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Ethical and Legal Issues

1. Introduction

Medical testing by genomic methods share many ethical, legal and social issues with other forms of clinical investigation. Genomic methods are simply methods and do not necessarily introduce new issues. However genomic testing is marked out by the opportunity and challenge of scale. Existing issues of informed consent, incidental findings, the right not to know, family studies and re-contacting are potentially magnified due to the of the volume of information that these tests yield.

Comprehensive genomic analyses (e.g. whole genome sequencing or exome sequencing) can generate information pertinent to the management of diseases other than the targeted clinical condition being investigated. Genomic testing can, therefore, be viewed as comprising both a diagnostic and a screening function. The scale of this overlap in test function is unprecedented. The implications of this complex testing scenario for the individual patient will require clear explanation in order to obtain informed consent.

Genomic testing should not be performed without careful consideration of these broader issues. For this reason, this chapter on ethical and legal implications of genomic testing precedes the chapters detailing the analytical, interpretive, reporting, and resource requirements for such testing.

2. Medical Responsibilities

2.1 Medical genomic testing is subject to ethical guidelines for medical practice and existing NPAAC guidelines.

There is an ethical dimension to all medical testing. Patients expect that they will be offered tests that are safe and provide information that is accurate and useful in the management of their condition. If tests are to be used in clinical management, it is expected that they will have undergone an evaluation of the evidence for their safety, analytic and clinical validity, and clinical utility. Tests which have not been evaluated in this fashion or where the evidence base is weak may be used for research purposes, but any reports should be identified as research only, or not validated to clinical standards (as appropriate) and the patient will need to give their informed consent to be a part of a research study.

Guidance on ethical issues relating specifically to genetic testing comprises foundation documents and a rapidly evolving peer reviewed literature, some of which are listed below. Medical genomic testing is subject to the existing NPAAC guidelines. When genomic testing is used for targeted DNA sequencing i.e. analysis of genes known to cause the patient's current disease, it falls within current guidelines for genetic testing by Sanger sequencing. Genomic testing for a clinical condition with a suspected genomic causation but with unknown a-priori genetic basis i.e. whole exome or whole genome sequencing falls more within current guidelines for microarray testing.

2.1.1 Resources

2.2 There should be an explicit medical consultation framework within which clinician and laboratory operate whenever genomic testing is undertaken.

While all pathology test requests imply a consultation between the referring clinician and the laboratory professional supervising the test, this should be an explicit requirement of referrals for genomic testing.

The pathology teams need to know the specific clinical question being asked of testing to allow planning of the analytical processes and to facilitate interpretation of the analytical result. The referring clinician should provide adequate clinical and laboratory information to assist in these decisions. Laboratory Directors should clearly distinguish between clinical testing with a strong evidence base from testing for research purposes in which there is an evolving evidence base.

Laboratories should clearly state their policy on reporting incidental findings and variants of unknown significance.

The referring clinician should know what analytical approach will be undertaken, the policies of the pathology service with respect to reporting of findings, incidental findings (including carrier status for recessive disorders), storage of data, and links with research bodies and biobanks, so that this information can be conveyed to the patient during the informed consent process. The pathology team and the clinician may wish to vary procedures regarding information provided, consent, and testing performed on a patient-by-patient basis.

2.3 Patients should receive counselling prior to genomic testing by a genetic counsellor or relevant medical specialist.

There is no consensus guideline on best practice with respect to the components and communication elements of counselling for genomic testing, however the core principles of genetic testing apply and should be discussed. These core principles include the requirement for a discussion of both expected results and incidental findings, that the interpretation of results requires reference to population and disease specific genomic databases, and that the interpretation of results may alter with increasing knowledge. Information about the storage of data, and protocols for re-analysis and call–back, should be communicated to the patient during the process of obtaining informed consent. The pre-test counselling should also clarify that results will be conveyed to the patient, discussed during post-test counselling, and distributed to specified clinicians and records. These principles also apply in settings in which consent is provided by an appropriate proxy for the patient e.g. in a paediatric setting.

The HGSA commentary emphasises importance of patient autonomy.

