPSA
DHP
Dip Pharm Med
DNA
ECG
EEA
EMEA
ESG
EU
EudraCT
FDA
FFPM
FIBMS
FRCA
FRCP
GAfREC
GCP
GLP
GMC
GMM
GMP
GP
GTAC
HIV
HMT
HSE
ICH
ICR
ILS
ISO
IMP
MABEL
MD
Association of the British Pharmaceutical Industry

Association for Human Pharmacology in the Pharmaceutical Industry
Advanced life support
Accelerator mass spectrometry
Association of Research Ethics Committees
Administration of Radioactive Substances Advisory Committee
BioIndustry Association
Basic life support
College of American Pathologists
Commission on Human Medicines
Control of Substances Hazardous to Health
College of Pathology (UK) Accreditation
Continuing Professional Development
Case report form
Contract research organisation
Clinical Trial Authorisation
Diploma in Clinical Pharmacology of the Society of Apothecaries
Diploma in Human Pharmacology
Diploma in Pharmaceutical Medicine
Deoxyribonucleic acid
Electrocardiogram
European Economic Area
European Agency for the Evaluation of Medicinal Products
Expert Scientific Group
European Union
European Union database of clinical trials
Food and Drug Administration of the USA
Fellow of the Faculty of Pharmaceutical Medicine
Fellow of the Institute of Biomedical Science
Fellow of the Royal College of Anaesthetists
Fellow of the Royal College of Physicians
Governance Arrangements for NHS Research Ethics Committees
Good clinical practice
Good laboratory practice
General Medical Council
Good manufacturing practice
General Practitioner (primary care physician or equivalent)
Gene Therapy Advisory Committee
Human immunodeficiency virus
Higher Medical Training
Health and Safety Executive
International Conference on Harmonisation
Institute of Clinical Research
Immediate life support
International Standards Organisation
Investigational medicinal product
Minimal anticipated biological effect level
Doctorate in Medicine
50
MFPM
MHRA
MIA (IMP)
MRCP
NCE
NEQAS
NHS
NOAEL
NRES
PET
PhD
PML
QP
RCP
REC
SAE
SI
SOP
SPECT
SUSAR
TOPS
UKECA
51
Member of the Faculty of Pharmaceutical Medicine

Medicines and Healthcare products Regulatory Agency
Manufacturers Authorisation for an IMP
Member of the Royal College of Physicians
New chemical entity
National External Quality Assessment Service
National Health Service
No-observed-adverse-effect level
National Research Ethics Service (formerly COREC)
Positron emission tomography
Doctorate in Philosophy
Progressive multifocal leukoencephalopathy
Qualified person
Royal College of Physicians
Research ethics committee
Serious adverse event
Statutory instrument
Standard operating procedure
Single photon emission computed tomography
Suspected unexpected serious adverse reaction
The Overvolunteering Prevention System
United Kingdom Ethics Committee Authority
Appendix 5: Glossary of terms

