Clinical Trials Seminar for Academic Sponsors and Investigators – HPRA (formerly IMB)
Offices 29th April 2014 – Reponses to Participants Queries
This document provides responses to participants’ queries on the following topics:

Safety Reporting

Clinical Trial Applications

Good Clinical Practice (GCP)

Investigational Medicinal Products (IMP) –Quality/Chemistry, Manufacturing and Control
(CMC)

Voluntary Harmonisation Procedure (VHP)

Advanced Therapy Investigational Medicinal Products
Safety Reporting
Q.1 General query regarding Serious Adverse Events (SAEs), Serious Adverse Reactions
(SARs), Suspected Unexpected Serious Adverse Reactions etc?
A: Refer to Dr. Clare Brennan’s presentation from 2012 Clinical Trials Seminar which provides a clear
and comprehensive overview of national, clinical trial adverse reaction reporting requirements.
Please also refer to the following legislation and guidance:
HPRA Guide to Clinical Trial Applications
Directive 2001/20/EC
S.I. 190 of 2004
“CT-3” Guideline
EudraVigilance website
Q.2 What are the differences between pharmacovigilance requirements for clinical trials (as
per SI No 190 of 2004) and studies that are not clinical trials?
A: They are many and varied. Post-marketing pharmacovigilance is governed by Directive
2001/83/EC as amended by Directive 2010/84/EU (S.I. 540 of 2007 and S.I. 272 of 2012) ,
whereas pharmacovigilance for clinical trials is governed by Directive 2001/20/EC (and S.I. 190 of
2004). For specific adverse reaction reporting queries for either clinical trials or post-marketing
please contact medsafety@hpra.ie
Q.3 What are the duties of a Pharmacovigilance (PV) Officer?
A: The role “PV Officer” is not defined in legislation and therefore the duties would be set by the
sponsor. However, in considering the safety reporting/pharmacovigilance requirements please
refer to the presentation, legislation and guidance linked above.
Q.4 What are the key points regarding safety reporting?
A: Please note the following points:
 Causality Assessment – consider importance of training given to investigators
 Expectedness Assessment – consider appropriate Reference Safety Information (RSI) at the time
of application – is an Investigator Brochure or Summary of Product Characteristics (SmPC) more
appropriate?
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 Unblinding of cases – SUSARs should be unblinded before submission – if you believe a waiver is
needed for this, apply for this at time of application, and provide details for investigators in the
protocol.
 Ensure a procedure for regulatory unblinding of SUSARs is in place before commencing trial.
 SUSARs must be reported electronically to EudraVigilance Clinical Trial Module (EVCTM) and the
HPRA. The HPRA can undertake the responsibility to report to EVCTM on a sponsor’s behalf in
exceptional circumstances and subject to prior agreement between the sponsor and HPRA. If
such reporting is required, sponsors should submit a request to the HPRA at time of CT
application. A provision to facilitate such reporting by Competent Authorities generally is
provided for in the new legislation.
Q.5 Can one do PV/SUSAR reporting if otherwise involved with the trial – e.g. dispensing to
trial participants / site monitoring?
A: This very much depends on the nature of the trial. If the trial is not blinded this would not
generally be a problem. However, where there is a blind in place, and the process in place for safety
reporting leads to the person with responsibility for reporting unblinding the report, careful
consideration should be given to the potential impact this may have on the integrity of the trial.
Likewise it may not be appropriate for a trial Monitor to be involved in generating Developmental
Safety Update Reports (DSURs) as they would be comparing results across treatment arms.
Q.6 What procedures should be in place for unblinding?
A: According to international guidelines, the treating physician (investigator) is responsible for the
medical care of the individual trial subject (Declaration of Helsinki 3§ and ICH GCP 4.3). The coding
system in blinded trials should include a mechanism that permits rapid unblinding (ICH GCP 5.13.4).
If the blinding is prematurely broken, it is the responsibility of the investigator to promptly
document and explain any unblinding to the sponsor (ICH GCP 4.7).
The medical care of the trial subjects includes medical decisions such as whether to start or stop
treatment or institute alternative treatment if required. In emergency situations the treating
physician, often an investigator, may need to break the treatment code immediately, or as quickly
as possible if he/she finds it is in the best interest of the trial subject. Consequently, in order to do
so, the investigator must have unrestricted and immediate access to break the treatment code.
Some sponsors have recently introduced a code breaking system that requires the investigator to
contact a sponsor representative and only after discussion with the representative, the investigator
receives information that unblinds the treatment. Some sponsors have even added a requirement
that the investigator submits a written form after the phone call before receiving the information
that unblinds the treatment.
The responsibility for breaking the treatment code in emergency situations resides solely with the
investigator. Consequently the sponsor can’t require or insist on being involved in the decision to
unblind, stall or delay in any way the unblinding of trial subject treatment in emergency situations.
Q.7 In the new clinical trials regulation is there any change to the requirement for sponsors to
report SUSARs to investigators?
A: There are currently no changes in this regard proposed the new Clinical Trials Regulation,
however it should be noted that pending development/amendment of the EU guidelines, a
definitive answer cannot be provided at this time.
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Q.8 How does one separate adverse reactions from background adverse events?
