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Slide 1. The rapid developments in molecular biology -- including genetic diagnostic and molecular therapeutic techniques -- will have a profound impact on public health worldwide.[1,2] Learning more about molecular pathways should make it easier to detect and characterize disease, monitor drug response, and develop therapies. Nevertheless, diagnostic and therapeutic genetics research raises challenging ethical questions.
Slide 2. A good example of such research involves DNA genotyping of participants to see how this relates to the side effects they experience and their outcomes. Imagine a clinical trial intended to learn more about drug treatment for people with an inherited susceptibility to cardiovascular disease (or CVD). The results of such a trial could be very important because CVD is the leading cause of death in the industrialized world.
In this hypothetical clinical trial, individuals with various non-genetic risk factors for premature CVD will undergo DNA genotyping to determine whether they carry a mutation that increases their risk of developing CVD. Then, based on their genotype, they would be assigned to different drugs. Participants would be followed to determine the efficacy and adverse reactions of the various drugs to determine if these differ among people with different genotypes.
In fact, trials like this hypothetical case are ongoing in the areas of infectious[4] and chronic diseases.
Slide 3a. Hundreds of gene therapy trials have also been conducted worldwide since 2004. Although most have been relatively safe, two highly publicized adverse events have helped shape the ethical debate.[5]
Slide 3b. One of the most well-documented gene therapy trials ended in the death of Jesse Gelsinger, a young man with a genetic liver enzyme deficiency. More recently, there has been much discussion about a clinical trial for severe combined immunodeficiency syndrome (SCID) in which three out of eleven subjects developed leukemia.[7].
Slide 4. The objectives of this module are to sensitize learners to (1) ethical issues raised by diagnostic and therapeutic genetics research and (2) ways of minimizing possible harms associated with this research. The emphasis in this module is on the ethical issues, although there are also important regulatory considerations.
Slide 5a. Genetic diagnostics include a range of technologies designed to determine an individual's genotype, or genetic makeup. Genetic testing can be used to detect mutations and/or polymorphisms that either cause relatively rare single-gene diseases or that increase one's susceptibility to complex disorders.
Slide 5b. As mentioned in Module #3 of this series, pharmacogenomics is the study of common genetic variations between individuals (also known as polymorphisms) and how these variations influence responses to drugs[8,9]. Pharmacogenomics involves genetic testing but it involves much more, as well.
Slide 6. Pharmacogenomics takes place at the intersection of genetic testing, drug development, and drug trials. Some of the ethical issues that arise in pharmacogenomics research do not differ from those associated with genetic testing, drug development, or therapeutic drug trials more generally. However, others are unique to pharmacogenomics research and will be highlighted in this module.[10]
Slide 7a. Pharmacogenomics has several potential benefits. From a clinical perspective, it is intended to "individualize" patient care by selecting medications and dosages for individual patients that are most likely to be effective and have the fewest side effects.[11]
Slide 7b. From a public health perspective, pharmacogenomics will help to reclassify human illnesses. In this new molecular taxonomy, for example, the term "cancer" alone would be inappropriate. Rather, it might be described as "syndrome sub-type A in person sub-type B with genotype C." Such a taxonomy would be the basis for developing better methods of prevention and early detection[1] and might reduce the stigma of being diagnosed with a particular disease. From a societal perspective, pharmacogenomics research is likely to reduce the occurrence of adverse drug reactions and the costs of treating them.[11] However, it is unknown whether pharmacogenomics will ultimately increase other health care costs..
Slide 8. There are three main types of pharmacogenomics research: pre-clinical studies for the purpose of drug development, clinical trials to assess toxicity and efficacy of drugs, and post-marketing studies to assess clinical applicability and adverse reactions to drugs in a broad population.[10] This module addresses the ethical issues raised by pre-clinical studies and clinical trials.
Slide 9a. Pre-clinical research includes both non-human animal studies and epidemiological studies on stored human samples. The latter typically requires the collection of an enormous amount of data from a large number of persons in order to identify and compare the genomic variations from different phenotypic groups.
Slide 9b. Sophisticated techniques, such as polymerase chain reaction (PCR) and gene sequencing are used to analyze genetic expression or function in these vast amounts of information. Chip technology or microarrays facilitate the storage and analysis of gene sequence and expression data.[13,14] This technology is currently very expensive. Although such research promises to be quite powerful, it carries a set of ethical issues.
Slide 10. Naturally, some of the ethical issues in pre-clinical pharmacogenomics research are similar to those arising in population-based genetics research in general. These include the privacy and confidentiality of information[15], insurance discrimination[11], informed consent, disclosing results, and the effects of genetic information on communities such as racial or ethnic minorities.[16,17] However, because these studies require data on both the genotype and phenotype of large numbers of subjects, especially strong privacy protections are needed.[18]
Slide 11. Most of the ethical issues raised by pharmacogenomics research stem primarily from its potential to change the way clinical trials are designed and conducted. Such changes include the nature of the sample, coordination of multiple research sites required by the large scope, challenges for data analysis, unique social risks, and the economic forces at play.