Accelerator mass spectrometry (AMS) an extremely sensitive and accurate method of
analysing a very small dose a microdose of an IMP labelled with an isotope (14C).
Accreditation recognition that a trial-related function meets an official quality standard.
Examples are accreditation of a quality system by ISO 9001, a pathology laboratory by a College
of Pathology, a Phase 1 unit by MHRA, and a REC by NRES (formerly COREC).
Administration of Radioactive Substances Advisory Committee (ARSAC) decides if the
amount of radioactivity subjects receive in a clinical trial is within acceptable limits.
Adverse event (AE) an unwanted clinical symptom, sign or disease, or an abnormal laboratory
finding, that is related in time to, but is not necessarily caused by, the administration of an IMP
to a subject in a clinical trial.
Agonist binds to a cell receptor and triggers a response by the cell. An agonist often mimics the
action of a naturally occurring substance.
Algorithm procedure for making a series of choices among alternative decisions to reach an
outcome.
Anaphylactic reaction an allergic reaction that is life-threatening.
Antigen a substance which when introduced into the body stimulates the immune system to
make a specific immune response, such as production of an antibody that binds to the antigen.
An antigen may cause an allergic reaction.
Appraisal a review of a persons performance and development needs.
Association of the British Pharmaceutical Industry (ABPI) a trade association of
pharmaceutical, biotechnology, research and development, or associated companies with either
their main or subsidiary premises in the UK.
Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) a group
of people who are involved in commercial Phase 1 trials and hold biannual symposia to educate
members.
Audit a systematic and independent review of trial-related activities and documents, to find
out if the activities were carried out, and if the data were recorded, analysed, and accurately
reported, according to the protocol, SOP, GCP, GMP and regulatory requirements.
Audit certificate written evidence that a trial-related function has been audited.
Audit report an auditors written report of his or her findings.
Audit trail documentation of events at each stage of a trial that allows an auditor to trace the
source of the data, track changes, and assess if the data are genuine.
Batch a defined amount of starting material, packaging material or IMP that is prepared in one
process or a series of processes and is expected to be uniform within specified limits.
Batch release the process of signing off a batch of IMP by a qualified person (QP).
Bioavailability a measure of how well a medicine is absorbed by the body.
Bioequivalence two medicines are bioequivalent if their bioavailability does not differ
significantly when they are used in a trial at the same dose and under similar conditions.
Biological investigational medicinal products potential new medicines, such as proteins,
cytokines, monoclonal antibodies, genetically-modified micro-organisms and gene therapy,
resulting from advances in cell biology and in biotechnology.
Biomarker a laboratory or clinical measure of the bodys response to an IMP that might
indicate that the IMP is working. When a biomarker can replace a clinical endpoint it is called a
surrogate endpoint.
52
Biotechnology the application of the biological sciences, especially genetics, to technological