A: The separation of adverse reactions from background adverse events is made via a causality
assessment. This assessment is a medical decision, and as such, in accordance with ICH GCP, should
be undertaken by a physician. Different methods may be applied for assessing the causal role of a
medicinal product on the reported adverse event, e.g. WHO-UMC system for standardised case
causality assessment. However, it is not a requirement of ICH GCP to employ a specific method and
the medical judgment of the Investigator is accepted. If an Investigator assesses an adverse event
to be related to an investigational medicinal product, this cannot be downgraded by the sponsor.
Development Safety Update Report (DSUR)
Q.9 What are the requirements for safety reporting to the HPRA during a clinical trial?
A: The requirements are as follows:
 The HPRA requires that an annual safety report, in the format of a Development safety update
report (DSUR) is submitted for any trial which is ongoing in Ireland.
 In addition, expedited reporting of SUSARs is required.
 A Detailed guidance on the collection, verification and presentation of adverse event/reaction
reports arising from clinical trials on medicinal products for human use is available on the
European Commission ‘Eudralex’ website (Volume 10, Chapter II)
http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm
 Information on safety reporting in clinical trials can also be found in the HPRA Guide to Clinical
Trial Applications on the HPRA website under “Publications”
http://www.hpra.ie/homepage/about-us/publications-forms
 Additional information on clinical trial safety reporting requirements within the EU can be found
on the Heads of Medicines Agencies website under the Clinical Trials Facilitation Group tab
(safety information at bottom of page): http://www.hma.eu/77.html
Q.10 What format should the annual safety report be in?
A: Since September 2011, the DSUR format has replaced the Annual Safety Report format.
Q.11 Is there a requirement for the sponsor to submit a DSUR as well as an annual safety
report to the HPRA?
A: The DSUR has replaced the annual safety report, hence only a DSUR needs to be submitted to
the HPRA.
Q.12 What is the purpose of the DSUR?
A: From the EMA guidance document on DSURs: the main objective of a DSUR is to present a
comprehensive, thoughtful annual review and evaluation of pertinent safety information
collected during the reporting period related to a medicinal product under investigation, by
(1) examining whether the information obtained by the sponsor during the reporting period is
in accord with previous knowledge of the investigational drug’s safety;
(2) describing new safety issues that could have an impact on the protection of clinical trial
subjects;
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(3) summarising the current understanding and management of identified and potential risks;
and
(4) providing an update on the status of the clinical investigation/development programme and
study results.
A DSUR should be concise and provide information to assure regulators that sponsors are
adequately monitoring and evaluating the evolving safety profile of the investigational
medicinal product. All safety issues discovered during the reporting period should be discussed
in the text of the DSUR; however, it should not be used to provide the initial notification of
significant new safety information or provide the means by which new safety issues are
detected.
Q.13 When is submission of the DSUR due?
A: Please note the following:
 The DSUR reporting period is aligned with the development international birth date (DIBD).
 This date is the sponsor’s first authorisation to conduct a clinical trial on the investigational
medicinal product (IMP) in any country worldwide.
 The start of the annual period for the DSUR is the month and date of the DIBD.
 The data lock point of the DSUR should be the last day of the one-year reporting period.
 The DSUR is due for submission within 60 days of the data lock point.
Q.14 If a sponsor is not the marketing organisation holders for the IMP and not aware of
when the Development international birthdate falls, when is the DSUR due?
A: The date of first authorisation of the clinical trial by the HPRA or within the EU may serve as the
data-lock point.
Q.15 Can safety information be sent to the Marketing Authorisation Holder (MAH) to include
in their DSUR for an experimental Investigational Medicinal Product (IMP)?
A: Yes – even if a medicine is not marketed, CT safety information may be sent to the company
developing the medicine for inclusion in the DSUR for the IMP.
Q.16 Where can I find information on what should be included in the DSUR?
A: Please note the following:
 A note for guidance on DSURs on the EC website (Eudralex Volume 10, Chapter II)
http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm
 A simplified version of the DSUR is required for non-commercial sponsors.
 An example DSUR for non-commercial sponsors is available on the ICH website
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html (ICH E2F).
Q.17 What are the key sections in the non-commercial DSUR?
A: Please note the following:
 The Cumulative table of Serious Adverse Events – broken down into treatment arms (if openlabel CT) – the DSUR is the only document where these are reported to the HPRA in
ongoing trials
 Broken down by treatment arm (if open-label)
 The Line-listing of Serious Adverse reactions
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 Another key section is the Overall safety assessment (section 18), including section 18.1:
Evaluation of the risks and section, and 18.2: Benefit/risk considerations (this important section
should discuss both the (potential) benefits and the risks to patients in the trial. A statement to
the effect of “The benefit/risk has not changed” is not sufficient per se.)
 Depending on the trial, Section 3 Actions taken in the reporting period for safety reasons
and section 4 Changes to reference safety information can be important
Q.18 Is a DSUR required if no patients have been recruited?
A: Please note the following:
 As outlined in the answer to query 4 above, the DSUR should provide an update on the status of
the clinical trial.
 However, if there are no patients recruited the trial anywhere in the world then a cover letter
stating there are no safety data to report and no DSUR will be submitted will suffice. In this case,
 The cover letter is due for submission within the deadline required for DSUR
submission (i.e. within 60 days of the annual safety reporting period.)
 The failure to recruit any patients should be justified in the cover letter.
 A comment should be made on whether it is anticipated that target accrual can be
met or whether the estimated duration of the trial may need to be amended.
