Memorandum by AstraZeneca Research and
1. AstraZeneca was formed in 1999 by the
merger of Zeneca plc and Astra AB. AstraZeneca is one of the world's
top five ethical pharmaceutical companies, providing innovative
and effective products to fight disease in important areas of
medical need. AstraZeneca is an international company with corporate
headquarters in London, six Research and Development centres in
the United Kingdom, Sweden and the USA, manufacturing operations
in 20 countries, and sales operations in over 100 countries. AstraZeneca
employs over 47,000 people world-wide with approximately 10,000
employed in the United Kingdom. In 1999 AstraZeneca's healthcare
business had a global turnover of £9 billion.
2. The R&D of AstraZeneca is focused
on seven major therapeutic areas: cardiovascular, central nervous
system, gastrointestinal, infection, oncology, pain control and
anaesthesia, and respiratory, with over 10,000 employees in R&D
globally, 4,700 of whom are located in the United Kingdom.
3. The world-wide expenditure on R&D
in 1999 was approximately £1.6 billion, of which almost one
third was spent in the United Kingdom.
4. AstraZeneca employs well over 100 specialist
genetics and genomics staff. In addition, many of its skilled
bioscientists carrying out research in disease areas routinely
use genetics/genomics as one of their research tools. The AstraZeneca
facilities are considered to be state-of-the-art in transcript
profiling, genotyping and proteomics.
5. Research and development in the pharmaceutical
industry makes an immense contribution to human health and well-being,
and most areas of our work are regulated by law, and governed
by strict ethical considerations. With regard to genetic research,
as with other kinds of clinical research, AstraZeneca upholds
high ethical standards, in accordance with the demands placed
Genetics, in a broad sense, is an area of great
current sensitivity and there is much debate about the ethical,
legal and social implications for genetic research. We are keen
to contribute to that debate and to promote full understanding
of how our company is involved. We are currently very actively
gathering information on guidelines, laws, policies and attitudes
around the world, to enable us to understand and comply with international
standards of best practice in this field. It is recognised that
there are many ethical issues around genetic investigations but
it is also clear that ethical viewpoints vary from country to
country and change with time. Whilst the debate continues, it
is difficult to define detailed company policies and procedures,
but we have developed some high-level policies for our involvement
in this field. In common with other pharmaceutical companies,
AstraZeneca is currently striving to define "best practice"
for the actual performance of genetic studies.
6. Consent and future use:
DNA will always be provided by
bona fide clinical investigators following the granting of
properly informed consent.
Patients will be asked to give specific
informed consent to the genetic investigations that will be performed.
DNA samples will never be used for
a genetic test outside the scope of the consent.
Samples will not be shared with third
parties, unless specific consent to do so is obtained.
AstraZeneca endeavours to supply
the clinical investigators who obtain informed consent from patients
with all relevant information, and to prepare information sheets
and consent forms that are both fully informative and comprehensible.
AstraZeneca will ensure that all
samples are coded to remove patient identity prior to being brought
into the company for testing.
The protection of patient confidentiality
is paramount, but the best mechanisms to achieve that are at present
AstraZeneca does not seek to acquire
any personal data relating to human subjects which is not strictly
necessary for the purposes of analysing and reporting the study.
AstraZeneca complies with all prevailing
regulations on personal data privacy.
8. Communication of data to patients: Any
communication of outcomes of genetic investigations to patients
will be handled by investigators and/or attending physicians,
without any involvement of the company.
9. Intellectual property: The donation
of a tissue or DNA sample to AstraZeneca for research may, as
part of analysis of samples from many other donors, play some
part in the development of the drug. The donor does not obtain
any ownership rights or financial recompense under any intellectual
property arising from AstraZeneca's own research using these samples.
This is made clear to donors before asking for consent to perform
10. Public accountability: As a company
working in the health care sector, AstraZeneca is fully aware
of the need to be accountable to the public for the way it conducts
Q1. Current and planned projects involving the
formation of DNA collections and collection of genetic information.
11. AstraZeneca in common with the majority
of large pharmaceutical companies has been conducting relatively
small scale genetic investigations for some years. The company
possesses collections of DNA samples from patients suffering from
diseases such as asthma, cardiovascular disease and inflammatory
diseases. These collections, currently representing several thousand
individuals, are gathered through collaborations with scientists
in many countries around the world, with the patients from the
United Kingdom actually representing a rather minor component.
