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ISSN 1367-076X
1 4 M AY 2 0 0 7
ABPI issues latest
draft of revised
Phase I guidelines
An inspection by the FDA has revealed that a biotechnology company began a
clinical trial and recruited 10 subjects without an investigational new drug
application (IND) in force. The company incorrectly believed that it did not require
an IND. The FDA disagreed and issued a warning letter. Report on page 2
How to avoid inspection problems
with the product specification file
Lack of the required information in the site product specification file is a
common finding during GCP and GMP regulatory inspections. It may result
in part from a lack of understanding about what is needed. However, there
also appears to be some reluctance amongst sponsors to share highly
confidential and potentially valuable information with the investigator site,
even though the site will be bound by strict confidentiality clauses. In
contrast, for commercial products, the requirement for licensed details to
be provided to the subcontractor’s qualified person is well recognised.
More information on page 4
Oklahoma IRB violates federal regulations
An FDA inspection has found an Institutional Review Board (IRB) in Oklahoma,
USA, to have seriously violated many of the regulations governing the operation
of IRBs. The Center for Biologics Evaluation and Research released a warning
letter stating that the IRB failed to review proposed research at appropriately
convened meetings. It also failed to notify an investigator in writing of its
approval of proposed research, and failed to prepare and provide adequate
documentation on the review of the trial. Minutes of the IRB meetings were
also deemed unsatisfactory. Full story on page 5
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The European Medicines Agency
(EMEA) has published its 2006 annual
report. The report details the record
number of applications received in
2006 and the substantially reduced
assessment times for agency procedures, in what the EMEA Executive
Director describes as “one of the
busiest years ever”. See page 7
Sponsor starts study without IND
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EMEA annual
report published
The US Department of Health and Human Services has released new draft
guidance for investigators, sponsors and Institutional Review Boards (IRBs),
entitled “Adverse event reporting -- improving human subject protection”.
The April 2007 document covers FDA recommendations for safety reporting in
studies involving drugs, biological agents and devices. The complaints from IRBs
about the unhelpful way in which they have previously received data have been
addresssed. The guidance, at <www.fda.gov/cber/gdlns/advreport.pdf>, will
be reviewed in our next isssue.
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In April 2007, the Association
of the British Pharmaceutical
Industry (ABPI) issued a further
70-page draft for new guidelines
on the conduct of Phase I clinical
trials (edition 4). ABPI Phase I
guidelines have been the industry
standard since 1998. Their
revision was already underway
before the disastrous first-in-man
trial of TGN1412 in March 2006.
The new edition will cover all
aspects of Phase I clinical trials –
including those relevant to the
few compounds that act in a
similar way to TGN1412 – and will
focus on the many changes that
have been made to the regulation
of clinical trials in recent years.
The guidelines will be reviewed in
a future issue of the newsletter.
New guidance: US adverse event reports
Electronic and paper versions available Visit: <www.canarybooks.com>
CQAdvisor, Issue 199, 2007
ISSUE
199
US sponsor fails in trial conduct responsibilities
Serious violations of sponsor responsibilities led to the issue of Form FDA 483 to a biotechnology
company in Colorado, USA.
The FDA’s Center for Drug Evaluation and Research
has published a warning letter originally sent to
the Chief Financial Officer of a Colorado-based
biotechnology company. The FDA was prompted
to undertake inspections of two oncology studies
sponsored by the company, following receipt of
information that the investigational product was
prepared from raw materials derived from human
placenta and thus potentially infectious. At the end
of the inspection, the FDA issued the sponsor with
a Form FDA 483, and subsequently determined that
it had failed to adhere to the applicable statutory
requirements and FDA regulations governing
sponsor responsibilities in the conduct of clinical
trials. The notable findings are outlined below.