 For multinational trials that have been approved by the HPRA where patients have been
recruited outside Ireland (but not yet in Ireland), submission of a DSUR is required. All relevant
sections of the DSUR should be completed, where possible, including (but not limited to) the
Executive Summary, Introduction, Overall safety assessment, etc.
 If no patients have been recruited within the reporting period but patients had been recruited in
previous years, submission of a DSUR is required, as long as the trial remains open to
recruitment.
Q.19 When can the sponsor stop submitting DSURs?
A: For clinical trials conducted in Ireland only, DSURs should be submitted until the trial has been
completed as per protocol and an end of trial declaration has been submitted to the HPRA.
For multinational trials, if a trial ends in Ireland before the trial has ended globally, it is
recommended that the sponsor notifies the HPRA in writing as justification for no longer
submitting amendments or Development Safety Update Reports (DSURs).
Further details on the End of Trial:
 The End of Trial should be defined in the protocol. This is usually defined as the last visit of
the last patients (or 30 days after the last visit of the last patient).
 An End of Trial Declaration (EOTD) should be submitted within 90 days of the end of the clinical
trial or within 15 days of the trial has ended earlier than planned.
 A DSUR is not required for the period following the submission of an EOTD, or for the final data
lock point.
 If patients remain in follow-up and are not required to physically attend the clinic (e.g. follow up
for survival only), submission of DSURs is still required, unless the End of Trial is otherwise
defined in the protocol. Thus, in these circumstances, the last “visit” of the last patient is the last
follow-up event in the study.
 An End of Trial Report is due for submission within 1 year of the end of trial. The end of trial
report should include a comprehensive safety evaluation. A note for guidance on structure and
content of clinical study reports is available on the European Medicines Agency website:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_0004
29.jsp&mid=WC0b01ac0580029590
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Q.20 If a clinical trial uses a combination of IMPs, can the sponsor submit a single DSUR for
the combination?
A: For trials involving multi-drug therapy, the sponsor can prepare either:
(1) A DSUR for the multi-drug therapy, or
(2) DSUR(s) for one or more of the individual components;
Q.21 Does the Clinical Trials Regulation require that sponsors use a qualified person for
pharmacovigilance for clinical trials?
A: There are currently no changes in this regard proposed by the updated regulation.
Q.22 What other safety actions require notification to the HPRA?
A: The following actions require notification:
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Urgent safety measures e.g. “Dear Investigator letter”: within 3 days
Temporary halt – can be substantial amendment or urgent safety measure.
Preliminary end of trial – declaration should be submitted within 15 days if premature end.
It is recommended that the sponsor informs the national competent authority and the Ethics
Committee of safety issues which might materially alter the current benefit-risk assessment of
an IMP while not falling within the actions listed above.
Q.23 Can the sponsor get an acknowledgement of submission of a DSUR?
A: Yes. An acknowledgement that the DSUR has been received and validated will be sent if
requested in the cover letter.
Q.24 What is used as Reference Safety Information (RSI) to assess expectedness?
A: The following are acceptable for use as RSI:
 Investigator Brochure (IB) – clearly identified section or SmPC (section 4.8 – adverse reactions
table).
 The RSI in effect at the start of the DSUR reporting period should be used for the duration of
the reporting period.
 Any proposed changes to the reference safety information used to assess expectedness should
be submitted as a substantial amendment.
 The RSI in effect at the start of the reporting period and the RSI in effect for the next reporting
period should both be submitted with the DSUR.
 The RSI used for the reporting period should be submitted with the DSUR.
 The RSI for the following reporting period should also be submitted with the DSUR.
Q25. Our trial uses a combination of IMPs. What should we use as the reference safety
information?
A: Expectedness of serious adverse reactions may be assessed against separate RSI tables for each
of the suspected IMPs, or a single table for the combination can be used, if available.
Q26. What reference safety information should be used when a licensed medicines is used in
an unlicensed indication/population.
A: For a trial that uses licensed medicines in an unlicensed indication and/or population the SmPC
may be used as RSI if justification for its use is provided in the clinical trial application. Additional
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information WRT formulation may be required if modifications have been made to facilitate the use
of the protocol. This information is best placed in the Investigators Brochure to avoid excessive
detail being in the protocol.
Clinical Trial Applications
Q1. If a study is being done in the US is there a need to notify the HPRA?
A: The HPRA only needs to be notified of trials being conducted in Ireland. Clinical trials cannot be
commenced in Ireland without the prior approval of the HPRA. For further information, please see
the Guide to Clinical Trial Applications.
Q2. Will the Annex 1 requirements (application dossier for the initial application) in the new
clinical trial regulations apply retrospectively to currently authorised trials?
A: No
Q3. In multinational trials can the trial documents differ across Member States?
A: Yes, ethics committees may impose local requirements on the consent documents.
Q4. How does one distinguish between an Investigational Medicinal Product (IMP) and a
Non Investigational Medicinal Product (NIMP)?
A: IMP: Directive 2001/20/EC, Article 2 (d), provides the following definition for an IMP: “a
pharmaceutical form of an active substance or placebo being tested or used as a reference in a
clinical trial, including products already with a marketing authorization but used or assembled
(formulated or packaged) in a way different from the authorized form, or when used for an
unauthorised indication, or when used to gain further information about the authorised form.”