The HGSA Code of Ethics states that individual autonomy should be respected by “actively promoting informed decision-making, which is not coerced, for all involved by providing accurate and balanced information and an opportunity to deliberate, based on individual values and beliefs”. The ACMG recommends pre and post-test counselling, and note that it could be considered coercive with respect to predictive information to only offer a choice between receiving reported incidental findings and not having genomic testing at all.

2.4 A formal consent process should be in place and patients should consent to testing for a medical service.

A standard consent form should be developed which is acceptable to all jurisdictions.

Online access is available to Information/consent/test ordering forms for various genomic assays provided by the Baylor College of Medicine (USA) and Ambry Genetics (USA).

Please note that these resources are examples only, and no commitment is made that these are suitable for specific purposes, times, or places.

2.4.1 Resources

Examples of genomic information sheets and consent forms:

2.5 The patient should provide specific consent to allow the contribution of their de-identified data to public databases.

The development of population reference ranges for laboratory analytes has been a fundamental process in the development of diagnostic testing. The clinical validity and utility of tests which identify deviations from population reference ranges can be assessed, and an evidence base for the use of the test can be built. This fundamental principle also applies to genomic testing i.e. documenting the frequency and clinical relevance of variants in different populations. All patients seeking genomic testing should, therefore, be asked for permission during the consent process to include de-identified results into publicly available databases for the common good.

2.6 Patients should receive a clear written record of the policy regarding the reporting of incidental findings.

As yet, there is no consensus on whether and what incidental findings should be reported to the patient. Patients may have the right to know, to know of some, or not to know about incidental findings. Doctors have both an obligation to do what the informed patient has requested and to advise the patient of any serious health risk revealed by testing. They also have an obligation to the blood relatives of the patient. These ethical dilemmas are made more complex by the fact that the significance of many findings is unknown and that the classification of benign and pathogenic mutations may be unreliable and alter over time with accumulation of new evidence.

The recommended use of targeted analysis, where it does not interfere in reaching a diagnosis, is a pragmatic approach to minimise these ethical dilemmas.

One approach is to classify findings into groups (or “bins”) as a function of the risk of disease and the existence of effective therapy. A process has been proposed in which stakeholders would determine which genes belong in the medically actionable bin (see Resources below). Achieving consensus on the management of incidental findings is likely to be a complex process as studies show the wide range of views of both patients and healthcare professionals as to what constitutes valuable information. The construction of databases with phenotypic annotation of genomic variants and evidence based research will be critical to the success of this approach.

It is current practice for doctors to seek consent from patients to notify them of actionable mutation results identified during testing. The list of these mutations needs to be documented and regularly reviewed. Should patients decline to be notified, many doctors have taken the decision not to proceed with genomic testing and have offered other diagnostic pathways.

In this period while debate and guideline development are in progress, doctors are using standard practices (clinical reasoning, the advice of peers and local ethics committees) to develop their own approach to these issues.

Whatever approach they choose, clear verbal and written communication of the policy about what findings will and will not be disclosed should be provided.

As this is an emerging technology, there is, as yet, no case law regarding medical liability of referring clinicians or pathologists in this field.

2.6.1 Resources

3. Laboratory Responsibilities

3.1 The accountable laboratory professional should sight a copy of the consent form before testing.

The existing NPAAC Requirements for Medical Testing of Human Nucleic Acids (see Appendix A) distinguishes between two classes of DNA tests:

  • Level 1 tests (the default classification; includes diagnostic testing and neonatal screening) and
  • Level 2 tests (DNA testing for which specialised knowledge is needed for the DNA test to be requested, and for which professional genetic counselling should precede and accompany the test; this includes predictive and pre-symptomatic tests).

The document notes that specific written consent and counselling issues are associated with Level 2 tests, and assigns responsibility to the laboratory director to document consent and defer testing if there is a concern about the consent process. Although diagnostic testing using genomic methods could be regarded as a Level 1 test, genomic testing should be regarded as a level 2 test because of the complexity of the issues associated with consent and variants of unknown significance.

Pathologists and scientists need to be assured that the patient has undergone pre-test counselling by an accredited genetic counsellor or relevant medical specialist, that counselling has included discussion of expected outcomes of testing and the likelihood and type of incidental findings, and that the patient has given informed consent.

