Megan Bettle
Director
Regulatory Review of Drugs and Devices
Health Canada

his session on precision medicine opened with the observation that “medicine has always been personal.” The ability to identify disease-associated gene mutations and follow them through families has broadened this concept. Inherited diseases are rarely just about the individual.

Key Takeaways

• Advances in genetic testing and technologies have led to rapid advances in the ability to diagnose disease, but the adoption of these new technologies necessarily results in trade-offs: costs in one area of the healthcare system take away from other areas.
• Responsible onboarding of precision medicine requires understanding not just of genotypes, but of how disease mutations are manifested, the uncertainties inherent in the testing, and the types of support that patients will need in their interactions with the healthcare system.

Precision Medicine: Lessons from Families

In the eastern Canadian province of Newfoundland and Labrador, a founder effect has resulted in extended families consisting of multiple generations with occurrences of sudden cardiac death at young ages due to an inherited arrhythmogenic cardiomyopathy. While the autosomal dominant inheritance pattern and a single nonsense mutation in the TMEM43 gene could initially be seen to be simple to understand, closer examination of family data shows a variable phenotype, with worse outcomes in males than in females with the same mutation. However, when recognized early and treated with implantable cardiac devices, males treated early gained over 31 years of additional life compared to controls with the same genetic mutation (historical untreated family members).

Other Newfoundland families with a similar inherited pattern of cardiomyopathy have also been identified, but in this case, the mutation occurs in a different gene, and the striking pattern of early death seen in TMEM43 families is not seen. Therefore, this observation reinforces that it is not enough in these cases just to know the family history and disease phenotype; not being able to distinguish between the two and not treating families according to their mutation would result in many young deaths.

These practical examples of precision medicine highlighted the importance of collecting families, rather than individuals, with a genetic disease, as well as maintaining historical blood and tissue samples, and old medical records. Only by looking at the genotype-phenotype interactions over generations can the signal in the noise be found and the true story of the family be told.

Unlocking Data for Personalized Healthcare

To date, medical progress has been based on treating the population rather than each patient as an individual. In one industry example, however, efforts are being made to move from treating disease from a mechanism of action perspective, to treating a patient with their own unique genomic information, and to treating a person. This goes beyond the disease and towards Real World Data on the social determinants of health.

The health data ecosystem is fragmented and data can be difficult to access, so how can we get a more complete view of the person? The Canadian Personalized Healthcare Innovation Network is a collaboration to support accessible data networks, expanded use of Real World Data and Real World Evidence, and use of patient-centred outcomes with the aim of supporting value-based reimbursement for efficient health investment. Responsible onboarding of precision medicine will need to have the appropriate data and infrastructure.

Economic Evaluation: Adoption of New Technologies and Tests

Healthcare resources are finite, and the introduction of new technologies requires decision-making about adopting technologies that maximize health improvements for their costs.

Health technology assessment, which includes consideration of health services research, quality of life measures, economic evaluation, and patient preferences, is conducted at multiple levels in the Canadian healthcare system, including at the national, provincial, and hospital levels. The assessment of gene-based diagnostic technologies and their subsequent adoption into the healthcare system requires a broad evaluation of their value and impacts, including the rate and impacts of false negatives and false positives, and the health and economic consequences of incidental findings, such as genetic risk factors for one condition identified in the screening for another, or gene variants of unknown significance.

The optimal position of precision medicine within pathways of care will depend on the situation, but rapidly evolving knowledge regarding genotype-phenotype links will increase diagnostic yield, clinical utility, and value for money. Serial testing strategies may be more useful and cost-effective than broad testing of many patients, and application in patients with complex diseases, difficult diagnoses, and long diagnostic journeys may improve care and save money overall.

A key question for all healthcare systems is: When new technologies are onboarded, where and how do we make disinvestments? Additionally, when most personalized medicine is available in high-density urban centres, how do we address the equity issues in a very large country like Canada where patients may live far away from these resources?

Where Next?

The panel discussion focused on the implementation considerations of genetic testing to support disease diagnosis and management, including having the proper genetic counseling support in place before any tests are done. Responsible implementation of precision medicine includes giving patients the information they need to make informed decisions, such as about what might come out of testing and the later interpretation of risks (which may still be small) that often do not just affect the individual patient but their families as well.