Therefore, to classify a "medicinal product" as an "investigational medicinal product" a sponsor
must consider both its intended use and the objectives of the study. For example, if it is to be used
as the test substance or reference substance (active comparator or placebo) in a study it would
meet the first criteria of an IMP. However, if the study is not intended to discover or verify: (a) its
clinical, pharmacological and/or other pharmacodynamic effects or (b) to identify any adverse
reactions associated with its use or (c) to study its absorption, distribution, metabolism and
excretion; with the objective of ascertaining its safety or efficacy, it would fail the second test. It
would therefore not be classified as an IMP. Medicinal products with a marketing authorization
(MA) are classified as IMPs when they are to be used as the test substance or reference substance
in a clinical trial. They can be used or assembled (formulated or packaged) in a way different from
the authorized form, or used for an unauthorized indication, or used to gain further information
about the authorized form
NIMP: Products which are not the object of investigation (i.e. other than the tested product,
placebo or active comparator) may be supplied to subjects participating in a trial and used in
accordance with the protocol. For instance, some clinical trial protocols require the use of medicinal
products such as support or rescue/escape medication for preventive, diagnostic or therapeutic
reasons and/or to ensure that adequate medical care is provided for the subject. They may also be
used in accordance with the protocol to induce a physiological response.5 These medicinal
products do not fall within the definition of investigational medicinal products in Directive
2001/20/EC and are called “non-investigational medicinal products” (NIMPs). They may be supplied
by the sponsor who provides details of these NIMPs and their proposed use in the trial protocol
and ensure that they are of the necessary quality for human use.
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If you have any doubts as to whether your product should be classified as an IMP or NIMP, please
contact clinicaltrials@hpra,.ie
Q5. How to establish whether a trial is a “clinical trial” – use of the algorithm in Annex I to
EUROPEAN COMMISSION VOLUME 10 - GUIDANCE DOCUMENTS APPLYING TO CLINICAL
TRIALS?
A: Article 2 (c) of Directive 2001/20/EC defines a clinical trial as:
a) clinical trial: any investigation in human subjects intended to discover or verify the clinical,
pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal
product(s), and/or to identify any adverse reactions to one or more investigational medicinal
product(s) and/or to study absorption, distribution, metabolism and excretion of one or more
investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy.
This includes clinical trials carried out in either one site or multiple sites, whether in one or more
than one Member State.
(c) non-interventional trial: a study where the medicinal product(s) is (are) prescribed in the usual
manner in accordance with the terms of the marketing authorisation. The assignment of the patient
to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within
current practice and the prescription of the medicine is clearly separated from the decision to
include the patient in the study. No additional diagnostic or monitoring procedures shall be
applied to the patients and epidemiological methods shall be used for the analysis of collected
data.
The decision tree in Annex 1 to VOLUME 10 - GUIDANCE DOCUMENTS APPLYING TO CLINICAL
TRIALS can be used to identify whether a trial is a clinical trial in the sense of that Directive. Start in
column A and follow the instructions. If any doubts exist about using this decision tree or whether
your trial is a “clinical trial” as defined in the Directive, please contact clinicaltrials@hpra.ie
Q6. Is the addition of a new study site considered a substantial amendment?
A: These amendments are not under the HPRA’s remit, it is the responsibility of the relevant ethics
committee to approve these amendments.
Please see the following guidance from the ‘HPRA guide to clinical trial applications’:
Changes to the trial site or investigator
Substantial amendments relating to the clinical trial site or the investigator which are required to be
sent to the ethics committee should be notified to the HPRA following approval by the ethics
committee. A revised XML file with an updated list of approved trial sites/investigators (Section G)
should be submitted as part of the next substantial amendment application for the trial.
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Good Clinical Practice (GCP)
Q1. What are common deficiencies found on inspection?
A: Many areas of compliance are identified from GCP inspections performed by the HPRA.
However, where findings have been identified, they have most commonly occurred in the following
areas:
-
Compliance with the clinical trial protocol
Record keeping, for example, incomplete or ambiguous source data, inconsistencies with
data reported in the case report form
Q2. What are the most common deviations from protocol found at inspection?
A: The types of deviations identified are specific to the protocol and the arrangements for conduct
of the trial. However, deviations are most commonly identified when the protocol requirement
differs to an existing practice implemented at the site. For example, clinical trial protocols may
require the analysis of additional laboratory analytes which are not part of a hospital routine panel
or dose limiting criteria which may be different. It is therefore recommended that care is taken to
identify protocol requirements that may require a change from existing practices, and to plan for
these accordingly.
The practical implementation of requirements at Investigator sites should also be considered when
the protocol is written.
Q4. What are the expectations for temperature monitoring of IMP?
A: The monitoring in place should be sufficient to enable verification that the IMP was stored
securely and at the appropriate temperature at all times. Requirements for temperature monitoring
should be documented in the clinical trial protocol, or separate manual, as needed. Further
information on best practice in this regard can be found in HPRA’s guide to Control and
Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and
Active Substances.
Q5. Are non-Investigator study personnel permitted to obtain informed consent?
A: S.I. 190 of 2004 (as amended) states that the conditions and principles for the protection of
clinical trial subjects are consistent with the principles contained in the 1996 version of the World
Medical Association Declaration of Helsinki. According to Basic Principle 9 of the Declaration, a
physician should obtain the subject's freely-given informed consent.