The NPAAC document does not require that the consent for Level 2 testing be sighted - only that the accountable laboratory professional knows that such consent has been provided. However, to ensure explicit consistency in the pre-analytical, analytical, and post-analytical phases of a genomic test (see Sections above and below), the laboratory professional may request to sight a copy of the completed consent form prior to testing. The laboratory should request a copy of the consent form for whole exome or whole genome sequencing.

3.2 Data generated by genomic testing are subject to the privacy legislation operating in each jurisdiction.

Under the Federal Privacy Act, the health service provider in the private sector is responsible for the security and privacy of a patient’s health information. Commonwealth State or Territory laws apply to health service providers in the public sector. There are specific provisions under the Federal Privacy Act to allow medical practitioners to disclose a patient’s genetic information without their consent to a relative if there is a serious threat to life, health, safety of the relative and the use or disclosure is necessary to lessen or prevent that threat (APP 6). Note that compliance with the NHMRC Guidelines (see below) is a legal requirement for anyone wishing to utilize this legal provision.

There is debate as to whether additional legislative security is necessary because of the identifiability of data generated by genomic testing. An alternative view has been put that it is not the data or DNA sequences per se that is identifiable, but rather that identifiability only occurs at the time that genome sequence is matched with that of the patient. As use of the sample without the patient’s permission is illegal under Australian privacy legislation, any matching of genomic data with a particular patient is illegal and the perpetrator is subject to existing legal penalties.

3.2.1 Resources

3.3 DNA samples and laboratory records should be retained in accordance with existing NPAAC requirements.

The existing NPAAC standard for samples submitted for medical testing specifies the retention of diagnostic material for “three months from the date of issue of the report for an individual or for completion of a family study or for completion of testing: whichever of the three periods is longest”. It is reasonable to apply this to samples submitted for genomic testing.

The document specifies that “The copy of the original report, or ability to reprint the information content of an original report has a minimum retention time of 100 years.” This may need to be altered to accommodate genomic testing. It should be noted that the standard specifies for only reports to be kept indefinitely; the raw data files from genomic testing are very large and their storage poses a significant cost and logistical burden.

The Privacy Act advises of the risks of keeping health information longer than is necessary as this may increase the risk of privacy breaches.

A 3 year study at South Eastern Area Laboratory Service (SEALS) in NSW has commenced to determine the need to access archived genomics reports. This is likely to inform laboratory practice. In the interim, laboratories are recommended to retain at least an aliquot of the DNA and the corresponding VCF file for 3 years.

3.3.1 Resources

  • NPAAC Requirements of the retention of laboratory records and diagnostic material (Sixth Edition 2013)

3.4 Data generated by genomic testing should be stored in accordance with the privacy legislation operating in each jurisdiction.

Standards Australia AS/NZS ISO/IEC 17799:2001 and AS/NZS 7799.2:2000 incorporate electronic storage of medical records. There are no specific standards for the storage of genetic information.

Enforcement provisions for misuse or loss or disclosure without consent of stored health information are legislated under Federal and State privacy legislation. There is no specific Australian legislation around genetic information. If health data from Australian patients is stored on cloud computing platforms which are physically located in another jurisdiction, they are not subject to Australian Privacy legislation. If data are lost, disclosed or stolen, the privacy and security legislation of that jurisdiction applies.

3.4.1 Resources

3.5 Upon request, the Laboratory Director should give patients access to the personal genomic information for which consent has been given.

Provisions are made for some exemptions in the National Privacy Principles (APP 12). Relevant examples include:

  • A serious threat to life, health or safety of an individual or to public health or public safety; or
  • Giving access would have an unreasonable impact on the privacy of other individuals; or
  • Various exceptions relating to current or anticipated legal proceedings or under certain legal authorities.

Procedures may need to be put in place to address specific cultural sensitivities relating to the access by patients to their genomic data.

3.5.1 Resources

3.6 The Director of the laboratory should observe the relevant provisions of privacy legislation in that jurisdiction should the business circumstances of the laboratory change.

For a laboratory operating in the private sector (and hence falling under the requirements of the Federal privacy legislation), the relevant Australian Privacy Principles include numbers 3, 6, 11 and 12. Where ownership of the health service provider changes (e.g. amalgamation, takeover, closure) but the original purpose for which the information was used does not change, the health information stays with the organisation and there is no requirement to inform or seek consent from the patient. However, if the new health service provider intends to use the information for purposes other than for which it was collected, the new provider may need to seek consent from the patient. Where a health service provider’s business ceases altogether, arrangements will need to be put in place to transfer and store the patient’s health information.