No IND
FDA regulations require a sponsor to submit an
investigational new drug application (IND) if it intends
to conduct a clinical study with an investigational new
drug; the IND must be in effect before the
investigational drug is used in the clinical study. The
FDA found that the biotechnology company began –
and was responsible for – a clinical investigation
where the study drug was administered to 10 subjects
without an IND in effect. The biotechnology company
acknowledged its role as study sponsor and agreed
that an IND should have been in effect prior to
conducting the study. However, the company originally
believed that the study could be conducted under 21
CFR Part 361 (Prescription Drugs for Human Use
Generally Recognized as Safe and Effective and Not
Misbranded: Drugs Used in Research) and that it
therefore did not require an IND. The FDA clarified
that the protocol in question did not meet the criteria
for 21 CFR Part 361:
• there was no documentation to indicate that
the amount of active ingredient involved was
known not to have any clinically detectable
pharmacological effect in humans
• there was no evidence that the dose administered
was based on data from the published literature or
other valid human studies
• the radioactive drug used in the research did not
meet appropriate chemical, pharmaceutical,
radiochemical and radionuclidic standards of
identity, strength, quality or purity as needed for
safety and was not prepared in sterile and
pyrogen-free form, ie. the sponsor had failed to
ensure that the study drug was appropriately
processed or tested to ensure that it was free of
transmissible human pathogens
• the protocol aimed to evaluate the ability of the
study drug to detect treatment-related apoptosis in
women being treated for primary breast cancer;
however, studies intended to evaluate the
immediate diagnostic use of a drug are excluded
from 21 CFR Part 361.
The warning letter explained that, by reviewing
INDs, the FDA aims to assure the safety and rights
of subjects, and to help assure that the quality of the
scientific evaluation of drugs is adequate to permit
an assessment of the drug’s effectiveness and safety.
The FDA also noted that the protocol in question
failed to consider factors that would need to be
addressed in an IND submission, and that the
sponsor failed to consider how these factors may
have threatened the rights and safety of study
subjects. In particular, the sponsor failed to provide
appropriate chemistry, manufacturing and control
information in order to ensure the proper
identification, quality, purity and strength of the
investigational new drug; furthermore, the relatively
short radioactive half-life of the study drug
precluded the completion of sterility testing prior to
test-article administration. The sponsor should
therefore have ensured that all materials used in
producing the investigational new drug were sterile,
and that the new drug itself was produced in an
aseptic environment. The FDA determined that
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© Canary Publications 2007
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sterility testing of the components was not
performed, and that the study drug was not
produced in an aseptic manner. The sponsor later
claimed in writing that it had completed sterility and
other tests, but the FDA found no documentation to
support this claim.
The sponsor also failed to take measures to
minimise risks to human subjects. The FDA found that
the sponsor had failed to ensure that the investigational new drug was free from transmissible human
pathogens and failed to assess its immunological
effects. Specifically, one protein used to prepare the
study drug was derived from human placenta and was
labelled “not for drug, household or other uses.” The
Material Safety Data Sheet stated, “Biohazard. ... Handle
as if capable of transmitting infectious agents.” In
addition, the FDA found no evidence that the dose of
drug had been tested to ensure that it would not
induce an immunological effect. In response, the
sponsor claimed that the certificate of analysis showed
that the lot had been tested; however, the FDA felt that
the limited testing was insufficient to ensure that the
product was free from the broad range of
transmissible pathogens that may have been present in
material derived from human placenta.
Lack of proper monitoring
During the inspection, the sponsor failed to provide
documentation demonstrating that it had monitored
the progress of two protocols in line with federal
regulations. It also failed to provide documentation that
its monitors were qualified by training and experience
to monitor studies. The company’s Chief Technology
Officer stated that he monitored both studies; however,
he did not provide supporting documentation for any
monitoring activities. In addition, there was no evidence
that he was qualified by appropriate training and
experience to perform such activities.
The FDA concluded its letter by reminding the
sponsor of its responsibility to ensure that it adheres
to FDA regulations; the FDA instructed the sponsor
to address the deficiencies and establish procedures
to ensure that any ongoing or future studies will be
in compliance with the regulations.
Source: <www.fda.gov/foi/warning_letters/g5932d.htm>
Quarterly update seminar
in clinical research & GCP
14 June 2007
at the Holiday Inn, Guildford, Surrey, UK.