However, there is no impediment to other HCPs, such as nurses, being involved in the informed
consent process, and this is found to be a common practice.
Q6. What are the requirements for obtaining consent from a minor?
A: The conditions and principles which apply in relation to a minor participating in a clinical trial are
documented in Schedule 1, Part 4 of S.I. No. 190 of 2004. The involvement of ‘every person with
parental responsibility’ for a minor in the informed consent process is specified in Schedule 1, Part
4. It should, therefore, be routine practice to obtain written consent from every person with
parental responsibility. Clarification on specific issues in relation to consent should be addressed to
the ethics committee given their remit as documented in Part 3, 13 (6)(g) of S.I 190 of 2004 .
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Q7. There tends to be a high turnover of sub-investigators in hospital-based trials. Do all
sub-investigators need to be on the delegation log?
A: Yes, all sub-investigators are required to be on the delegation log (CPMP/ICH/135/95 4.1.5).
Q8. Monitoring Visit Frequency – How often?
A: In accordance with CPMP/ICH/135/95section 5.18.3, monitoring of the trial should reflect the
nature and complexity involved.
Q9. How and where should source data be defined?
A: Source data are defined in CPMP/ICH/135/95 section 1.51, as 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 contained in source documents which may be electronic and/or paper records. The
following list gives examples of source documents where source data may be located:
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medical records
laboratory reports
subject diaries
comment cards
nurses’ notes
dispensing logs
electrocardiogram (ECG) print-outs
case report forms (CRF)
X-ray images
radiological reports
Q10. What are the requirements for source data?
A: Irrespective of whether recorded on paper or electronically, source data must be accurate,
legible, contemporaneous, original, attributable, complete, consistent, available when needed and
enduring.
These requirements are documented in CPMP/ICH/135/95 sections 1.51, 1.52, 4.9.1, 4.9.2, 4.9.3,
5.5.3, 5.5.4, 5.5.5, 5.5.6 and 6.4.9. Expectations regarding electronic source data are further
described in EMA/INS/GCP/454280/2010, the Reflection Paper on Expectations for Electronic
Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials.
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Accurate: The use of electronic systems should ensure that the data are at least as accurate as
those recorded by paper means.
Legible: Source data must be readable and signatures identifiable. When electronic systems
are used data must be readable at the input and output stage in a form meaningful to an
independent reviewer.
Contemporaneous: Clinical observations should be recorded at the time the observation
occurs.
Original: The first record made by the appropriate person, for example an ePRO record
produced by the subject and not the investigator or the first result generated in an
environment where analysis/ tests/ scans/imaging/ evaluations, etc. are performed in support
of a clinical trial.
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Attributable: It should be clear who has documented/changed clinical trial data. As with paper
data, it is important that electronic data are time and date stamped when the data are created
or amended.
Consistent: The use of features such as drop-down lists may help to ensure that data are
consistent.
Available when needed: Clinical trial data must be easily available for review by treating
physicians and during audits/inspections. The documents should be retrievable in a
reasonable time.
Enduring: Long-lasting and durable.
Source data and their respective capture methods should be clearly defined prior to subject
recruitment, either in the protocol or in a trial specific source data agreement, signed and dated by
the investigator and the sponsor. The source data agreement should be sufficiently detailed to
describe, for example, what is included in the medical notes. All trial investigators must be aware of
the location of source data.
Investigational Medicinal Products (IMP) –Quality/Chemistry, Manufacturing and Control
(CMC): Chemical, Biotechnology and Advanced Therapy products
Q1. Is it necessary to have the dossier for the investigative medicinal product (IMP) approved
before the clinical trial application is submitted to the HPRA?
A: Each clinical trial application must contain information on the IMP. This information is assessed
as part of the application
The extent of the information required for the IMP will depend on whether the IMP:
(1) Is an authorised product i.e. a product which holds either a national or European marketing
authorisation. In this case a simplified Investigational Medicinal Product Dossier (IMPD) or a
copy of the Summary of Product Characteristics (SmPC) is sufficient.
(2) Has been approved by the HPRA in an earlier CT application. In this case submission of a
simplified IMPD is acceptable. This dossier must contain a cross reference to the previous CT,
highlight all modifications made to the dossier and provide all relevant data to support any
modifications made.
(3) Is not authorised and has not been previously approved by the HPRA. In these situations the
requirements of the IMPD for biological and chemical IMPs are clearly laid out in the guideline
entitled “Guideline on the Requirements for Quality Documentation concerning Biological
Investigational Medicinal Products in Clinical Trials” and “Guideline on the requirements
to the chemical and pharmaceutical quality documentation concerning investigational
medicinal products in clinical trials” respectively. IMPDs submitted to the HPRA must be in
line with the guidance provided in these guidelines.
Placebo/Reference products:
An IMPD is also required for any placebo or reference medicinal product used in the CT.
Queries generated in the IMPD and any other quality aspect will be forwarded to the sponsor prior
to or on day 25 of the procedure along with any queries raised on the pre-clinical or clinical aspects
of the application. The IMPD is approved as part of the clinical trial process and separate prior
approval of the IMPD prior to submission of the clinical trial application is not required
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Q2. Are medicinal products that are authorised but being used in a new way considered
IMPs?