Slide 12. Clinical trials traditionally assume that the sample will be homogeneous with respect to relevant characteristics among individuals. By contrast, in pharmacogenomics trials, inter-individual heterogeneity is required. As a result, potential research participants typically undergo genotyping or "genetic profiling" before they are enrolled in the research.
Slide 13. Selecting subjects by genotype raises ethical questions about the possibility of physical harm if those who are thought to be appropriate candidates for exposure to the study drug turn out to experience more harm than good. There are also questions about distributive justice and fairness. For example, including or excluding subjects based on genotype may lead to loss of the potential benefits of research participation for those who are excluded or to unfair representation of certain groups or populations in the trial. Selecting subjects by genotype may also limit the generalizability of the results.
Slide 14. The scope necessary for the kind of pharmacogenomics trial described at the beginning of this module (the hypothetical case involving genetic testing to determine an increased susceptibility to CVD) would require that multiple research sites collect identifiable information about the participants so that genotype-phenotype correlations can be made. In addition, there may be variability among the sites in the ethnicity of subjects and the frequency of polymorphisms might be found more or less often than expected.
Slide 15a. Because the scope of these trials may require the creation of large data banks and the possible sharing of linked or identifiable genetic information, there is heightened potential for breaches of confidentiality and privacy.
Slide 15b. In addition, the variability among sites may include increased rates of harms to participants due to poor drug metabolism in certain locations.
Slide 16. The large sample size necessary for these trials creates challenges for data analysis because, currently, there is no clear consensus on the "best" experimental design or statistical tools to arrive at valid conclusions. The methodological challenges created by large and heterogeneous samples raise fundamental ethical questions about the scientific merit of pharmacogenomics studies.
Slide 17a. Pharmacogenomics research may also create psychosocial risks for participants. For example, genetic profiling to stratify research subjects might create new classifications of conditions that will be sub-clinical or "hidden." Individuals with no apparent health problems might label themselves as ill if they are told that they have a specific polymorphism.
Slide 17b. Similarly, subjects who are found not to respond favorably to a particular drug may be labeled "non-responders." This labeling may ultimately result in various types of stigmatization. For example, clinicians who are unable to offer an effective therapeutic agent to these individuals may inadvertently or subconsciously blame the patient for being a "non-responder." There are also related risks of insurance and employment discrimination.
Slide 18a. The economic forces driving pharmacogenomics research may also involve ethical challenges. For example, companies might choose to develop those drugs for which there is a large group of responders, and not pursue drugs for which the responder group is small. Such narrowing of the market for drugs might result in the creation of "orphan" populations who are left out of the drug development process.[9] The Orphan Drug Act is designed to address this problem.
Slide 18b. In addition, pharmacogenomics research raises important legal and ethical questions concerning intellectual property. For example, should new genotypes or gene sequences identified through pharmacogenomics research be patented the way new drugs are patented?[20] Although a thorough discussion of patents is beyond the scope of this module, it should be noted here that obtaining a patent for a gene or a gene sequence can impede the sharing of genetic information that may facilitate diagnostic or therapeutic advances.[21]
Slide 19. Some strategies can be implemented to minimize possible harms associated with pharmacogenomics research. Researchers should develop appropriate study designs and statistical methods. In addition, they should develop standards to assess when the strength of evidence from pre-clinical studies justifies incorporating genetic profiling into the process of selecting and stratifying research participants.
Slide 20. Second, IRB members should be trained to evaluate the scientific validity of the pharmacogenomics trials, understand the chip and microarray technologies that may be used in them, and the potential effects of inclusion and exclusion criteria.[23]
Slide 21. Third, policy makers should develop policies and guidelines to address the social challenges of population and individual stratification. Finally, studies of cost-effectiveness should be conducted to guide policy decisions on marketing incentives.[9]
Slide 22a. In genetic diagnostics, genetic information is obtained from people to learn something about their susceptibility to disease or their response to drugs. On the other hand, genetic therapeutics involves using genes or genetic material to do something to people in the hopes of improving their health. Genetic therapeutic research most commonly refers to "gene therapy" or gene transfer research. As mentioned in Module 4 of this series, the central feature of all gene transfer research is the need to successfully deliver therapeutic genetic material to the target cells.