It is anticipated that such collections will grow in the next
few years as the search for the genes that cause diseases goes
on. However, the major growth in the collection of DNA samples
for genetic analysis will be in association with clinical trials.
This is an area that is expected to expand exponentially, as advances
in technology open up opportunities to use genetics to transform
the way drugs are developed and marketed. It is anticipated that
DNA samples collected from clinical trials will amount to several
thousand, perhaps rising to tens of thousands, per year. Again,
these samples will be collected world-wide, representing the many
countries in which AstraZeneca performs drug trials, and the proportion
of United Kingdom-derived samples will be relatively small.
12. These collections will be almost entirely
composed of DNA samples extracted from blood. While DNA can be
extracted from solid tissues, the establishment of banks of solid
human tissue samples is likely to be on a much smaller scale and
used predominantly for non-genetic research (eg histology). One
use to which these tissue samples may be put is for investigations
into the level at which certain genes are expressed in normal
and diseased tissues, respectively. These "genomic"
investigations measure transient levels of RNA, and should not
be confused with the analyses of DNA sequence that comprise genetic
studies. Nevertheless, AstraZeneca recognises that the acquisition
of human tissue and of DNA for research share many of the same
Q2. The purpose of collecting genetic information
in AstraZeneca; practical constraints; and alternative approaches.
13. AstraZeneca, like other pharmaceutical
companies, conducts human genetic research in two main areas,
that may be described as Disease Genetics and Pharmacogenetics.
There is potential for overlap between these areas.
14. In Disease Genetics, the objective is
to identify the genes that cause or underlie susceptibility to
disease. Such an insight into the mechanisms of disease will allow
us to identify new targets for drug therapy, and thus the development
of new, effective treatments. These "gene hunting" investigations
generally involve the establishment of DNA collections based on
hundreds of families containing patients suffering from the disease
15. Pharmacogenetics involves the analysis
of genetic variability of populations of patients receiving a
given drug and its association with variability in response to
that drug. These genetic investigations take place in conjunction
with normal drug trials. The ability to understand the genetic
basis of variability in response to drug treatments will allow
us to use this information predictively and optimise treatment
to individual patients. The goal is to be able to use simple diagnostic
tests to identify which patients will respond best to which treatment,
and to avoid giving an inappropriate drug to a patient at risk
of experiencing side effects.
16. Constraints to genetic analysis: Within
the ethical constraints noted above, the major constraint to the
full exploitation of genetic analysis is cost, which is significant
even for a major pharmaceutical company. With technology advancing
at a great rate and genotyping costs falling steeply, this may
soon cease to be such an impediment.
17. Alternative approaches: We are continuously
seeking to improve our discovery and development processes for
the overall benefit of healthcare.
Q3. The nature of the genetic information that
is being collected, and the manner in which it is stored and protected.
18. All genetic data is stored in secure
computer systems, with restricted access, with all personal identifiers
(names, addresses, dates of birth etc) replaced by code numbers.
Code keys are generally held externally, eg by clinical investigators.
They may sometimes be deliberately destroyed, so that the data
and samples are permanently "de-identified". The processes
used to protect confidentiality vary, dependent on the type of
study, and the demands of external regulatory agencies and ethical
19. In Disease Genetics investigations,
the information that is collected includes genotype data for each
sample, identifying a large number of "markers" in the
genome sequence of each individual, as well as clinical information
relevant to the study. The statistical association of these markers
and the clinical data allows researchers to pinpoint the location
of "disease genes" to a precise locus on a given chromosome.
Before being brought into AstraZeneca, these samples and data
are stripped of all identifiers that could allow the genetic data
to be coupled to the patient's identity and are also often "de-identified"
by destruction of code keys.
20. In Pharmacogenetics investigations,
the genetic data are collected as part of drug trials. At present,
much of such research is of a purely experimental nature, and
code keys can then be destroyed. Some data, however, may be used
in submissions to regulatory agencies for approval of a drug.
In common with other kinds of data from drug trials, genetic data
forming part of a regulatory submission may need to be available
for audit by regulatory agencies for 15 years. As such, the data
cannot be permanently de-identified and other processes to protect
patient confidentiality need to be taken. Such steps may include
double-encryption and the holding of code keys by independent
21. The definition of best practice in this
new area of clinical research is the subject of current debate
between the pharmaceutical industry and regulatory authorities
world-wide. At present, there appear to be conflicting demands
from different quarters, on the one hand, to "de-identify"
such samples and data, which would involve destruction of the
code key, and, on the other hand, to comply with the requirement
for regulatory agencies to be able to perform audits and trace
such data to its source. All parties are keen to find solutions
that are in the best interest of the patient.