BROOKWOOD
INTERNATIONAL
ACADEMY
Brookwood International Academy
PO Box 9, Guildford
Surrey GU3 2WZ
Tel: +44 (0)1483 811383
Fax: +44 (0)1483 812163
Email: info@brookwoodacademy.org
Web: www.brookwoodacademy.org
This regular, quarterly, one-day seminar consists of a series of
overviews and discussions that aim to update clinical researchers
about the latest developments affecting trials in Europe.
Topics in this seminar ...
• What’s new in clinical research? Headlines of recent guidelines
and requirements
• Further update on changes to the UK ethics service and
R&D requirements
• Computerised systems in clinical trials: implementation and
compliance issues
• Practical guide to the UK clinical trial regulations
The full programme and booking details can be found on our website
<www.brookwoodacademy.org>
“21 years of Brookwood courses”
CQAdvisor, Issue 199, 2007
page 3
How to avoid inspection problems with the product
specification file
Lack of the required information in the site product specification file is a common finding
during GCP and Good Manufacturing Practice (GMP) regulatory inspections. John Parker,
Quality Manager at a UK contract research organisation (CRO), outlines his experiences and
provides advice on how to avoid inspection problems.
The manufacture of Investigational Medicinal
Products (IMPs) in accordance with EU GMP
regulations places particular requirements on
CROs that undertake manufacturing activities.
Such CROs must be in possession of sufficient
detailed information to enable their site qualified
persons (QPs) to release IMP in accordance with
the clinical trial authorisation (CTA) and product
specification file (see article 13 (3) of Directive
2001/20/EC). When IMP is released, access is
required to appropriate sections of the CTA, just as
access is needed to the product licence when a
QP releases a commercial product in accordance
with its product marketing authorisation.
Lack of the required information in the site
product specification file is commonly found
during GCP and GMP inspections. It may result
partly from a lack of understanding about what is
needed; however, there also appears to be some
reluctance amongst sponsors to share this highly
confidential and potentially valuable information
with the investigator site, even though the site
will be bound by strict confidentiality clauses.
In contrast, for commercial products the
requirement for licensed details to be provided
to the subcontractor’s QP is well recognised.
Content of the product specification
file
The amount of information needed in the product
specification file will vary from study to study,
depending on the nature of the manufacturing
activities outsourced by the sponsor, all of which
should be clearly defined in technical agreements
between the interested parties. Such agreements
should be worded to permit the provision of the
required information. When determining the
documents needed, reference should be made to
Annex 13 of the Rules and Guidance for
Pharmaceutical Manufacturers and Distributors,
and to the European Commission detailed
guidance for the request for authorisation of a
clinical trial to the competent authority dated
October 2005, in particular section 4.1.6 on IMPrelated data and attachment 2 (the Common
Technical Document for IMP quality data).
The simplest of GMP activities will generally
involve labelling and dividing bulk IMP into persubject supplies. For such operations, the
following should be available in the product
specification file as a minimum requirement
(or at least reference should be made to where
the specific document can be found):
• details of the approved sites of manufacture
(including sites where only assembly is performed)
• a description of the drug product/placebo
• a copy of the label text submitted and approved
• transmissible spongiform encephalopathy (TSE)
certification
• a description of the manufacturing process –
specifically the parts defining packaging/
blinding
• details of containers/closures to be used,
including those for comparators and placebo
• stability data to support shelf-life and extensions
to the expiry date – these should be provided
for the active product/placebo, and also for
marketed products where they are re-packaged
outside the boundaries of their marketing
authorisation
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© Canary Publications 2007
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• relevant technical agreements
• protocol/Investigator’s Brochure/randomisation
codes
• details of storage/shipment conditions and any
relevant shipping records to confirm that the
material was shipped to site under the
appropriate conditions (eg. if specific
temperature/humidity control is needed)
• QP release certificates for previous stages in
the supply chain, certifying manufacture to GMP
and the CTA
• audit statements or QP release within the EU if
imported
• for products manufactured in a third country,
the importing QP’s statement that the product
has been manufactured to GMP
• regulatory and ethics committee approval
• the results of any relevant testing.
As the complexity of the GMP operation increases,
so will the amount of data needed. Some sponsors
find it easier to provide the entire IMP dossier
rather than to extract the relevant sections.
