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5.5 Clinical Trials in the EU 95
5.5.7 Manufacture of Investigational Medicinal Product
The manufacture of all investigational medicinal products, including placebo,
intended for clinical trial, must be authorised and conducted according to Good
Manufacturing Practice (GMP). This should be supervised and certied by a
‘qualied person’. An import authorisation is required for product from outside the
EU, which should also be manufactured to GMP standards (see Chapters 11 and 12
for information on GMP, manufacturing authorisations, and qualied persons).
Batches should be tailor-made for the proposed trial and should be labelled with
information as appropriate regarding the product, sponsor, investigator, subject and
trial together with the statements‘Forclinicaltrial use only’ and, where themedicine
will be used outside of the clinical site, ‘keep out of reach of children’. There should
be full accountability for the distribution, storage and fate of drug products at both
the manufacture and trial sites.
5.5.8 Clinical Trial Authorisation
Before a clinical trial can commence, it is necessary to obtain authorisation from the
Competent Authority in each Member State where a trial will be conducted. Under
the clinical trials regulation, a single application dossier must be submitted via CTIS
to the Competent Authorities of each Member State, where it is proposed to run a
trial. These are referred to as ‘Member States concerned’. A single Member State will
be identied to act as the reporter Member State who will coordinate review of the
application when more than one state is concerned. One of their rst tasks is to per-
form a validation (completeness check) of the dossier within 10 days, the heading
for which is shown in Figure 5.3. The reporting Member State is also responsible
for drawing an Assessment Report Part I that considers aspects such as the general
scientic value of the trial, compliance with the requirements for manufacture and
labelling of the trial drug, and the adequacy of the IB. In parallel, each Member
State concerned prepare an Assessment Report Part II that focuses on aspects relat-
ing to how the trial will be conducted in their own territory, such as how subjects
are recruited, compensated and consent obtained, adherence to GCP, the suitability
of trial site, and adequacy of insurance cover. The review period allowed for com-
pletion of these assessments is 45 days from the validation date of the application
dossier, but this time frame can be extended if the trial involves an advanced ther-
apy or there are requestsforfurther information or clarications. Finalauthorisation
of a clinical trial in their territory rests with each Member State concerned, a deci-
sion that they must give within ve days if they are satised with both parts of the
completed assessment report. All communication is channelled through CTIS so
that all parties have visibility on the progress of the application. In the best-case
scenario, where there are no complications or requests for further information, the
sponsor must receive a decision within 60 days of submission of an application
dossier.
96 5 Clinical Trials
APPLICATION DOSSIER FOR THE INITIAL APPLICATION
A. Introduction and general principles
B. Cover letter
C. Eu application form
D. Protocol
E. Investigator’s brochure (IB)
F. Documentation relating to compliance with good manufacturing practice (GMP)
for the investigational medicinal product
G. Investigational medicinal product dossier (IMPD)
H. Auxiliary medicinal product dossier
I. Scientic advice and paediatric investigation plan (PIP)
J. Content of the labelling of the investigational medicinal products
K. Recruitment arrangements (information per member state concerned)
L. Subject information, informed consent form, and informed consent procedure
(information per member state concerned)
M. Suitability of the investigator (information per member state concerned)
N. Suitability of the facilities (information per member state concerned)
O. Proof of insurance cover or indemnication (information per member state
concerned)
P. Financial and other arrangements (information per member state concerned)
Q. Proof of payment of fee (information per member state concerned)
R. Proof that data will be processed in compliance with union law on data protection
Figure 5.3 Principal headings for an initial clinical trial Application Dossier as set out in
Appendix 1 to Regulation (EU) No. 536/2014.
5.5.9 Independent Ethics Committee Opinion
As part of the assessment by each Member State concerned a favourable opinion
from an Independent Ethics must be obtained. The focus of the Independent Ethic
Committees is to ensure that the rights, safety, and welfare of human subjects
involved in a trial are protected, and in doing so, generate public condence in the
process. Ethics committee should consist of both healthcare professionals and lay
members such as people with legal or religious backgrounds. They should have a
formal legal status and operate according to dened procedures/standing orders.
They may be organised on a national, regional or institutional basis.
The committees will consider the following:
● The relevance of the clinical trial and the trial design.
● The anticipated benets and risks justication.
● The trial protocol.
● The IB.
● The suitability of the investigator and supporting sta.
● The quality of facilities.
● The informed consent procedures and selection of subjects.
● Insurance cover for subjects, sponsor and investigators.
● The nancial arrangements for subjects and investigators.
