INTRODUCTION

  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.

INVESTMENT IN GENETICS AND GENOMICS BY ASTRAZENECA R&D

  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.

ETHICAL STANDARDS FOR GENETIC RESEARCH IN ASTRAZENECA

  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 upon us.

  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.

ASTRAZENECA POLICIES REGARDING GENETIC RESEARCH

  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.

  7.  Confidentiality:

—  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 unclear.

—  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 these investigations.

  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 its research.

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 ethical issues.

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 under investigation.

  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 committees.

  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 external bodies.

  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 tools.

  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 drug response.

  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 data collected;

—  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 human subjects.

Dr Kevin Cheeseman
Programme Manager for Clinical Genetics and Genomics

18 October 2000