Supplementary memorandum by AstraZeneca
(PI 33A)
AN OVERVIEW OF THE CLINICAL TRIALS AND PUBLICATION
PROCESSES
A. THE CLINICAL
TRIALS PROCESS
Introduction
AstraZeneca is committed to conducting clinical
trials to international standards of safety, scientific and medical
integrity. There are currently within the UK in excess of 30,000
regulations and guidelines that apply to the drug research and
development process. AstraZeneca adheres to these, as monitored
through a comprehensive series of internal checks and external
quality assurance checks.

The MHRA conducts statutory Good Clinical Practice
(GCP) inspections. AstraZeneca (UK and Global) underwent such
an inspection in November 2004 and it received very positive feedback
on the quality of its clinical research organisation.
The Research and Development Process
Research and Development encompasses discovery,
pre-clinical development, clinical evaluation (Phase I-IV), which
leads to licence submission, and lifecycle development. It currently
takes in the region of 10-13 years for a candidate drug to be
licensed and to receive its marketing approval:

Currently approximately 10,000 chemical entities
are investigated to successfully develop one drug through to licence
approval. Of these 10,000 chemicals, typically 1,000 demonstrate
the necessary biological activity, and only 10 proceed through
to clinical trial development, only one of which will successfully
receive approval.
The Clinical Trial Process
There are 4 key stages of the clinical trials
process following successful pre-clinical development:
Phase I: This stage is concerned
most with safety of the candidate drug and examines the pharmacokinetics
of the drug in healthy volunteers (usually 10-50 patient studies).
Phase II: This stage is examining
safety and efficacy of the drug in diseased patients (patient
numbers in the 100's). Within this stage dose-ranging studies
are conducted.
Phase III: This stage examines the
efficacy and safety of the drug in much larger populations of
diseased patients, usually numbering thousands.
Phase IV: These studies examine the
licensed drug in large every-day settings and populations and
may compare the drug with appropriate competitor drugs (possible
in Phase III as well).
The Clinical Trial
There are several key phases in a clinical trial
from design (involving external investigators), approval from
relevant authorities and ethics bodies, study set-up, patient
consent and enrolment, treatment, data collection (throughout),
data analysis, report writing, and publication (which is reviewed
in depth below). Depending upon the treatment period a single
study will take a minimum of several months to complete the cycle;
most will take in excess of two years and many will take considerably
longer:

At each stage of the study design and clinical
trial there are numerous patient safety, data quality and process
review checks to ensure that high standards of scientific, medical
and ethical integrity are being upheld. Herewith a schematic representation
the quality control and quality assurance to AstraZeneca studies:

It is normal practice for large-scale trials
to have independent data safety monitoring boards (DSMB) that
comprise independent statisticians and physicians of international
renown. Their role is to monitor the safety and efficacy outcomes
of the study on an ongoing basis, and to validate the statistical
analysis and interpretation of results.
Publication
AstraZeneca has had a long standing publication
policy. It is AstraZeneca policy to encourage the appropriate
communication of information on its products and research and
development activities to the international medical and scientific
community and AstraZeneca endeavours to publish the results of
all its clinical trials.
Below is an illustration of how a manuscript
is developed for submission to the Lancet for publication.
This demonstrates the lead and accountability for authorship taken
by the study Steering Group and the input of AstraZeneca at both
the review stage before submission and before Lancet editorial
review.