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5.5 Clinical Trials in the EU 97
The committees must deliver their opinions within the time frame allowed for the
overall assessment report.
5.5.10 Amendments to Clinical Trials
In the course of a clinical trial, the sponsor may need to amend a clinical trial, as
a consequence of the emergence of new information or changes in circumstances.
If the amendments are deemed to be substantial, in that they are likely to have a
substantial impact on the safety or rights of the subjects or on the reliability and
robustness of the data generated in the clinical trial then the sponsor must submit an
application dossier to obtain authorisation of the modication. Addition of new trial
sites or change of a principal investigator is deemed to be substantial modications.
The original reporter Member State will review and update aspects impacting Part I
of the assessment report while the Member States concerned will review and update
Part II as necessary. Reduced timelines apply to this review process compared with
the original review.
5.5.11 Case Report Forms (CRFs)
All protocol-required data are recordedat the trial site on Case Report Forms (CRFs),
which may be in electronic or hard copy format. Data for individual subjects are
recorded on separate CRFs. The CRFs are used to transfer trial data to the sponsor
for analysis and evaluation.
5.5.12 Adverse Event Reporting
It can be expected that during the course of a trial some adverse events will be
observed with subjects. These can range from the appearance of anticipated side
eects to serious adverse events. The reporting requirements for an event will
depend on an assessment of its seriousness, cause, and predictability. A serious
adverse event or reaction is dened as any untoward medical occurrence or eect
that at any dose results in death, is life-threatening, requires hospitalisation or
prolongation of existing hospitalisation, results in persistent or signicant disabil-
ity or incapacity, or is a congenital anomaly or birth defect. Irrespective of the
cause, the investigator must immediately report all serious adverse events to the
sponsor, unless they are specically excluded from immediate reporting by
the protocol.
If they are classied as Suspected Unexpected Serious Adverse Reactions
(SUSAR’s) that are fatal or life-threatening, the sponsor must then report electroni-
cally within seven days to a EudraVigilance database maintained by the EMA. Other
SUSAR’s must be reported within 15 days. The information is then discriminated
electronically to the Member States concerned.
98 5 Clinical Trials
5.5.13 Annual Safety Report
In addition to the expedited reporting described above, sponsors shall submit, once a
year throughout the clinical trial, or on request,a safety report tothe same EudraVig-
illance database. This should cover SUSARS’s, other serious adverse reactions, and
an analysis of subjects’ safety during the course of the trial.
5.5.14 Monitoring of Trials
In accordance with GCP, the sponsor should appoint clinical trial monitors. These
act as the main communication interface between the sponsor and the trial site,
and should regularly visit the site to oversee that the trials are being conducted and
correctly documented in accordance with the protocol and GCP. Reports should be
supplied to the sponsor after each visit. It is also good practice for the sponsor to
establish an auditing system for independently verifying that the activities in rela-
tion to the collection andprocessingof data at the trial site,and at related laboratories
or sponsor’s facilities, are conducted in accordance with applicable protocols, pro-
cedures, regulations, GCP, and GLP.
The competent authorities are obliged to appoint Inspectors for checking that all
activities associated with clinical trials are conducted in compliance with the reg-
ulations. They can inspect any sites concerned with the clinical trial, particularly
the trial site (GCP), the manufacturing site of the investigational medicinal prod-
uct (GMP), any laboratory used for analyses in the clinical trial (GLP), and/or the
sponsor’s premises.
5.5.15 End of Trial
The sponsor must inform the Members States concerned through CTIS of the end of
a trial within 15 days of its completion. The sponsor will then prepare a trial report,
where the data is analyzed and assessed, with conclusions presented and also a sum-
mary report that is comprehensible for laypersons.
5.5.16 Trial Master File
The sponsor and investigator, as appropriate, must retain all essential documents
relating to the trial. Documents should be securely archived for at least twenty-ve
years after their completion, with restricted access to maintain subject conden-
tiality. Collectively these constitute the Trial Master File and facilitate audit and
evaluation of the conduct of a clinical trial and the quality of the data produced.
A summary of essential documents is shown in Figure 5.4.