John Parker may be contacted by e-mail at
digjonman@talktalk.net.
Oklahoma IRB violates federal regulations
An FDA inspection has found an Institutional Review Board (IRB) in Oklahoma, USA, to have
seriously violated many of the regulations governing the operation of IRBs.
The FDA’s Center for Biologics Evaluation and Research
has released a warning letter that details the results of
an inspection of an Oklahoma IRB conducted in
February 2006. The inspection, which was performed
under the FDA’s Bioresearch Monitoring Program,
found that the IRB had significantly violated the
regulations governing the operation and
responsibilities of IRBs, as discussed below.
Deficiencies cited
The FDA’s warning letter stated that the IRB had
failed to review proposed research at appropriately
convened meetings:
• the initial review and approval of one protocol
was not conducted at a convened meeting of the
IRB. Instead, the IRB approved the study by
written ballot after a sub-investigator distributed
the initial study protocol, information sheet,
consent forms and an approval form to the IRB
members, and IRB members returned individual
approval letters.
• the review and approval of an addendum to the
protocol and the related consent form were not
discussed during a convened IRB meeting;
documentation indicated that the study materials
were not distributed and discussed, but that three
IRB members signed and submitted written ballots
approving the protocol addendum.
The IRB also failed to notify an investigator in
writing of its approval of proposed research:
• it did not notify the investigator in writing that it
approved the protocol, associated consent forms
and information sheets for the study in question
• it failed to notify the investigator of its approval of
several revisions to the informed consent forms.
Preparing and maintaining adequate documentation
of IRB activities is one of the IRB’s responsibilities
under the federal regulations. However,
• the minutes for six IRB meetings were of
insufficient detail to show actions taken by the
IRB and the vote on these actions
• the minutes for three IRB meetings did not
identify the versions of the protocols and consent
forms that were discussed
• the IRB did not maintain documentation of its
activities on research proposals, such as review of
informed consent documents submitted by the
investigator
• the IRB did not maintain all correspondence
between the IRB and the investigators.
CQAdvisor, Issue 199, 2007
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Furthermore, the IRB failed to maintain and follow
adequate written procedures for conducting its
initial and continuing review of research. The IRB’s
policies and procedures required progress reports
about the research to be submitted to it on at least
an annual basis, as well as a summary of the general
course of the research. The IRB should also have
maintained all correspondence between the IRB
and the investigator. However, there was no
documentation of any such progress reports in the
IRB files, nor was there any documentation of followup by the IRB on the failure to submit progress
reports. In addition, the IRB did not review and
approve consent forms for 10 collection sites
involved in the study.
The FDA recommended that the IRB revise its
written procedures to include the duration of the
IRB approval in its approval letters to investigators,
as well as a tracking number for each study that the
IRB intends to review, to facilitate review and
record-keeping requirements.
Conflicts of interest
The FDA also recommended that the IRB consider
potential conflicts of interest and how such conflicts
are addressed, particularly as the IRB grows in size
and its procedures are revised. It was noted that at
least one individual who acts as a clinical
investigator for all studies being conducted at the
study site also attends all IRB meetings, participates
in research discussions and is present for voting
on proposed research. This individual is also
responsible for setting the meeting agenda; sending
information and research proposals to IRB members;
sending information to and receiving it from IRB
members; and maintaining IRB files. However, the
FDA regulations determine that no IRB member may
participate in the IRB review of any project in which
he/she has a conflicting interest, except to provide
information requested by the IRB.
IRB response
The IRB submitted a written response to the
inspection findings, stating that it
• planned to add additional members and increase
the number of IRB meetings per year to ensure
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•
•
•
•
that convened meetings occur before the
implementation of new protocols
would implement corrective actions, including
adding more details to correspondence
planned to recruit additional support personnel
would dedicate additional personnel to
maintaining IRB documentation
would further develop the document control
system for use with research documents and
IRB operations.
FDA reply
In its warning letter, the FDA requested a copy of all
IRB procedures that have been revised in response
to the violations identified. The FDA also requested
more information to explain how the IRB plans to
maintain control of IRB documentation using a
centralised document control system.