A: An IMPD is not normally required for products used for a new therapeutic indication as the
quality data would be the same. If the dosages are significantly different some information may be
required. In addition, for parenteral products if it is proposed to administer an authorised product
via a route of administration that is not approved for the authorised product, additional quality
information may be required.
Q3: Is IMP manufacturing licence equivalent in all EU countries?
A: The format of IMP licences may vary from country to country, but the requirements are the
same. The HPRA will accept manufacturing licences issued by other EU/ EEA authorities.
Q4. What information must be provided within the IMPD for products authorized in the US
but not in the EU?
A: The documentation equivalent to the SmPC should be submitted within the clinical trial
application for products which are authorized in the US but not the EU.
Q5. What information must be submitted within the IMPD for products manufactured in the
US but not yet authorized?
A: The IMPDs for chemical and biological IMPs must contain the information as outlined in the
Guideline on the Requirements for Quality Documentation concerning Biological Investigational
Medicinal Products in Clinical Trials and the Guideline on the requirements to the chemical and
pharmaceutical quality documentation concerning investigational medicinal products in clinical
trials respectively. In addition, the following documentation must be provided to demonstrate
Good Manufacturing Practice (GMP).
 A Qualified Person’s declaration, issued from the EU site of batch release, that confirms that the
manufacturing site works in compliance with GMP,
 Copy of the manufacturing authorisation of the site of batch release which must be issued from
a concerned member state.
Q6. If the product holds a marketing authorization issued by an EU Member State will it be
sufficient to submit the SmPC instead of an IMPD? If the SmPC is not in English does it need
to be translated?
A: Yes it is sufficient to submit a copy of the SmPc for a product authorized by an EU Member State
instead of an IMPD. An English version of the SmPC will be required along with a copy of the
original SmPC. A declaration from the Sponsor stating that the translation is a true translation of
the original SmPC is also required.
Q7. Can you issue labels in a non-english language?
A: IMPs should be labelled in English.
Q8. If a drug is repackaged (e.g. into a new vial) is this considered modified?
A: This is considered to be modified and would require a substantial amount of new information. If
the immediate packaging for a sterile product is compromised this could cause significant issues
with approval of the clinical trial. Sponsors are advised to avoid this if at all possible.
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Q9. Who can prepare an IMPD for a Placebo?
A: Anyone with a suitable knowledge can write an IMPD for a placebo but the manufacturing site
needs a GMP license to manufacture IMPs.
Q10. What information must be provided to demonstrate the stability of the drug substance
(DS) or drug product (DP)?
A: The following requirements apply when requesting a shelf-life for either the DS or DP.
 A stability protocol covering the proposed storage period of the DS/DP must be provided which
includes details on stability release specifications, analytical methods and test intervals. Testing
intervals should follow the guidance outlined in ICH Q1A (R2) note for guidance on stability
testing (stability testing of new drug substances and products) or ICH Q5C note for guidance
(Stability testing of biotechnological/ biological products) for chemical or biological IMPs
respectively.
 The quality of the batches used in stability studies should be representative of the material used
in the trial.
 The container type used in stability studies must be the same type of container as used for the
clinical trial material.
 Studies should evaluate stability under the proposed storage conditions of the IMP.
Accelerated and stress condition studies are recommended as they may help understand the
degradation profile of the product and support extension of shelf-life.
 Focus should be placed on stability indicating methods to provide assurance that changes upon
storage in the purity/impurity profile and potency can be detected.
 A potency assay should be included unless otherwise justified.
The following data requirements apply:
 Data should be presented for at least one batch representative of the manufacturing process of
the clinical trial material.
 Stability data of relevant development batches or batches manufactured using previous
manufacturing processes could be provided to assist in extending the shelf-life of the current
batches
Shelf-life determination and extension of shelf-life:
 Should be based on available real time data.
 Extension of shelf-life can be done by way of non-substantial amendment provided that a
proposal for shelf-life extension, defining the criteria based on which the sponsor will extend
the shelf-life during an ongoing stability study, has been submitted in the IMPD and has been
approved by HPRA. In developing such criteria sponsors should address the following points:
 Extension beyond the real time data covered is permitted if supported and justified by
relevant data including accelerated data.
 Maximum extension must not exceed two-fold of the real time data and not be for
greater than 12 months. The extension must not extend the shelf-life of the DS/DP
beyond the intended duration of the planned stability studies stated in the protocol.
 A commitment to conduct the proposed stability programme as outlined in the IMPD
must be provided along with a statement confirming that if unexpected stability issues
arise that the HPRA will be informed of these along with any planned corrective
actions.
Q11. How much stability data is needed for new medicine formulations?
A: It depends on the trial, the medicine and on the expected shelf-life of the product.
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Voluntary Harmonisation Procedure (VHP)
Q1. Who decides on the reference national competent authority (NCA) in a VHP procedure?
A: In the VHP procedure, a MS volunteers as reference national competent authority (REF-NCA),
depending on their experience with the trial or substance. A sponsor can suggest a particular REFNCA, and this can be taken into consideration.
The VHP as currently operated is an agreement amongst members NCAs and does not take into
account the differences in the ethics committees structures across member states. It is expected
that there will be an updated ethics committee structure nationally following the implementation
of the new CT Regulation.
The VHP will be superseded by the procedures defined in the new CT Regulation when the overlap
period has terminated.
Q2. What is the procedure for developing the consolidated list of questions and what are the
national timelines?