or industrial uses.
BioIndustry Association (BIA) a trade association for the UK bioscience sector.
Bivalent antibody antibody with two binding sites.
Blinding a procedure in which one or more of the parties to a trial do not know which IMP
(active, placebo or comparator) is allocated to which trial subject.
Calibration demonstrating that an instrument or device gives results within specified limits by
comparing them with the results obtained with a standard over a range of measurements.
Case report form (CRF) a printed, optical, or electronic document designed to record all of
the information that is required by the clinical trial protocol, and is to be reported to the sponsor,
for each trial subject.
Central Office for Research Ethics Committees (COREC) responsible for coordinating,
training and accrediting all UK research ethics committees. (Name changed to National
Research Ethics Service [NRES] in March 2007).
Certificate of analysis a document of the identity, purity and strength of an IMP.
Chief investigator leads a group of principal investigators.
Clinical (human) pharmacology the scientific basis of Phase 1 trials.
Clinical Trial Authorisation (CTA) sponsors must obtain a CTA from the MHRA before they
can start a trial of an IMP.
Clinical trial (study) tests the safety and activities of an IMP in humans.
Clinical trial (study) report) includes all the results of a trial and an analysis and clinical
interpretation of them.
Comparator a marketed medicine, a placebo, or another preparation of an IMP used for
comparison in a trial.
Complement system many small plasma proteins that work together to clear pathogens, such
as bacteria, and promote healing.
Compliance meeting the relevant requirements for a trial-related function.
Confidentiality making sure that only authorised people see a sponsors proprietary
information or know a trial subjects identity.
Concentration-response curve relationship between concentration of the IMP in blood or
tissues and its effect.
Continuing Professional Development (CPD) process by which physicians keep up-to-date,
develop new skills and maintain a high standard of professional practice.
Contract a written, dated and signed agreement among the parties to a trial, such as the
sponsor, investigator and CRO, that sets out the duties and responsibilities, including financial,
of each party (the protocol can be the basis of the contract).
Contract research organisation (CRO) a commercial, academic or other type of organisation
that may carry out the sponsors trial-related duties and functions.
Control of Substances Hazardous to Health (COSHH) regulations to protect workers against
any substance in the workplace that might damage their health.
Curriculum vitae (CV) written details of the researchers qualifications and experience that
enable sponsors, MHRA or REC to assess the eligibility of the researchers to do a trial.
Cyclotron produces radioactive isotopes of short half-life for research or diagnostic imaging.
Cytokine small proteins produced by cells, mainly white blood cells, in response to an immune
stimulus. They mediate and regulate immunity and inflammation.
Cytokine storm uncontrolled release of cytokines which react with immune cells. A cytokine
storm damages tissues and organs, which may be fatal.
53
Data Protection Act legislation to give people the right of control of personal information that
is held about them.
Declaration of Helsinki guidelines of the World Medical Association that protect the rights,
safety and well-being of subjects who take part in clinical trials, and are revised every four years
Directive 2001/20/EC is based on the 1996 version.
Delayed hypersensitivity reaction a harmful immune response caused by re-exposure to a
protein to which the body has become sensitive as a result of a previous exposure.
Deoxyribonucleic acid (DNA) the substance in cells that carries the genetic code for the
individual.
Diploma in Pharmaceutical Medicine (Dip Pharm Med) a qualification in pharmaceutical
medicine awarded by the Faculty of Pharmaceutical Medicine.
Diploma in Human Pharmacology (DHP) a qualification for principal investigators for Phase
1 trials to be awarded by the Faculty of Pharmaceutical Medicine.
Direct access permission to examine, analyse, verify and reproduce the relevant records and
reports of a clinical trial.
Documentation the process of creating records, in a written, magnetic, optical or other form,
that describes the methods and conduct of the study, factors affecting it, and the action taken.
Records include the protocol and any amendments, copies of submissions and approvals from
the MHRA and REC, curricula vitae, information and consent forms, monitors reports, audit
certificates, relevant letters, reference ranges, raw data, completed CRF and the final study
report.
Dose the amount of an IMP given to the trial subject on one or more occasions (single- or
multiple-dose). A dose may be one or more tablets, capsules, injections or other form of the IMP.
Dose-response curve relationship between doses of an IMP and their effect.
Efficacy whether an IMP is effective.
Endoscopy looking into parts of the body such as the stomach and windpipes with an
endoscope, a thin fibre-optic telescope with a light at the end.
Essential documents documents that are kept in the trial master file and enable the sponsor or
MHRA to assess if a trial was carried out properly and to judge the quality of the data produced.
European Agency for the Evaluation of Medicinal Products (EMEA) coordinates the
regulatory authorities, such as the MHRA, of all the EU countries.
European Commission (EC) an institution in Brussels that drafts proposals for EU legislation
and does the day-to-day work of running the EU.
European database of clinical trials (EudraCT) a database in which all EU clinical trials must
be registered.
European Economic Area (EEA) the EU plus Iceland, Norway and Lichtenstein.
European Union (EU) a group of European countries with common policies.
Exclusion criteria reasons for excluding a subject from a trial, such as taking another
medicine, having an illness or having out-of-range laboratory results.
Expert Advisory Group of the Commission on Human Medicines The Commission on
Human Medicines advises the Government and the MHRA about medicinal products. Expert
Advisory Groups such as the one for higher risk biological IMP support the Commission.
Expert Scientific Group (ESG) Report on Phase 1 Clinical Trials report of an enquiry into
the First-in-Human trial of TGN1412.
Faculty of Pharmaceutical Medicine a section of the Royal College of Physicians that sets and
maintains standards in pharmaceutical medicine through Higher Medical Training.
Fc receptor protein found on the surface of certain white blood cells that contribute to the
protective function of the immune system.
54
Finished product an IMP that has undergone all stages of manufacture, including packaging
