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Issues concerning peoples’ rights in relation to their genetic information are becoming increasingly important not least due to the burgeoning market for direct-to-consumer genetic tests. The Australian government is considering banning these products due to concerns about the interpretation of test results, especially for serious genetic conditions and feel that they would cause more harm than benefit [Finkel E (2008) Science 322 (5905): 1177]. Others might argue that individuals should have the right to decide if they would like to obtain genetic information directly or not, especially since the harms and/or benefits of such information will vary on an individual basis.
Regardless of what an individual patient may consider is reasonable, professional groups such as medical professionals or researchers may additionally be required to comply with sector specific guidance as to who may have access to genetic information or how best to balance their obligations to individuals and other interested parties (e.g. relatives). Some of these issues have been addressed by the UK’s Human Genetics Commission in its report on genetic information, where it makes recommendations on the use of genetic information in clinical practice and medical research, and for non-clinical purposes such as insurance, employment, forensic databases and family relationship testing (see previous news).
26 November 2008The European Patent Office (EPO) has upheld an appeal by company Myriad Genetics with respect to European patent No. 699754, which relates to a "Method for diagnosing a predisposition for breast and ovarian cancer" by detection of mutations within the BRCA1 gene. The original patent was awarded to Myriad, the University of Utah Research Foundation and the United States of America in January 2001 following discovery of BRCA1, but it was opposed by several groups. The EPO subsequently revoked the patent in May 2004 (see previous news), but Myriad lodged an appeal against this decision.
Now the EPO Technical Board of Appeal has reversed that decision and reinstated the patent, but in an amended form (see press release). The patent now relates to diagnostic methods for the detection of a predisposition for breast and ovarian cancer caused by a specific group of frame-shift mutations within BRCA1, but does not include about the normal or mutated forms of the BRCA1 gene itself. Other patents lodged by Myriad relating to BRCA1 have previously been amended (see previous news).
Earlier this month the Technical Board of Appeal also decided to maintain in significantly amended form Myriad’s European patent No. 705903, relating to "Mutations in the 17q-linked breast and ovarian cancer susceptibility gene", originally granted in May 2001 and significantly limited in 2005 (see previous news).
The American College of Preventative Medicine (ACPM) is developing a continuing medical education programme entitled: Genetic Risk, Screening and Intervention. The course is aimed at improving physicians’ understanding of “genetic risk factors for disease, the current evidence about the use of genomic tools and technologies to determine risk, and promising practices for utilizing those tools to aid in disease prevention” (see press release). Components of the course include comparing and contrasting the evidence for genetic screening and risk factors to epidemiological approaches to identify disease risk, exploring the harms and benefits of different types of genetic tests and examine the evidence around genome wide association (GWA) studies.
Risk prediction based on genetic factors, especially for common complex disorders such as diabetes is complex process (see previous news). Physicians are increasingly required to understand emerging genetic technologies and their relative merits in determining risk and the impact this has on health care. In addition, as genomic tools become available online direct-to-consumer, physicians need to be informed about them in order to provide accurate advice to their patients. In the UK, the NHS National Genetics Education and Development Centre works with various groups to facilitated genetics education at all levels for all professionals.
21 November 2008The US Department of Health and Human Services (HSS) has published the second report from the Initiative on Personalized Health Care. This programme aims to “improve the safety, quality and effectiveness of healthcare for every patient in the US” by using genomics; key goals are to:
The first report was produced in 2007 (see previous news), and focused on prospects and barriers for using genomic and related information to offer more individualised health care, particularly federal activities in these areas. The latest report, Personalized Health Care: Pioneers, Partnerships, Progress includes updates from private and academic health care centres where selected personalised approaches are being used in clinical practice, and commissioned papers on the opportunities and challenges for such care from different stakeholder perspectives (see press release). It also incorporates a summary of a 2008 National Summit on Personalized Healthcare held in Utah, where participants sought to create an action plan to overcome specific barriers to progress in this area.
The introduction to the report states that in coming years, as capacity to deliver evidence-based care increases and “new, molecular-based understanding of health and disease” emerges, the conjunction of the two will yield tools for improved care, and for individualised care including not only the most accurate diagnosis and safest, most effective treatment, but also individual disease risk prediction and preventative advice, and pre-symptomatic disease identification and treatment to prevent or delay clinical expression. It is envisaged that in the future patients and clinicians will have access to personal electronic health records (possibly including their genetic profile), new software tools to enable decisions about care, and opportunities to participate in a “learning health care system” by contributing data to large-scale on-going research. An increasing role for the patient to act as a decision-maker is also sought, with treatment recommendations based not only on available clinical and biological information but as on the preferences of the individuals.