Finally, the FDA informed the IRB that failure to
respond adequately to the warning letter may result
in further administrative actions against the IRB,
including the FDA withholding approval of new
studies reviewed by the IRB, prohibiting the
admission of new subjects to ongoing studies,
terminating all ongoing studies approved by the
IRB and initiating regulatory proceedings for
disqualification of the IRB.
Source: <www.fda.gov/foi/warning_letters/g5938d.htm>
Notice board
• BARQA events
The British Association of Research Quality Assurance (BARQA)
is holding a course entitled ‘Clinical Investigator Site Audits’ on
19 June 2007 at Heathrow Hotel, London. The course will
explore whether
• auditors are being effective or just finding the same
observations over and over again
• audits provide protection against inspection findings
• the audit strategy is optimal
• there are better alternatives to investigator site audits.
BARQA will also run the following professional development
courses in June (venue: Cambridge)
• The Auditing Course (6–7)
• Current Best Practice at the GMP/GCP Interface (12–13)
• Auditing Computerised Systems (25–27).
For more information visit <www.barqa.com>.
© Canary Publications 2007
EMEA annual report published
The European Medicines Agency (EMEA) has published its 2006 annual report. The report
details the record number of applications received in 2006 and the substantially reduced
assessment times for agency procedures, in what the EMEA Executive Director describes as
“one of the busiest years ever”.
The report covers all the EMEA’s activities
throughout 2006. It sets out the work of the
EMEA’s Management Board, its partnership with
national competent authorities and European
institutions, and other general aspects of the
EMEA. The operational and technical work of
the EMEA is reported, including its inspection
activities. Implementation of the EU telematics
strategy, administration and other support activities
are described. The report also summarises the
operation of the decentralised (mutual
recognition) procedure. The full annual
report, which runs to 134 pages including
appendices, can be found on the EMEA website
<www.emea.europa.eu/htms/general/direct/
ar.htm>.
With respect to medicines for human use,
notable statistics include the following:
• 78 applications for marketing authorisation
were received, 37 more than in 2005, including
18 applications for orphan medicines, nine for
generics and one application for a scientific
opinion on a medicinal product intended for
use outside the EU
• 51 positive opinions for initial marketing
authorisation were given, the highest number
ever
• 257 scientific-advice and protocol-assistance
requests were received, an increase of 25%
over 2005
• 104 applications for orphan designation
were received.
Record number of applications
Outlook for 2008
In 2006, the EMEA received record numbers of
initial marketing authorisation applications, postauthorisation variation applications and requests
for scientific advice. Despite an increase in the
volume of applications, the agency was able to
achieve a substantial reduction in assessment times
for initial evaluation, orphan designation and
scientific advice, thereby helping to speed up the
availability of new and innovative medicines to
patients.
In adopting the annual report, the EMEA
Management Board also adopted the agency’s
draft work programme for 2008. With a
preliminary draft budget for 2008 of
164.5 million Euros (compared with
154.5 million Euros in 2007 and 138.7 million
Euros in 2006), 2008 will see the agency
focussing on
• improving the safety and availability of
medicines
• stimulating research and development
• strengthening the European medicines network
• improving the transparency and provision
of information
• increasing the EMEA’s international role, in
particular cooperation with non-EU partners.
Last year was the first full year in which the
agency operated under the terms of the revised
pharmaceutical legislation. According to EMEA
Executive Director Thomas Lönngren, the fact
that the agency managed record numbers of
applications while speeding up assessment times
demonstrates that it has successfully adapted to
the new legal framework.
CQAdvisor, Issue 199, 2007
Source: <www.emea.eu.int/pdfs/general/manage/mbpr/
10558607en.pdf>
page 7
News in brief
New report on protecting subjects
A report summarising the proceedings of the ‘National
Conference on Alternative IRB Models: Optimizing Human
Subjects Protections’ (held in November 2006) is now
available on the website of the Association of American
Medical Colleges. The conference explored perceived
barriers to the use of alternative IRB models and suggested
strategies for overcoming them so as to optimise human
subject protection. The conference summary report and
presentations can be accessed via the Office for Human
Research Protections homepage at <www.hhs.gov/ohrp/>,
under ‘Special Issues’.