and labelling in its final container.
First-in-Human clinical trial a clinical trial in which a potential new medicine is given to
humans for the very first time.
General Medical Council (GMC) registers and regulates UK physicians.
Genes a biological unit of heredity a sequence of DNA that codes for one protein. The human
genome has about 70,000 genes.
Gene therapy the deliberate introduction of genetic material into human somatic cells for
therapeutic, prophylactic or diagnostic purposes.
Gene Therapy Advisory Committee (GTAC) reviews proposals to conduct gene therapy
research and advises about gene therapy.
Genetic testing to detect the presence or absence of, or variation in, a particular gene using
a DNA, biochemical or other test. The metabolism of many medicines is affected by genetic
differences in enzymes.
Genetically modified micro-organisms (GMM) micro-organisms that have had their genetic
material altered by artificial means.
Good clinical practice (GCP) an international ethical and scientific quality standard for
designing, conducting, recording, monitoring and reporting studies that involve human subjects.
GCP ensures that the rights, safety and well-being of the trial subjects are protected, and that the
trial data are credible and accurate.
Good laboratory practice (GLP) a set of principles for planning, performing, monitoring,
reporting and archiving laboratory studies.
Good manufacturing practice (GMP) a set of principles which ensures that medicinal
products are produced and controlled to the quality standards appropriate to their intended use.
Governance Arrangements for NHS Research Ethics Committees (GAfREC) guidelines
issued by the National Research Ethics Service (NRES) that all REC must follow.
Half-life time for the concentration of an IMP or medicine to halve in the body.
Health and Safety Executive (HSE) responsible for enforcing regulations that ensure the
health and safety of staff and visitors in the workplace.
Hepatitis viruses B and C (HVB and HVC) viruses that are transmitted by blood or blood
products and cause liver disease.
Higher Medical Training in pharmaceutical medicine consists of seven advanced training
modules in pharmaceutical medicine, of which clinical pharmacology is one, leading to the
award of the Certificate of Completion of Specialist Training (CCST) by the Royal Colleges of
Physicians.
Higher risk agent an IMP that the ESG Report deemed more likely to cause harm than other
IMPs when tested for the first time in humans: biological molecules with novel mechanisms
of action; new agents with a highly species-specific action; and new agents directed towards
immune system targets.
Human immunodeficiency virus (HIV) the virus that causes AIDS.
Human Tissue Act legislation to regulate the removal, storage and use of human organs and
tissues.
Imaging taking a picture of part of the body using a special detector and a computer.
Immune response a white blood cell, antibody or cytokine response to an antigen, infection or
some other stimulus.
Importing bringing an IMP into the UK from a third country, such as the USA.
Inclusion criteria conditions that must be met if a subject is to join a trial.
Indemnity a guarantee inserted in the protocol, contract or subject information leaflet that the
55
sponsor will compensate a trial subject who is harmed by taking part in a clinical trial.
Informed consent a process by which subjects voluntarily confirm their willingness to take
part in a trial after having been fully informed about it. Informed consent is documented by
means of a written, signed and dated consent form.
Inspection the act by a regulatory authority of reviewing the documents, facilities, records,
and any other resources related to the clinical trial and that may be located at the trial site, at the
facilities of the sponsor or CRO or at other establishments.
Insurance provides cover for the sponsor or investigator in the event of a claim for damages by
a trial subject.
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice
(GCP) ICH version of GCP, which provides a unified standard for the EU, Japan and USA to
facilitate the mutual acceptance of clinical data by the regulatory authorities in those countries.
Investigational medicinal product (IMP) a potential new medicine, a placebo or a
comparator. Includes a marketed product when used or assembled in a way different from the
approved form, or when used for an unapproved indication or to gain further information about
an approved use.
Investigational medicinal product dossier (IMP dossier) gives information about the quality,
manufacture and control of the IMP, including any comparator or placebo, and pre-clinical data
and any clinical data.
Investigator a researcher who carries out a clinical trial. A principal investigator leads a team
of researchers. A chief investigator leads a group of principal investigators. In some units, the
chief investigator and the principal investigator may be the same person.
Investigators brochure contains all the information and evidence, including non-clinical and
any clinical data on the IMP, that support the proposed trial.
in vitro outside the body, such as in a test tube (the opposite of in vivo).
in vivo in the living body.
International Standards Organisation (ISO) responsible for the ISO 9000 and other quality
standards.
Isotope one of two or more atoms having the same atomic number but a different atomic mass.
Isotopes, such as 14C and 3H are used as tracers in medical tests.
Ligand a molecule that binds to a protein or receptor.
Manufacture any process carried out in the course of making an IMP, except dissolving or
dispersing it in, or diluting or mixing it with, another substance used as a vehicle to administer
the IMP.
Manufacturers Authorisation for IMP [MIA (IMP)] a licence, granted by the MHRA, to
import or manufacture an IMP.
Marketing Authorisation a licence, granted by the MHRA, that enables a manufacturer to sell
a medicinal product so that doctors can prescribe it for patients.
Medicines and Healthcare products Regulatory Agency (MHRA) a body required by law
to assess the safety, quality and efficacy of medicinal products and devices, and to enforce GCP,
GMP and GLP.
Metabolism the breakdown of substances, including IMP, by the body.
Microdose less than one hundredth of the predicted pharmacological dose but not exceeding
100 micrograms.
Monitoring the act of overseeing the progress of a clinical trial, to ensure that it is conducted,
recorded and reported in accordance with the protocol, SOPs, GCP, GMP, GLP, and any
regulatory requirements.
Monoclonal antibodies identical antibodies cloned from a single cell by a biotechnology
method. They target a specific cell or protein in the body. Several monoclonal antibodies are in
clinical use and many more are under development.
56
Mutual Recognition Agreement (MRA) an agreement between the EU and an exporting