The essential role of advanced information technology in this process is acknowledged, as is the lack of progress in adoption of health information technology and electronic health records (“painfully slow”), and a timescale of “years or even decades” alluded to. Whilst it is true that some early examples of personalized care are already taking place (as cited in the report), a timescale even of decades (subsequently expanded into expected progress in 5, 10, 15 and 20 years) for the introduction of a whole new approach to medicine based on a comprehensive understanding of the human genome in health and disease is perhaps overoptimistic
Emerging data from genome-wide association studies about genetic susceptibility to disease and the recent enactment of the US Genetic Information Non-discrimination Act (GINA – see previous news) are put forward as key milestones in progress towards an era of personalised health care, and the first recommendations of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP - see previous news) cited as another crucial development. The central importance of translation within the scientific enterprise is noted, and the current US system of health insurance and reimbursement found inappropriate for the future practice of medicine, with alternatives including closer alignment of the work of the FDA and the Centers for Medicare & Medicaid Services proposed.
Progress with the Human Variome Project, a collaborative global initiative that seeks to improve health by bringing together data on human genetic variation and its impact on human health (see previous news) have been published in the journal Science. Specifically, the project seeks to collate and curate existing and emerging data on all specific genetic variations known to affect human health (including rare genetic disorders and forms of common disease), and make it available for clinicians and researchers, facilitating the development and practice of evidence-based genetic medicine. This aim is very much in keeping with the practice of public health genomics, which incorporates knowledge integration across different disciplines as a key process to support the evaluation of evidence to support improvements in population health.
Of the more than 20,000 human genes that have been successfully sequenced, information on variations associated with health effects is available for only around 3,000, but this figure is expected to rise dramatically as research in this area expands. The project is supported by the WHO, UNESCO and OECD member countries; there is ongoing input of data from international resequencing projects and genomewide association studies (GWAs). As well as collating this information, the Human Variome Project is developing standards for the storage, communication and application of genetic variation information, providing a single globally accessible resource for exploring the links with health and disease. It will also investigate means by which developing countries can participate with the initiative.
Lead author Professor Richard Cotton of the Genomic Disorders Research Centre in Melbourne, Australia (the co-ordinating centre for the Human Varione Project) commented: "There is a staggering error rate of up to 40 percent in some reporting of genetic variations…This means clinicians and specialists cannot solely rely on the research literature to inform the life and death decisions of diagnosis and prognosis of genetic disorders" (see press release).
The new policy forum article sets out pilot projects across the world examining how relevant genetic, clinical and biochemical data can be gathered and organized in a country-specific or gene-specific manner [Cotton RG et al. (2008) Science 322(5903):861-2]. It cites the example of a pilot examining specific genes involved in predisposition towards colorectal cancer. Co- author Professor Finlay Macrae of the University of Melbourne Department of Medicine observed: "Genetic predispositions to colon cancer are now well recognized. Testing for mutations in some of these genes is critical to establishing risk for bowel cancer in some families. However, the information needed to interpret mutations is widely scattered and not readily available"(see press release). InSiGHT, the International Society for Gastrointestinal Hereditary Tumours, is reportedly developing systems that will allow the low-cost collection of data on rare mutations and common variations in the four mismatch repair genes from laboratories and hospitals in different countries.
Barriers to and strategies for establishing a neurogenetic disease database are also set out, proposing that international, multi-disciplinary, disease-centred networks could be established to integrate information from different databases and develop common guidelines and systems. The paper also raises the idea of industry and patient-support group sponsorship for data curation initiatives, which is being pursued through an Adopt-A-Gene Program.
An alternative technique for PGS is the use of comparative genomic hybridisation (CGH) (see previous news). CGH allows regions on every chromosome to be analysed for aneuploidies compared with current techniques, which are restricted to specific chromosomal defects. A number of studies have indicated that this technique may increase the success rate of IVF and the results of the first clinical study of this technique were presented at the annual meeting of the American Society of Reproductive Medicine. The study carried out by scientists at the University of Oxford and the Colorado Centre for Reproductive Medicine in the US has shown that CGH may be a better approach for pre-implantation genetic screening (reported by BBC news). The clinical trials were undertaken on 23 women with an average age of 37, in order to assess the effectiveness of CGH; chromosome screens were obtained for 91% of embryos tested and 70% percent of the cycles that went to embryo transfer resulted in clinical pregnancy (see press release). The results of this study suggest that the rate of implantation following CGH is dramatically greater than that achieved using other screening methods (BBC news). Dr. Dagan Wells from the University of Oxford is currently applying for a licence for its use in the UK. Although work on CGH has been on-going for a number of years, it has not been widely adopted as it is requires expertise, is labour intensive and takes several days. However, technological advances are making it a more amenable method of screening and if conjugated with microarray platforms (referred to as array CGH) it can allow high-throughput processing of multiple samples simultaneously.