Further information is provided in the following
section on the publication process.
B. THE PUBLICATION
PROCESS
The AstraZeneca Philosophy
AstraZeneca is committed to providing healthcare
professionals and patients with relevant information that enables
them to make the best treatment decisions. To that end, scientific
and medical publications are an important means of communicating
the results of the company's research and development. Hence,
AstraZeneca has put in place a mandatory Publication Policy that
outlines the company's principles with regard to external communication
of scientific and medical information. Specifically this policy
describes the company's aim to publish the results of AstraZeneca-sponsored
clinical trials; our commitment to maintain high standards of
medical and scientific integrity by presenting results in an accurate,
objective and balanced fashion; and states that selective publication
that would misrepresent the medical profile of an AstraZeneca
product is not acceptable (ie, we must not selectively publish
only those trials that have a positive outcome for AstraZeneca
products and suppress those that appear unfavourable). Compliance
with this policy is formally monitored.
Relationship between AstraZeneca and External
Investigators
AstraZeneca works in collaboration with external
investigators in the design and conduct of a clinical trial, and
in preparing publications from that trial. Whilst AstraZeneca
plays an important role in co-ordinating the publication process,
the lead author (usually an external investigator) will play the
major role in terms of publication content. This is only right
and proper since it is that lead author who through authorship
takes public responsibility for the overall design, data and conclusions
in the publication.
External Publication Guidelines
There are a number of well-established external
guidelines developed by professional bodies to improve the quality
and ethical transparency of publications. Probably the best known
are the guidelines established by the International Committee
of Medical Journal Editors (ICMJE) and published in its Uniform
Requirements of Manuscripts Submitted to Biomedical Journals (www.icmje.org).
Publications on AstraZeneca-sponsored trials in biomedical journals
follow the ICMJE guidelines and in addition will comply with individual
journal's policies and Instructions for Authors.
Data Access and Analysis
The database for a clinical trial is usually
created and maintained by the pharmaceutical company. Expert AstraZeneca
statisticians and programmers are responsible for managing these
trial databases. To give a sense of the size and complexity of
these databases, for just a single AstraZeneca trial (Exanta,
SPORTIF III) there were 12,500,000 pieces of data collected that
resulted in 200,000 pages of study data.
Once the trial is completed, AstraZeneca would
supply authors with the statistical tables and figures that relate
to any planned publication.
It is normal practice for large-scale trials
to have independent data safety monitoring boards (DSMB) that
comprise independent statisticians and physicians of international
renown. Their role is to monitor the safety and efficacy outcomes
of the study on an ongoing basis, and to validate the statistical
analysis and interpretation of results. In the Exanta study quoted
earlier, the DSMB reviewed all data monthly on an ongoing basis
throughout the trial.
Despite the safeguards afforded by rigorous
internal and external quality controls, some critics remain concerned
that the pharmaceutical company "owns" the database.
AstraZeneca believe they have nothing to hide. For registration
trials, AstraZeneca routinely make the electronic database available
to registration agencies such as the FDA, and have complied with
requests from medical journals for a further additional independent
statistical analysis as part of the journal's peer review process.
Authorship
The authorship of publications carries significant
responsibilities and must be approached in a rigorous manner.
For any publications involving AstraZeneca-sponsored trials, authorship
is determined by strict criteria contained in ICMJE guidelines.
Each author should have participated sufficiently in the work
to take public responsibility for appropriate portions of the
content. In particular, authorship credit should be based only
on (1) substantial contributions to conception and design, or
acquisition of data, or analysis and interpretation of data; (2)
drafting the article or revising it critically for important intellectual
content; and (3) final approval of the version to be published.
Conditions (1), (2), and (3) must be met. Hence, it should be
clear that the practice often referred to as "gift"
authorship is not acceptable practice within AstraZeneca.
Where AstraZeneca scientists, physicians and
statisticians have played an important part in a study (eg, the
conception and design, or analysis and interpretation) they will
also be listed as authors. We continue to do this because we believe
in transparency despite disturbing evidence that declaring competing
interests negatively affects readers' perceptions of studies in
terms of their importance, relevance, validity and believability
(BMJ 2004, 328, 742-743).
AstraZeneca believes it is proper for company
authors to engage with external authors in discussion on sound
scientific grounds, but that there should be no attempt to influence
inappropriately the scientific or medical opinions of these external
investigators.
Role of Professional Medical Writers
Ghostwriting is the practice whereby someone
other than the named author (eg, a professional writer) has been
responsible for preparing the publication, typically with little
or no involvement from the named author, and the contribution
of the actual writerthe "ghost"is not
disclosed. AstraZeneca does not support "ghostwriting".
However, we do believe that professional writers have a legitimate
role to play in assisting authors, providing any such collaboration
follows ethically acceptable practice.
In an ideal world, the scientists, statisticians
and physicians who were involved in design, conduct and interpretation
of a study should be the people preparing the publication. However,
the best clinical investigators do not necessarily make the best
writers. They may lack the time, expertise or language skills
to produce a well-written publication promptly (for example, many
of the investigators will not have English as their first language).
In these circumstances, most pharmaceutical companies, including
AstraZeneca, may use professional writers and editors (internal
staff or agency/freelance) to assist in publication development.
The use of professional writers may be particularly helpful to
aid the process of publishing results from large multicentre studies
involving many contributors.
AstraZeneca believe that the named authors must
retain responsibility for the article's content, this is achieved
by the named authors being fully involved from the outset; the
principal author should determine the extent of involvement of
professional writer and, importantly, surrenders no responsibility
for the content of a manuscript by accepting this help; and finally
there must be no attempt by the writer to manipulate the opinions
of the named authors.
If pharmaceutical companies did not provide
this service to external investigators, a number of negative consequences
are likely. Namely, publications would take longer to get out
into public domain; more publications would be rejected because
of poor quality; some publications would never see the light of
dayindividual investigators would have little incentive
to publish "worthy but dull" studies; critics believe
there is publication bias in the medical literature nowthis
situation would worsen if pharmaceutical companies did not provide
writing or editorial support to busy clinical investigators.
Acknowledgments and Disclosures
It is AstraZeneca policy to ensure adherence
to the principles of good publication practice that are described
by International Committee of Medical Journal Editors (www.icmje.org)
and hence all authors should provide details of any conflict of
interest, or financial support/financial connections to the work.
Again, we continue to do this because we support transparency
despite evidence that this declaration unreasonably biases readers'
perceptions.
Products Withdrawn from Development
The pharmaceutical industry is often criticised
for not publishing clinical studies that cease to be of direct
commercial relevance to them. Since the merger of Astra and Zeneca
in 1999, we have withdrawn a number of products from development.
One such example is Viozan (sibenadet), a dual dopamine D2-receptor
and beta2-adrenoceptor agonist that was being developed for treatment
of chronic obstructive pulmonary disease. The lessons learned
from this failed development were published in a supplement to
Respiratory Medicine. The following quotation from Stephen
Rennard MD in the introduction to that volume (Respiratory
Medicine 2003, Volume 97, Supplement A, pages S1-S79) underlines
our ethical policy to share information with the whole medical
and scientific community.
"Finally, many drugs that fall in development
for one reason or another do not result in compiled publications
such as this. AstraZeneca is to be commended for recognising the
value of the lessons learned from the sibenadet development programme
and for helping to make them readily accessible through the development
of this supplement."
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