third country to allow an IMP to be imported into the EU.
National Research Ethics Service (NRES) responsible for coordinating, training and
accrediting all UK research ethics committees. (Name changed from COREC in March 2007)
Needlestick (sharps) injury an injury caused by penetration of the skin by a needle or other
sharp object, which may result in infection with blood-borne viruses such as hepatitis B and C,
and HIV.
New chemical entities (NCE) potential new medicines that are derived from chemical
substances. They are sometimes referred to as small molecules.
No-observed-adverse-effect dose level (NOAEL) the highest IMP dose level that is free of
toxic effects in animal toxicology studies.
Nuclear medicine use of radioactive isotopes for diagnosing or treating disease.
Nursing and Midwifery Council (NMC) the organisation that controls nursing in the UK. All
nurses must be registered with the NMC to carry out nursing duties.
Pharmaceutical medicine the discipline concerned with the discovery, development,
assessment, registration, monitoring and medical marketing of medicines.
Pharmacodynamics the study of the effects of an IMP on the body and the mechanisms by
which it acts (what the IMP does to the subject).
Pharmacokinetics the study of the time course of the concentrations of an IMP and related
substances in the blood and other parts of the body (what the subject does to the IMP). The
concentrations depend on the processes of absorption (from the site of administration of the
IMP), distribution in the tissues, metabolism (breakdown) and excretion (getting rid of it).
Pharmacology information about the activities of an IMP in animals or humans.
Pharmacovigilance collecting information about the safety of an IMP.
Phase 1 trials of an IMP in subjects, either healthy subjects or patients, who will not benefit
from the IMP.
Phase 2 early trials of an IMP in subjects with the target disease who are expected to benefit
from the IMP.
Phase 3 late trials of an IMP in many subjects with the target disease who are expected to
benefit from the IMP.
Phase 4 post-marketing trials of a medicine to compare it with other treatments.
Photon a quantum of electromagnetic radiation.
Placebo a preparation that looks and may taste like the IMP that is being tested but contains
no active substance (a dummy medicine).
Positron a positive charge emitted from the nucleus of a radioactive isotope.
Positron emission tomography (PET) a scanner gives a picture of the radioactivity taken
up by a slice of an organ, such as the brain, after administration of a radioactive isotope. PET
measures metabolism or locates chemical transmitters.
Pre-clinical studies studies in laboratory animals in vivo or in tissues, cells, components of
cells or biological fluids of laboratory animals or humans in vitro before the start of Phase 1 trials.
Also called non-clinical studies.
Principal investigator leads a team of investigators (researchers).
Progressive multifocal leukoencephalopathy (PML) a rare and fatal infection of the brain
and spinal cord caused by reactivation of JC polyoma virus (a normally harmless virus that 80%
of people carry) in patients with severely impaired immunity.
Protocol a document that describes how a clinical trial will be done and includes information
about the trial, such as the background, reasons, aims, ethics, design, methods, records, data
management and statistics.
Protocol amendment a document that describes a change to a protocol.
57
Publication policy a policy agreed between the investigator(s) and sponsor for publishing the
results of a trial in a scientific or medical journal.
Pulse oximetry a non-invasive and painless way to measure, from the surface of the skin, the
amount of oxygen in arterial blood.
Quality assurance (QA) all those planned and systematic actions that are established to ensure
that the trial is performed and the data are generated, recorded and reported in compliance with
GCP and with MHRA regulations.
Quality control (QC) checking the quality of trial-related activities.
Qualified person (QP) someone who ensures that each batch of an IMP that is made within
the EU meets the requirements of GMP and that each batch of an IMP made outside the EU
meets GMP requirements at least equivalent to those in the EU.
Quarantine the status of materials, product or information that is isolated pending a decision
on its approval or rejection.
Radioactive isotope an unstable form of an element that breaks up into other elements and in
so doing gives out radiation that can be measured.
Radiolabel technique of incorporating a radioactive isotope into a molecule.
Radiopharmaceutical product a product that includes a radioactive isotope.
Randomisation the process of allocating trial subjects to IMP (active, placebo or comparator)
by chance, so as to reduce bias.
Receptor a structure on the surface of a cell (or inside the cell) that selectively receives and
binds a specific substance.
Regulatory (competent) authorities bodies such as the MHRA that review submitted clinical
data and conduct inspections.
Reproductive toxicology a series of toxicity tests in animals to assess the risk of giving an IMP
to a fertile woman or man, or a woman who is pregnant.
Research ethics committee (REC) an independent group of medical and scientific
professionals and members of the public, with no financial interests or affiliations with the
sponsor or researchers, who give an opinion on the ethics of a trial.
Rescue medication treatment given to a subject to relieve a problem brought about by taking
part in a clinical trial.
Resuscitation Council (UK) provides education and reference materials to healthcare
professionals and the general public in the most effective methods of resuscitation.
Risk potential for harm.
Scintillation counter a machine for measuring radiation, that counts light flashes emitted from
a detector substance exposed to radiation.
Serious adverse event (SAE) or serious adverse drug reaction (serious ADR) any untoward
medical event that at any dose of a medicinal product:
results in death
is life-threatening
requires a stay in hospital or prolongs an existing stay in hospital
results in persistent or significant disability or incapacity or
is a congenital anomaly or birth defect.
Shipping (dispatch) packing and sending trial-related material somewhere.
Sievert a unit of radiation exposure. The average person in the UK receives about 2.5
milliSievert of background radiation annually from the environment. A chest X-ray represents
about 10 days of background radiation.
Signature a distinct record (initials, or full handwritten or electronic signature) of the person
who was responsible for a particular action or review.
58
Single photon emission computed tomography (SPECT) similar to positron emission