Techniques for pre-implantation genetic diagnosis (PGD) or pre-implantation haplotyping (see previous news) are used for the diagnosis of mutations that cause specific serious genetic disorders. In contrast, techniques such as array CGH and karyomapping (see previous news) are applied to the whole genome and can be used to identify multiple genetic abnormalities as well as specific mutations. The advantage of these techniques is that they allow more thorough screening in order to identify chromosomally normal embryos thereby increases the chances of a healthy pregnancy - one of the purposes of IVF. However, the clinical significance of some mutations or chromosomal changes (i.e. deletions/duplications) identified by these techniques is not yet known nor is their influence on the successful establishment of a healthy pregnancy. Consequently, these techniques raise a number of ethical issues; a European ethics task force is already assessing the use of microarrays in PGS in order to develop a code of practice and regulate their use (see previous news).
Epilepsy is not always easy to diagnose; there are various possible underlying causes including brain damage or infection, but the majority of cases have no known cause. It is hoped that the study, now recruiting a projected 3750 epilepsy patients and 3000 controls, might ultimately lead to improvements in diagnostic and therapeutic capability for the condition by identifying genes that influence both epilepsy and responses of affected individuals to anti-epileptic medicines.
The report explains some of the barriers preventing widespread adoption of personalised medicine such as ambiguous regulation, lack of translational research and limited coverage by health insurers, as well as potential mechanisms to overcome them. Its recommendations include calling on the US federal government to develop a strategic long-term plan that coordinates public and private sector efforts to advance research and development relevant to personalised medicine, and in particular the US Department of Health and Human Services (HHS) to establish a personalised medicine coordinating office. It also calls for a more transparent, iterative and systematic approach to regulation by the US Food and Drug Administration (FDA).
One of the obstacles in the regulation of molecular diagnostics are the difficulties in demonstrating clinical utility and validity; to address this, PCAST suggests government funding for development of tools which would allow standardisation and evaluation of molecular diagnostics, as well as increased cooperation with and endeavour by industry to demonstrate the utility of their developments. In addition, they also recommend a balance between funding for discovery and translational research in order to ensure that new discoveries are better able to reach clinical practice.
Much of the report echoes and re-iterates the PHG Foundation’s findings in relation to the evaluation of genetic tests and molecular biomarkers, which is an area of ongoing focus at national and international levels. With more diagnostic tests becoming available all the time, it is becoming increasingly important to produce appropriate mechanisms to assess and evaluate them, to distinguish between clinically useful and redundant tools, and to understand their possible impact on clinical practice. However, this requires not only investment in the discovery and development of new biomedical technologies, but also translational efforts including resources to reliably determine their benefits.
4 November 2008A team from the Gynaecological Cancer Research Centre at the UCL Institute for Women’s Health in London has launched a new project to identify individuals at increased genetic risk of developing forms of cancer. The Genetic Cancer Prediction through Population Screening (GCaPPS) pilot project has begun from a branch of the high street chemist Boots in Mill Hill, London; it is aiming to recruit volunteers from the local Ashkenazi Jewish population to be tested for genetic predisposition towards specific cancers.
Mutations in the BRCA1 and BRCA2 genes are associated with hereditary breast-ovarian cancer; individuals with such mutations have a substantially increased risk of developing these types of cancer, as well as certain other forms such as prostate cancer in men. Members of the Ashkenazi Jewish population are 10-20 times more likely to carry such a BRCA mutation than the general UK population; up to one in every 40 Ashkenazi Jews have a BRCA mutation. Although there are many different rare mutations that may occur within the large BRCA genes, there are just three specific founder mutations that are particularly common in this population sub-group, making screening practical.
Volunteers must have four Ashkenazi grandparents to be eligible to participate in the study, and will receive genetic counselling before opting for testing; those in whom mutations are identified will receive information about options for the early detection and prevention of cancers, as well as the risks of passing on the predisposition to their children.