Principal Author & Editor: Prof David Hutchinson
Senior Writers: Jane Baguley, Gareth Griffiths
Correspondents:
Joris Bannenberg
Gitte Raaschou Beck
Fabio Camarri
Pamela Charnley Nickols
Paul Chester
Eugen Chicevic
Sheelagh Corcoran
Nigel Dent
Gerhard Fortwengel
Hideki Fujiwara
Maria Galikova
Francois Geelen
Yves Geysels
Lisbeth Tofte Hemmingsen
Irene Herod
Ilian Ivanov
Ezequiel Klimovsky
Tina S Klint
Bettina Klesse
Paul Marcus
Julie Meeson
Daniela Sima
Sam Tong
Colin Wilsher
Contact us by e-mail: cqadvisor@canarybooks.com
Paediatric study costs on the up
The average costs involved in completing paediatric research
on marketed prescription drugs, in response to a request
from the FDA, increased from US$3.9 million in 2000 to
US$30.8 million in 2006, according to a report from the
Tufts Center for the Study of Drug Development (CSDD). To
improve the labelling of prescription drugs for children, the
FDA manages a programme in which it asks pharmaceutical
companies to conduct paediatric studies on marketed
products; in exchange, companies receive an additional
6 months of market protection (paediatric exclusivity) for all
their products that contain the active ingredient under study.
Despite the soaring costs of paediatric studies, companies
appear to be complying well with the Best Pharmaceuticals
for Children Act that authorises this programme. During the
first 10 years of the initiative, paediatric studies have been
undertaken on more than 100 diseases and conditions. These
have led to new labelling for 120 new or already approved
drugs for use in children. As noted in the March/April 2007
Tufts CSDD Impact Report
• since the paediatric exclusivity programme began, the
FDA has issued 336 requests for 782 studies involving
46,000 children
• the cumulative number of paediatric studies completed
and subsequently accepted by the FDA rose from 58 in
2000 to 568 in 2006
• efficacy/safety studies, the most resource-intensive and
expensive type of study, now account for 40% of all
paediatric studies conducted, up from 25% in 2000
• the time required to complete a study and submit a final
report has nearly doubled since 2000
• the mean number of patients required for studies in
response to an FDA request was up 178% in 2006
compared with 2000, and the mean number of studies
per request rose by 60%.
Source: <http://csdd.tufts.edu/NewsEvents/>
page 8
Literature regularly reviewed includes:
QA Journal
QUASAR (BARQA publication)
Clinical Trials Advisor
Eurodirect publications
CRFocus
The Statistician
The Monitor
Pharmaceutical Physician
DIA Journal
Bulletin of Medical Ethics
JRSM
Pharmaceutical Review
Applied Clinical Trials
EFGCP Newsletter
AIOPI Newsletter
The Times
MAIL
NLN Newsletter
FDA Warning Letters
ESRA Rapporteur
Websites regularly reviewed includes:
DG Enterprise, EFPIA, EMEA, FDA, ICH, IFPMA, MHRA,WHO
Aims & Scope:
• to publish news and information about the results of
GCP audits and inspections in the ICH regions
• to provide news, views and opinions about ICH
GCP implementation
• to provide answers to readers’ CQA questions and the
views of inspectors
• to summarise and make readers aware of relevant articles
and information in other publications, press releases and
information on the Internet
• to provide information about meetings, conferences,
training courses and publications.
Published by: Canary Ltd, PO Box 9, Guildford, Surrey GU3 2WZ, UK
Telephone: +44 1483 811383; Fax: +44 1483 812163
Email: info@canarybooks.com
© Canary Publications 2007
All rights reserved. No part of this publication may be copied, transmitted, reproduced
in any way without the written permission of the publisher.
Disclaimer: Whilst we try to ensure that information published is correct, the Editors,
Advisors or publishers accept no liability for losses or damages arising. You should
always seek a second opinion before acting on any information provided.
Design: LIMA Graphics Ltd, Frimley, Surrey, UK
Print: Surrey Litho, Great Bookham, Surrey, UK
© Canary Publications 2007