tomography but uses an isotope with a longer half-life (hours rather than minutes) that does not
have to be made by a cyclotron machine.
Single photon emitters radioactive isotopes that mainly emit gamma or X-rays.
Small molecules see new chemical entities.
Somatic cells cells other than egg or sperm cells.
Source data all information in original records, and certified copies of original records,
of clinical findings, observations, or other activities in a clinical trial necessary for the
reconstruction and evaluation of the trial. Source data are found in source documents.
Source documents original or certified copies of documents, data and records such as charts,
laboratory notes, memoranda, diaries, checklists, dispensing records, printed output from
instruments, and records kept at the pharmacy, laboratories and other departments involved in
the trial.
Sponsor an individual, company, institution or organisation that is responsible for the
initiation, management and/or financing of a clinical trial.
Standard operating procedures (SOP) detailed, written instructions to ensure that trialrelated procedures are done in the approved way by everybody.
Statutory instrument (SI) a power delegated by Parliament. Parliament can delegate its
power to make and amend law to a person or organisation. A statutory instrument is one of these
powers and is used by government ministers to amend legislation.
Sterility the absence of living organisms.
Subject identification code a unique identifier assigned by the investigator to each trial
subject and used instead of the subjects name when the investigator reports adverse events and/
or other trial-related data.
Subrogation substituting one person or organisation for another, including all rights and
responsibilities.
Suspected unexpected serious adverse (drug) reaction (SUSAR) a serious adverse event
considered by the investigator or sponsor to be possibly or probably related to the IMP under
test and for which the nature and/or severity differs from the information in the investigators
brochure.
Target disease the disease for which a potential new medicine is being developed.
Technical agreement agreement between sponsor and investigator for the IMP.
TGN1412 a monoclonal antibody that differs from those in clinical use in that it activates
rather than blocks the bodys immune response so it is called a superagonist.
Third country countries, such as Japan and the USA, that are members neither of the EU nor
the EEA.
TOPS (The Overvolunteering Prevention System) an internet-based system to prevent
subjects from taking part in Phase 1 trials too often.
Toxicokinetics the toxicity of an IMP in animals expressed as the amount that gets into the
bloodstream (exposure) rather than the dose.
Toxicology studies in animals or on tissues to test the safety of IMPs before they are tested in
humans.
Trial master file file that contains essential documents for the trial filed in a logical way.
Trial site place where the clinical trial is done.
Trial subject someone who takes part in a clinical trial and either receives the IMP or is a
control and receives placebo or active comparator.
QT interval a component of the ECG which if prolonged by a medicine can lead to a
potentially fatal abnormal heart rhythm called torsade de point.
59
Unit the premises in which clinical trials are carried out.