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5.5 Clinical Trials in the EU 99
1. PRE- TRIAL DOCUMENTS
1.1 Investigator’s Brochure (IB)
1.2 Signed protocol and amendments, if any and sample Case Report Form (CRF)
1.3 Information given to trial subject
– Informed consent form
– Any other written information
– Advertisement for subject recruitment
1.4 Financial aspects of the trial
1.5 Insurance statement
1.6 Signed agreement between involved parties
1.7 Dated, documented approval/favourable opinion of Institutional Review Board /
Independent Ethics Committee
1.8 Institutional Review Board/Independent Ethics Committee composition
1.9 Regulatory authority authorisation/approval/notication of protocol
1.10 Curriculum vitae and/or other relevant documents evidencing qualications of
investigators and sub-investigators
1.11 Normal values/ranges for medical/laboratory /technical procedures and/or tests
included in the protocol
1.12 Medical/laboratory/technical procedures/tests
1.13 Sample of labels attached to investigational product containers
1.14 Instructions for handling of investigational products and trial-related materials
1.15 Shipping records for investigational product and trial-related materials
1.16 Certicates of Analysis of investigational product shipped
1.17 Decoding procedures for blinded trials
1.18 Master randomisation list
1.19 Pre-trial monitoring report
1.20 Trial initiation monitoring report
2. DOCUMENTS GENERATED DURING THE COURSE OF THE TRIAL
2.1 Investigator’s Brochure updates
2.2 Revisions to protocol, CRF, informed consent form, etc.
2.3 Dated, documented approval/favourable opinion of Institutional Review
Board/Independent Ethics Committee of amendments
2.4 Regulatory Authority authorisations/approvals/notications where required
2.5 Curriculum vitae for new investigators and/or sub-investigators
2.6 Updates to normal values/ranges for medical/laboratory/technical procedures
and/or tests included in the protocol
2.7 Updates of medical/laboratory/technical procedures/tests
2.8 Documentation of investigational products and trial-related materials shipment
2.9 Certicates of analysis for new batches of investigational products
2.10 Monitoring visit reports
2.11 Relevant communications other than site visits
2.12 Signed informed consent forms
2.13 Source documents
2.14 Signed, dated and completed Case Report Forms (CRF)
2.15 Documentation of CRF corrections
2.16 Notication by originating investigator to sponsor of serious adverse events and
related reports
Figure 5.4 Essential documentation for a Trial Master File.
100 5 Clinical Trials
2.17 Notication by sponsor and/or investigator, where applicable to regulatory author-
ities and IRB’s/IEC’s of unexpected serious adverse drug reactions and other safety
information
2.18 Notication by sponsor to investigators of safety information
2.19 Interim or annual reports to IRB / IEC and authorities
2.20 Subject screening log
2.21 Subject identication code list
2.22 Subject enrolment log
2.23 Investigational products accountability at the site
2.24 Signature sheet
2.25 Record of retained body uids/tissue samples
3. POST-TRIAL DOCUMENTS
3.1 Investigational products accountability at the site
3.2 Documentation of investigational product destruction
3.3 Completed subject identication code list
3.4 Audit certicate (if available)
3.5 Final trial close-out monitoring report
3.6 Treatment allocation and decoding documentation
3.7 Final report by investigator to IRB/IEC whererequired, and where applicable, to the
regulatory authorities
3.8 Clinical Study Report
Figure 5.4 (Continued)
5.6 Clinical Trials in the US
The relevant regulations governing the conduct of clinical trials in the US are shown
in Table 5.4. As they also reect the principles of GCP, they are quite similar in
requirements to those of the EU. However, because they apply to a single jurisdic-
tion, they are framed to provide more prescriptive detail than can be found in the
equivalent EU legislation. Similarly, they are supported by theICH and FDA-specic
guidelines. As mostof the practices arethe same as discussedin the previous section,
the chapter will now just look at some of aspects that are unique to the US regula-
tions.
5.6.1 Investigational New Drug Application (IND)
Requests for permission to conduct clinical trials with pharmaceuticals in the US are
termed investigational new drug applications (INDs). The applications are actually
a request for an exemption to supply a drug without a marketing authorisation. A
cover sheet (Form 1571) must accompany the application. This cover sheet should
also be used with each subsequent communication with the FDA, with each form
consecutively numbered, starting at 000 for the initial submission. A copy of the
form is shown in Figure 5.5
The content of the application is quite similar to EU requirements, although the
structure and terminology are slightly dierent. The main headings are shown in
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5.6 Clinical Trials in the US 101
Table 5.4 Code of federal regulations parts relevant to clinical trials.