A: Following the initial assessment of the REF-NCA, a list of grounds for non-acceptance (GNAs) is
prepared and circulated to the other Participating National competent authorities (P-NCA). The
GNAs are discussed and added to/ reduced as appropriate. The consolidated list of GNAs is then
sent to the VHP-coordinator, who forwards them to the sponsor. The case is clock-stopped
pending responses. Following the conclusion of the VHP, a national clinical trial application needs
to be submitted in each participating MS as outlined in the Clinical Trial Directive (2001/20/EC). It
is agreed by the MSs, that after a positive VHP the decision of the NCA should be issued within 10
days and no scientific discussion on the agreed documents of the VHP (e.g. Protocol, IB, IMPD) will
be started again during the national phase.
Q3. Are there a minimum or maximum number of participating Member States?
A: The minimum number of member states is two, there is no maximum number. EEA countries
(Norway, Iceland and Liechtenstein, may participate.
Q4. What is the cost of participating in the VHP participation?
A: There is no cost associated with participating in the VHP procedure. Costs for the national phase
are the same as usual. The HPRA waives CT application costs for academic trials.
Q5. What about the translation of documents?
A: Documents submitted for the VHP procedure need to be provided in English.
Translation of documents (the patient information leaflet and consent form) occurs at the national
application stage, as required by the relevant authorisation body. The sponsor must make
arrangements for appropriate translation.
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Advanced Therapy Investigational Medicinal Products – General Information
Quality:
Two areas were highlighted for the quality development of an Advanced Therapy Medicinal
Product:
1. Choice of potency assay
It is well understood that the determination of biological activity for ATMPs poses significant
challenges. This is especially true in the case of cell-based medicinal products, where determination
of the biological effect of a specific cell population is not always straight forward.
Potency assays for cell-based products should have a sound scientific rationale and whenever
possible be based on the mechanism of action of the cells in the intended clinical indication. A
good understanding of the biological or cellular effect of the cells will greatly aid in the
development of the most appropriate potency assay.
Depending on the nature of the product, potency assays could include functional in vitro or in vivo
tests or measurement of the expression of relevant cellular markers. Where cell based products
exert their effect through several potential mechanisms of action, a combination of assays could be
envisioned.
Preferentially a suitable potency assay should be in place before the commencement of Phase I
trials. As knowledge of the product evolves it is accepted that the potency assay may change to
reflect the most relevant mechanism of action based on all the available data. As with all potency
assays, the assay must be quantitative and able to discriminate suboptimal batches.
2. Starting materials for cell based and gene therapy based medicinal products
For ATMPs, many raw materials of biological origin are commonly used in production; for example
recombinant proteins, enzymes, antibodies etc. Wherever possible, GMP grade starting materials
should be used and where research grade materials are used they must be qualified and a
justification for their use provided.
For each raw material of biological origin, a risk assessment should be carried out which addresses
the source, manufacture and control of the starting material. The risk posed by potential
adventitious agents must also be discussed. For recombinant proteins etc. which are used in cell
culture, an appropriate biological assay may be needed.
For materials extracted from human blood or plasma, authorised products should be used where
available; failing this, it is desirable that the product have an EU plasma master file. For all blood or
plasma materials other than authorised products, it must be demonstrated that the blood is
sourced from healthy donors and has undergone all the required viral testing.
Where critical raw materials are changed during the development, a comparability study may be
required to demonstrate that there was no significant impact on the quality of the product. EDQM
is working on a general chapter on raw materials used in the production of cell based and gene
therapy medicinal products and all applicants are encouraged to follow this guidance once
published.
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Non-clinical:
Three areas highlighted for the non-clinical development of an Advanced Therapy Medicinal
Product (ATMP) were:
1. Choice of suitable non-clinical animal models.
The objectives of the non-clinical studies are to demonstrate proof of principle of the
investigational medicinal product (IMP) and to define the pharmacological and toxicological effects
predictive of the human response. The goals of the non-clinical studies include the provision of
information to select safe doses for clinical trials, support the route of administration and
application and identify target organs for toxicity and parameters to monitor in patients.
The non-clinical studies should be performed in relevant animal models. The choice of such animal
models will depend on the IMP. If relevant animal models cannot be developed (e.g. no animal
model of the disease exists or immunogenicity issues) in vitro studies may be used solely to replace
animal studies. Animal model(s) may include immune-compromised, knockout or transgenic
animals. Homologous/analogous models may be valuable to examine the in vivo behaviour of
IMPs who’s behaviour might be altered in a heterologous model where species specific differences
exist (e.g. for stem cell differentiation). The rationale underpinning the non-clinical development
and criteria used to choose a specific animal model must be justified.
2. Biodistribution studies.
While it is acknowledged that conventional absorption/distribution/metabolism and excretion
studies performed for conventional medicinal products may not be relevant for ATMPs,
distribution, exposure to, persistence and clearance of the IMP should be examined. This data
coupled with other pre-clinical safety endpoints determined in the toxicity studies can help to
determine whether the presence or persistence of the ATMP correlates with any tissue specific
detrimental effects seen in the animals. This in turn can inform the dosing selection and
monitoring schedule for various safety parameters within a clinical trial setting.
For cell based medicinal products (CBMP), cells may migrate within the host, thus presenting
clinical concerns regarding adverse reactions deriving from displaced, possibly differentiating cells.