United Kingdom Ethics Committee Authority (UKECA) responsible for recognising NHS
research ethics committees to review clinical trials.
Unblinding finding out in an emergency or at the end of the trial which IMP (active, placebo
or comparator) a subject has been allocated in the randomisation process.
Validation documented programme to make sure that any equipment or specific process,
method or system works correctly and gives the expected results.
Vulnerable subjects people at risk of being persuaded against their will to take part in a
clinical trial. Examples are medical students and staff of the investigator.
60
Appendix 6: Consultation responses

Feedback from the following organisations were received, either on the 2007 edition, or in
response to the ABPI consultation on the draft 2012 revision. The list is not exhaustive and many
more organisations were invited to comment.
ABPI member companies
ABPI Expert Networks in particular the Experimental Medicine Expert Network and Legal
Expert Network.
Authorising Authority for Phase 1 Ethics Committees (AAPEC)
Cancer Research UK
Clinical Contract Research Association (CCRA) members
Department of Health (DH)
Independent Ethics Committees for Medical Research (Edinburgh, Plymouth)
Good Clinical Practice (GCP) Inspectorate, MHRA
Medicines and Healthcare products Regulatory Authority (MHRA)
Medical Research Council (MRC)
National Research Ethics Service (NRES)
Royal College of Physicians (RCP)
61
Association of the British Pharmaceutical Industry

7th Floor, Southside, 105 Victoria Street, London SW1E 6QT
t +44 (0)870 890 4333 abpi@abpi.org.uk
abpi.org.uk

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Guidelines for phase 1

Updated in 2014 by:

Developing a new medicine

Safety record of Phase 1 trials

Research ethics committee

Investigational medicinal products

15 Non-investigational medicinal products

Resuscitation procedures, equipment, medicines and training

Compensation, indemnity and insurance

Data management, statistics, report and publication

Essential documents, trial master file and archiving

24 Project management and monitoring

26 Health and safety

Appendix 1: Qualifications relevant to Phase 1 trials

1: Developing a new medicine

Number and type of subject

Is the IMP safe in humans?

Is the IMP safe in patients?

Is the IMP really safe in patients?

many thousands or millions

Just how safe is the new medicine?

Breaches of GCP or trial protocol

6: Safety record of Phase 1 trials

Two monoclonal antibodies53, 54 in clinical use have caused progressive multifocal

the safety or physical or mental integrity of the trial subjects

The sponsor decides whether an amendment is substantial, and whether a substantial

the frequency and duration of exposure to the IMP

Obtaining informed consent

a medical history and examination

Timing of recruitment and screening

asking subjects about adverse events

10: Research Ethics Committee

have adequate space for different IMPs to be stored apart

12: Investigational medicinal products

the CTA application is approved in writing

production processes that are often not validated

13: Biotechnology products

a substantial multidisciplinary team of researchers

Genetically modified micro-organisms

14: Radioactive substances

the equipment to undertake the procedure involved

15: Non-investigational medicinal products

16: Qualified Person

17: Resuscitation procedures, equipment, medicines and training

a procedure to report serious adverse events

a defibrillator with an ECG monitor (both mains and battery operated)

19: Compensation, indemnity and insurance

21: Pathology laboratory

be purpose-built or adapted for the purpose

22: Data management, statistics, report and publication

23: Essential documents, trial master file and archiving

24: Project management and monitoring

25: Quality management

keep a current version of each procedure at each point of use

the CTA and REC applications

26: Health and safety

safety in the workplace

The report on medical experiments in staff volunteers. ABPI, 1970.

72 Ionising Radiations Regulations1999. SI 3232. HMSO