21 CFR Part 312 Investigational New Drug IND
Sec. 312.6 Labeling of an investigational new drug
Sec. 312.20 Requirement for an IND
Sec. 312.21 Phases of an investigation
Sec. 312.22 General principles of the IND submission
Sec. 312.23 IND content and format
Sec. 312.30 Protocol amendments
Sec. 312.31 Information amendments
Sec. 312.32 IND safety reports
Sec. 312.33 Annual reports
Sec. 312.41 Comment and advice on an IND
Sec. 312.42 Clinical holds and requests for modication
Sec. 312.47 Meetings
Sec. 312.50 General responsibilities of sponsors
21 CFR Part 50 Protection of Human Subjects
21 CFR Part 54 Financial Disclosure by Clinical Investigators
21 CFR Part 56 Institutional Review Boards IRB
Table 5.5 IND headings.
1 Cover sheet (Form FDA-1571)
2 A table of contents
3 Introductory statement
4 General investigational plan
5 Investigator’s brochure
6 Protocols
7 Chemistry, manufacturing, and control information
8 Pharmacology and toxicology information
9 Previous human experience with the investigational drug
10 Additional information
Table 5.5. However, the FDA will now also accept IND application dossiers struc-
tured according to the CTD format. (See Chapter 6 for the CTD format).
A Form 1572 is used for investigators to summarise their educational qualica-
tions and experience, and to make a required formal declaration as to their com-
mitment to conduct the study according to the protocol, GCP, and the regulations.
The sponsor should also collect nancial disclosure information from the investiga-
tors at this stage, although formal declarations on Form 3455 are not required until
submission of a marketing authorisation application.
102 5 Clinical Trials
Once the FDA receives the initial submission, an IND reference number is
assigned. The application is then passed on to the appropriate review centre;
either the Center for Drug Evaluation and Research (CDER), or the Center for
Biologics Research and Evaluation (CBER). Various experts will then review the
submitted documents, the purpose being to ensure that the safety of subjects is not
compromised and in the case of phase II and III studies that the quality of study
Figure 5.5 Form FDA 1571, Investigational New Drug application (IND). Source: FDA,
2019/U.S Department of Health and Human Services/Public Domain.
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5.6 Clinical Trials in the US 103
Figure 5.5 (Continued)
design is scientically adequate. The FDA is allowed 30 days to complete the initial
review after which the study can commence, provided it has been approved by an
Institutional Review Board (IRB).
5.6.2 Institutional Review Board (IRB)
Under US regulations, each institution conducting research with human subjects
must have its own IRB. The IRBs perform the same functions as the Independent
104 5 Clinical Trials
Ethics Committees in Europe. They should contain at least ve members, one of
which should be independent of the institution. There should be available a mixture
of scientic and nonscientic expertise capable of assessing research proposals from
legal, ethical, and scientic perspectives. They must grant written authorisation to
the investigator before a study can commence. They are alsoresponsible for on-going
review of research and must report to the FDA:
● any unanticipated problems that place subjects at risk,
● serious non-compliance with the regulations or
● decisions to suspend IRB approval.
5.6.3 Communication with the FDA
Once the initial IND application has been assigned a reference number, the sponsor
can keep submitting information to the FDA le to enable the clinical development
to move through the various trial phases.
Protocol amendments are used to inform the FDA of items such as changes to
existing protocols, new protocols (for phase II or III studies), or new investigators
(trial sites). The changes can be implemented once they have been approved by the
relevant IRB. However, the FDA can place a trial on ‘clinical hold’ at any stage, if it
is concerned over aspects such as safety risks to subjects, investigator qualications,
quality of the IB, insucient IND information to enable risk assessment, or decien-
cies in design to achieve the objectives of phase II or III studies. Alternatively, the
FDA may oer advice, or request clarication, if their concerns are of a less serious
nature. The sponsor canalso meet with the FDA before submitting the IND (pre-IND
meeting), and morecritically, at the end ofPhase II studies. Here, the sponsor should
seek to establish that the phase III studies designs proposed to conrm ecacy, will
satisfy FDA expectations when it comes to submitting an application for marketing
approval.
Information amendments are used toinformthe FDAof new pharmacology or tox-
icology data, nal non-clinical study reports, new chemistry-manufacturing-control
information, or notice of discontinuation of a clinical study.
The sponsor must also submit an annual report on the progress of the trial,
within 60days of the anniversary of IND going into eect. This should provide brief
summaries of the status of each study, the clinical and non-clinical information
gathered during the previous year (including adverse reactions and safety reports),
the general investigation plan for the coming year, and if applicable, changes to
the IB or Phase I protocol, or marketing authorisations/developments in other
countries.
The sponsor is obliged to submit safety reports for SUSAR events to the same time-
lines as apply in Europe. They must also report within 15 days ndings from animal
studies that would suggest an increased risk to human subjects, e.g. carcinogenicity,
mutagenicity, etc.
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