Slide 22b. Two types of cellular targets are involved in gene transfer research -- somatic cells and germ-line cells. Somatic cell gene transfer affects only the individual who is treated, but alterations to the human germ-line could affect future generations because the new genetic material is delivered to the reproductive cells.[25] Because of this possibility and the controversy surrounding it, gene transfer research in humans has, to date, been limited to somatic gene transfer.[22,25]
Slide 23. The main ethical issues raised by somatic cell gene transfer experiments are the potential health risks to research subjects and the difficulties of obtaining informed consent.[25,26]
Slide 24a. In somatic cell gene transfer experiments, matching the vector to the disease and target tissue is essential for long-term success.[27]
Slide 24b. Nevertheless, some of the potential health risks of such experiments relate to the unintended effects caused by the vectors in which the genetic material is transferred. There are two main types of vectors, non-viral and viral.
Slide 24c. Viral vectors are the most efficient vehicles for gene delivery, but they are often complex and difficult to sterilize. They may result in uncontrolled infection, either in the research subject or in others.
Slide 24d. They also may mutate in dangerous ways, and it is possible for mutated genes to accidentally integrate into the germ-line cells of the patient, leading to the transmission of possibly damaged genetic material to future generations. In addition, viruses may not behave in humans the way they do in mouse or monkey models used in pre-clinical studies. In fact, certain viral vectors may be more toxic in some species than in others.
Slide 25a. Because of these concerns and others regarding somatic cell gene therapy trials, it is difficult to determine the feasibility of the approach, the safety of the product, and the appropriate dose range to evaluate in humans. Such uncertainty must be considered when determining the ethical acceptability of proposed trials.
Slide 25b. There may be pressure from patient support groups or others to develop trials for lethal diseases before the data support them. However, it is important to weigh the right of participants to seek and have access to experimental interventions for lethal diseases against the potential risks of the intervention itself and the vulnerability of prospective subjects who are very ill.
Slide 25c. Finally, fetuses and very young children may increasingly be targeted for gene therapy trials, in part because they can be particularly suitable candidates from a scientific perspective. However, discussion of the scientific advantages associated with fetal gene transfer trials and the ethical issues raised by the inclusion of fetuses in research[28] are beyond the scope of this module.
Slide 26a. Obtaining informed consent for somatic cell gene transfer experiments entails some of the same challenges as other early-phase clinical trials. For example, difficulties in defining and describing benefits can lead to the "therapeutic misconception" in which participants confuse research with treatment and overestimate the likelihood of benefit to them from participating in the research.[26]
Slide 26b. In addition, informed consent for somatic cell gene transfer research is complicated by the difficulty of explaining the risks associated with the type of vector being used and the process of gene transfer. Furthermore, it is difficult to interpret and explain the results of non-human animal studies and how they may relate to human trials. Also, some of the most relevant information that could inform such discussions may not be available because of unreported scientific "failures."
Slide 27a. As with pharmacogenomics research, certain strategies can help to minimize the potential harms associated with somatic cell gene transfer experiments. First, preclinical studies are essential to determine the potential efficacy and safety of the gene therapy approach. The limitations of animal studies for extrapolating data on toxicity and dose to humans should be well understood.
Slide 27b. Second, products that are used in clinical trials should be manufactured under well-controlled conditions to ensure quality. Third, adverse events in the development of gene products should be reported so that relevant information is available for inclusion in the informed consent process. Similarly, conflicts of interest need to be disclosed and managed.
Slide 28a. Extensive oversight of gene transfer research already exists. The Food & Drug Administration (FDA) has chief responsibility for ensuring that all gene transfer products are safe and effective. The National Institutes of Health (NIH) provide more limited oversight through its Recombinant DNA Advisory Committee (RAC), which considers the ethical implications of new gene transfer research protocols that have NIH funding.[29] When submitting protocols to the RAC, researchers must respond to a series of questions about the objective and rationale of the proposed project, as well as questions about informed consent and privacy.[30] An important characteristic of NIH oversight is that the review process is conducted in public. This is a key difference from the FDA, which is required by law to safeguard proprietary information from public access.[22]
Slide 28b. There is also local oversight by committees such as Institutional Review Boards (IRBs) and Institutional Biosafety Committees (IBCs). Once the clinical trial is approved, it must be monitored closely to ensure enrollment of appropriate subjects, and appropriate documentation and reporting of all clinical data and adverse events. As new data become available from animal or clinical studies regarding safety of the approach, the protocol and consent forms should be modified and the regulatory agencies notified.
Slide 29a. In summary, diagnostic and therapeutic genetics research has enormous potential to benefit society. Highly individualized therapies could reduce toxicities, enhance efficacy, and decrease the economic burden caused by drugs or therapies that are ineffective or toxic.
Slide 29b. The potential harms and other ethical concerns associated with diagnostic and therapeutic genetics research should be reduced by sensitizing those engaged in the oversight of this research to the ethical issues associated with it.
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