3.6.1 Resources (as per 3.5.1)

4. Scope of Testing

4.1 Throughout the process of testing, there should be explicit distinctions between targeted diagnostic testing i.e. of selected genes, whole exome or genome sequencing, screening of an unaffected person, and research studies.

An understanding of the role of genomic testing in investigation of disease is rapidly evolving.

Genomic testing may be indicated in the investigation of patients with a Mendelian phenotype or family history which strongly implicates a genetic aetiology. The case for targeted diagnostic testing is clear where the phenotype is consistent with a known disease in which mutations in a number of genes are known to be causative.

Genomic testing may also play a role in the investigation of families with a Mendelian phenotype where the specific genetic aetiology is not established i.e. genome-wide diagnostic testing. It may also play a role in the investigation of multiple affected individuals from different families or single individuals with very rare genetic disorders, where randomised clinical trials to assess clinical utility and other measures of efficacy of genomic testing are not possible. These referrals are based on clinical judgment. This approach is analogous to investigations such as cytogenetic analysis, microarrays or tissue biopsy where the target pathology is unknown.

There is debate about the use of genomic methods in preconception carrier screening for relevant mutations, prenatal screening, and as a first tier approach for newborn screening.

A recent report from the Foundation for Genomics and Population Health in the UK concludes that “Extensive interrogation of genomic data for preventive purpose is not recommended.”

These different purposes of genomic testing involve different ethical considerations as well significant differences in analysis and interpretation. The clinician, laboratory, and patient should have a clear understanding of the purpose and scope of a test, and this should be reflected in pre-test counselling and consent, in the analysis and interpretation, and in the reporting and distribution of a genomic test.

4.2 When genomic testing is used in the investigation of a heritable disease, the analytical approach should be targeted so that only genes relevant to the specific disease phenotype are analysed, provided that this approach does not compromise test performance.

Current recommendations are that the analytic approach be clinically targeted at a candidate gene or set of genes which are known to cause the disease phenotype in question. “Genome-wide” diagnostic testing should only be considered if it is clear that testing with a narrower scope (using filters) will yield insufficient results.

Where the phenotype is non-specific or not recognized as a particular syndrome, wider capture of data with targeted data interrogation that can be performed in a tiered manner is useful.

4.2.1 Resources

4.3 Patients should provide consent if their genomic data derived from clinical testing are to be used for research purposes.

There are no specific conditions to be applied to the research use of samples or data that had been obtained for diagnostic testing using genomic methods. Collaborations between pathology practices providing diagnostic testing and researchers take several forms and are subject to the provisions of privacy legislation in the various jurisdictions and to the NHMRC National Statement on Ethical Conduct of Human Research.

Collaborations between institutions are subject to the framework outlined in the Australian Code for the Responsible Conduct of Research (2007).

Patients should have provided informed consent for the use of their samples or data for research; this consent should be distinct from the consent process for clinical testing. Consent may be

  • Specific to a project under consideration, or
  • Extended where consent is given for the use of data or tissue in future research projects that are an extension of or closely related to the original project or in the same general area of research, or
  • Unspecified where consent is given for the use of data or tissue in any future research.

There is ongoing debate in Australia about unspecified, also known as “open-ended”, consent to the use of genomic data in research. Should the patient give extended or unspecified consent, further consents are required to enter data or tissue into databases or biobanks. The informed consent process should clearly state the protocol with respect to re-contacting the patient about incidental findings identified during subsequent research projects.

The view presented by NHMRC is that human tissues samples should always be regarded, in principle, as re-identifiable. All requests from researchers for the release of de-identified data from samples submitted for diagnostic testing and of associated laboratory data to biobanks or databases, will require approval by the Ethics Committee with responsibility for oversight of activities of the pathology service.

Provided a suitable ethical framework is in place, the diagnostic laboratory can provide samples and data to the researchers, but should retain sufficient sample for the minimum retention period and laboratory records to meet NPAAC requirements for the retention of the health record.

4.3.1 Resources

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