The research project, which is the first randomly controlled trial of BRCA gene screening among the Ashkenazi Jewish population, will aim to recruit 1,000 people during the initial pilot phase and a further 9,000 in total, with researchers tracking participants over three years. It is thought that the project may demonstrate universal testing within this population will identify more individuals with BRCA1/2 mutations than the current approach of offering testing only to those with a significant family history of relevant cancers, and it is hoped that a strategy for the prediction and prevention of BRCA-associated cancer.
Director of the UCL Institute for Women’s Health Director Professor Ian Jacobs, who is also the principal investigator for the GCaPPS project, said: “The data from GCaPPS will provide the basis for informed decision-making about the introduction of BRCA population testing in the Ashkenazi Jewish community and other populations” (see press release). The research project is supported by The Eve Appeal, and Jewish organisations including Jewish Care and Norwood, as well as Boots.
Members of the Ashkenazi Jewish population are also at increased risk of another form of genetic disease, a serious neurological disorder called Tay Sachs Disease; a review of the current Tay Sachs screening programme for the National Screening Committee by the PHG Foundation and Guy’s Hospital, London will be completed at the end of this year.
The World Medical Association has recently announced its 2008 revision of the Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. The text is the result of the sixth comprehensive review of the Declaration, which was adopted by the WMA General Assembly in Helsinki, Finland in June 1964 and amended in 1975 (Tokyo), 1983 (Venice), 1989 (Hong Kong), 1996 (South Africa) and 2000 (Edinburgh). Notes of clarification to two specific paragraphs were added in 2002 and 2004.
The majority of the changes to the Declaration are incremental rather than radical, reflecting current perspectives and language pertaining to medical research. For example, the duty of the physician set out in paragraph 3 of the Introduction is to promote and safeguard the health of ‘patients, including those involved in medical research’, rather than the health of ‘the people’, and physicians no longer ‘obtain’ but rather ‘seek’ consent.
More substantively, provisions for the formulation of the research protocol have been subtly streamlined. In particular, paragraph 15 now incorporates the Note of Clarification on paragraph 30 (Tokyo 2004) regarding access of participants to benefits resulting from the research. As a result, arrangements for post-study access by study subjects to interventions identified during the study as being beneficial, or access to other appropriate care or benefits, must be described in the protocol.
Another point previously in issue was the extent to which a research ethics committee should be required to conform to the national laws and regulations of countries in which the proposed research was to take place. The need for such ‘conformity ’ is now gone, but the REC must ‘take into consideration’ laws and regulations, with the addition of ‘applicable international norms and standards’, so long as these do not reduce or eliminate any of the protections for research subjects set out in the Declaration.
The protection of research participants is arguably enhanced by the fact that ‘confidentiality of personal information’ and ‘integrity’ of such subjects, previously matters for precaution, are now embodied in the duty of physicians involved in research under paragraph 10, along with the protection of life, health, privacy and dignity. More controversially, doctors also have a new duty to protect to the ‘right to self-determination’ of their subjects, reflecting the increased level of recognition in the Declaration of the needs of communities.
The 2008 Declaration also requires a greater level of consideration of the effect of research on populations and communities than did previous texts. Paragraph 17 makes express the need for justification of research involving a disadvantaged or vulnerable population or community; it must be responsive to the community’s health needs and priorities, or the population must stand to benefit from the results of the research. Communities are again expressly mentioned in paragraph 18, in regard to the need for an assessment of risks and benefits of the research – for individuals or communities - that must precede every medical research study involving human subjects.
The requirements of informed consent are a main focus of Part B (The Principles for All Medical Research), without significant changes to the previous draft, other than an express recognition of the information needs of individuals and sensitivity to potential subjects who may be in a dependent relationship with the physician or may consent under duress. The only addition to the Declaration, a matter on which the PHG Foundation commented, is contained in paragraph 25. It admits that in some situations, in which identifiable human material or data is being used, a need to obtain consent might be impractical or jeopardise the research results; in these cases the research may be permitted once ethics committee approval is obtained.
Finally, the PHG Foundation made a further contribution to the circumstances in which a placebo or no treatment might be permitted. Whereas a new intervention would normally need to be tested against the ‘best current proven intervention’, the new text articulates two express situations in which a placebo might be acceptable: where there is no current proven intervention, or where there are compelling and scientifically sound methodological reasons for the use of a placebo, and the subjects are not at risk of serious or irreversible harm. This provision incorporates the prior Note of Clarification on paragraph 29 of the Declaration (Washington 2002) without conflating the two sets of circumstances into one paragraph, as set out in the proposal (from which we dissented) in the consultation document.