22. A very large proportion of the genetic
data collected in pharmacogenetics investigations, and even in
disease genetics investigations, are currently considered to be
non-sensitive, having little or no obvious implications for the
present or future health of the subject or their family. For example,
the revelation that an asthma patient carries a gene believed
to underlie susceptibility to asthma does not change the situation
for that individual at all: they already knew they had the disease.
Similarly, investigations that demonstrate that most members of
a population carry versions of genes that allow them to metabolise
a given drug normally, such that they exhibit no unusual side-effects,
generate volumes of genetic data that are of great importance
to the company developing that drug, but which are not considered
sensitive for any of the individuals studied. Even when individuals
are found to carry genes that cause them to be relatively deficient
in metabolising a drug, the implication may be no more than that
they would be best advised to avoid using that drug. Participating
in a genetic research study should not be classified (eg for insurance
purposes) as having had a "genetic test" performed.
Since the ethical, social and legal risks of collecting such genetic
data appear to be extremely low, and the potential benefit, in
terms of developing better treatments, is high, there is a very
strong argument in favour of continuing, and expanding, the use
of genetic analyses in pharmaceutical research.
23. It is recognised that, as with all areas
of research, there is an element of uncertainty, and that what
appears to be of no importance now may be revealed to be of greater
import in the future. The processes that AstraZeneca uses to protect
patient confidentiality are designed to take into consideration
that element of uncertainty, and to treat all genetic data as
if it was very sensitive.
Q4. Company responsibilities
24. The Company position on these matters
has already been covered in the introductory sections on ethical
standards and policies (paragraphs 5 to 11).
Q5. How do they see their activities in the area
of genetic databases developing in the future? What advances in
sequencing, screening and database technology are they anticipating?
25. AstraZeneca expects an increase in the
number of samples for genetic testing originating from patients
in clinical trials. Genetic data from these trials will normally
be stored, with other clinical trial data, in a highly secure
and confidential clinical trials database. Genetic data from projects
where all links to identity have been permanently removed (de-identified)
may be stored in a single database, to allow correlation between
phenotype (such as disease susceptibility) and genotype to be
maximised. The required high levels of security and data handling
are already available and the main advances will come in building
systems capable of transferring large amounts of data seamlessly
and securely, and in the development of querying and analysis
26. An advance in screening technology is
genotyping of many thousands of SNPs (single nucleotide polymorphisms)
as a result of the work of the SNP Consortium, of which AstraZeneca
is a founder member. The use of SNPs in genetic research is not
new, but the availability of a genome-wide map will greatly expedite
their use in localising disease genes and identifying genes for
27. During the last two years, AstraZeneca
has had to rely less on the physical sequencing of DNA, as the
Human Genome Project has neared completion, and more on the analysis
of sequence through the development of bioinformatics tools. We
expect this trend to continue and sequencing to become less important
in the generation of genetic databases.
28. Genetic analysis in clinical trials
will be carried out mainly through genotyping of previously identified
candidate genes or SNPs. At present, most of this work is carried
out using validated methodology such as gel-based or fluorescent-based
techniques. This work will be carried out in accredited laboratories
working to standards of Good Laboratory Practice (GLP) and inspected
by the appropriate regulatory authorities.
Q6. What lessons should be learned from genetic
database initiatives in other countries?
29. The DeCode project to collect genetic
data from the population of Iceland has been subject to criticism
on ethical grounds. These criticisms have generally concerned
the apparent requirement for subjects to "opt-out" if
they objected to their data being incorporated. The accepted approach
in the pharmaceutical industry is for subjects to actively "opt-in"
and this is the approach that AstraZeneca uses.
30. Conclusion: We recommend to the Committee
that it is necessary to:
ensure total confidentiality of personal
maintain best ethical practices in
the obtaining and use of human genetic information;
assure a secure framework within
which the discovery and development of improved medicines can
be enhanced by the analysis of genetic data;
avoid the introduction of regulation
other than that which is necessary to protect the rights of individual
Dr Kevin Cheeseman
Programme Manager for Clinical Genetics and Genomics
18 October 2000