This should be evaluated in animals using appropriate methods for specific identification of the
cells.
For gene therapy medicinal products (GTMP), the distribution, persistence and clearance of the
gene transfer product or the transgene/expression vector used to deliver the nucleic acid.
Observation time should cover persistence of signal (i.e. duration of transgene expression and
activity) and include time-points for which there is no signal detection, if applicable. The dosing
should mimic the clinical use with appropriate safety margins.
Details of the assays used should be discussed, including negative/positive controls used and the
sensitivity of the techniques used (e.g. limits of detection).
3. Tumourigenicity
Tumourigenicity should be addressed for all ATMPs before clinical use in Phase I studies.
Respective data may be provided by means of literature evidence, in vitro or in vivo data.
The presence of oncogenic potential of GTMPs should be evaluated in silico (e.g. presence of
oncogene protein sequences, or mode of action of the GTMP in the genome). If oncogenic
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potential has already been detected then tumourigenicity should be evaluated in appropriate in
vivo/in vitro models (e.g. by analysing proliferative capacity, dependence on the exogenous stimuli,
response to apoptosis stimuli and genomic modification).
For CBMP, the risk of inducing tumourigenesis due to neoplastic transformation of host cells and
cells from the CBMP should be considered, as appropriate, on a case-by-case basis. The risk of
tumour formation may vary depending on the origin of cells, extent of manipulation and site/route
of administration. The differentiation state, pluripotency or lineage commitment and culture
conditions of the intended cells have important implications for identifying the potential risks (e.g.
tumourigenic potential). For CBMP, particularly stem cell based medicinal products, extensive in
vitro assessment of tumourigenicity and chromosomal stability should be examined before their
initial clinical use in Phase I studies. Karyotyping, cytogenetic analysis, telomerase activity,
proliferative capacity and senescence could be of relevance. For the determination of
tumourigenicity, special attention should be paid to the cell material used during product
development, in terms of age, sex, treatment history etc. for the proposed indication and studied
clinical patient population.
Further information on the non-clinical aspects for the development of ATMPs can be obtained in
scientific guidelines available on the European Medicine’s Agency (EMA) website:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000298.
jsp&mid=WC0b01ac05800862bd
For advanced therapy medicinal product clinical trials and trials using genetically modified
organisms, the HPRA strongly recommends that the applicant requests a pre-submission
meeting to discuss the potential clinical trial submission.
Q1. What are the requirements for approval of a Gene Therapy Clinical Trial in Ireland, when
the trial is already authorised in the USA?
A: Gene Therapy Medicinal product (Regulation 1394) is a biological medicinal product which has
the following characteristics.
(a) It contains an active substance which contains or consists of a recombinant nucleic acid in or
administered to human beings with a view to regulating, repairing, adding or deleting a genetic
sequence;
(b) Its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid
sequence it contains, or to the product of genetic expression of this sequence.
A Gene Therapy clinical trial requires authorisation in accordance with Article 10 of the Clinical
Trials on Medicinal Products for Human Use Regulations, SI No 190 of 2004.
The clinical trial is assessed in accordance with the Irish Medicines Board Guide to Clinical Trial
Applications. Clinical, Preclinical and Quality aspects of the dossier are assessed. Extended timelines
may apply to clinical trials involving Gene Therapy Medicinal products as per Article 16.2 of the
Regulations.
For the approval of clinical trials, the GMO environmental aspects of the therapy are also assessed
by the Environmental protection agency.
The EPA should be contacted for information regarding the necessary level of detail and required
forms to be completed for approval of the trial.
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Guidance for advanced therapy clinical trials:
 The following European Medicines Agency guidelines provide useful information when
preparing for submission of an application for a Gene Therapy Clinical trial
(www.ema.europa.eu) Reflection paper on management of clinical risks deriving from insertional
mutagenesis (EMEA/CAT/190186/2012),
 Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009),
 Clinical aspects of tissue engineered products (EMA/CAT/CPWP/573420/2009),
 Quality, non-clinical and clinical aspects of medicinal products containing genetically modified
cells (EMA/CAT/GTWP/671639/2008),
 Risk-based approach according to Annex I,part IV of Directive 2001/83/EC applied to Advanced
Therapy Medicinal Products (CHMP/CPWP/686637/2011)
 Follow-up of patients administered with Gene Therapy medicinal products
(CHMP/GTWP/60436/07),
 Guideline on Environmental Risk Assessments for Medicinal Products Containing, or Consisting
of, Genetically Modified Organisms (EMEA/CHMP/473191/06),
 Guideline on Scientific Requirements for the Environmental Risk Assessment of Gene Therapy
Medicinal Products (EMEA/CHMP/GTWP/125491/2006). The information provided in this
guideline may also be helpful for the preparation of an application for approval of a clinical trial.
 Directive 2001/18/EC on the Deliberate Release in to the Environment of Genetically Modified
Micro-Organisms.
 Directive 98/81/EC amending Directive 90/219/EEC on the Contained Use of Genetically
Modified Micro-Organisms.

Directive 2000/54/EC on the Protection of Workers from Risks related to Exposure to Biological
Agents at Work.
 Analysis of the Applicability of the Contained use Legislation for Clinical Trials.
http://www.eurocobusiness.com/resources/clinical_trial_study_report%20EU.pdf
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