Pharmacogenomics and Information-based Medicine

---

The discipline of pharmacogenomics is aimed at discovering patterns in DNA, RNA, protein expression and biomarker data that correlate with disease risk, disease progression and drug response (clinical outcome) in an individual or a group of patients. The biopharmaceutical industry is using pharmacogenomics to develop targeted treatment solutions that take into account genetic and other contributors to patient variability in response to drugs.

An early example of pharmacogenomics is the optimization of drug dosage based on a patient’s profile of metabolizing enzymes. Other examples of pharmacogenomics can be found in disease areas such as oncology. Drugs that show statistically insignificant efficacy in clinical trials may be approved for the treatment of a subpopulation. For instance, Genentech Inc.'s (South San Francisco, CA) breast cancer drug Herceptin® should only be taken by the subpopulation of patients (20 to 30 per cent) who express the Her2 gene in their cancerous tissues. Novartis International's (Basel, Switzerland) drug Gleevec® received expedited U.S. Food and Drug Administration approval despite targeting only 20 per cent of adult-onset leukemia patients.

The FDA's Critical Path Initiative is focused on the use of pharmacogenomics on adaptive clinical trials to improve clinical end points, and on the use of validated biomarkers. Particularly, the clinical drug-development phases are re-focused by pharmacogenomics as follows:

Phase 1
Understand impact of drug
metabolism.

Phase 2
Relate response to genetic variation;

Phase 3
Target drug responders to reduce required study size and speed
completion.

Phase 4
Faster and improved querying,
segmentation and reporting of
pharmacovigilance data.

Pharmacogenomics must be seen in the context of our health-care ecosystem. The biomarkers and gene/disease relationships applied in pharmacogenomics are generated by medical research into clinical genomics performed in academic medical research centres (AMRCs) and biobanks. The targeted treatments developed by the biopharmaceutical industry and diagnostics companies are then used to treat patients in a "personalized" way.

Imaging technologies will play an increasingly important role in diagnosing disease progression and monitoring the impact of drugs. Pharmacogenomics is hence creating new opportunities to improve medical care and open the door to a new era of personalized medicine. IBM Corp. (Armonk, NY) has defined "information-based medicine" as the process of improving existing biomedical and pharmaceutical practices with knowledge generated from the integration of diverse clinical and biomedical data.

Information-based medicine will enable patients, providers and payers of care, biomedical researchers, and the institutions and organizations they represent, to improve the diagnosis and treatment of disease by accelerating the industry toward targeted therapies and personalized health care.

However, several technological challenges related to the volume and complexity of genomic, clinical and image data have to be overcome before this vision can be realized. Recent scientific breakthroughs, in particular high-throughput molecular analysis, have resulted in the generation of huge volumes of experimental data that are difficult to manage and analyze (e.g. microarray gene expression experiments). Fortunately, recent progress in the development of advanced visualization techniques has increased the reliability of interpretations.

Another rapidly growing source of large-scale data volumes is clinical information contained in medical records or in clinical trial records that can help to reveal patterns of disease and outcome. The practice of medicine is in the early stages of transforming from an episodic focus on identifying symptoms of disease toward a more longitudinal understanding of susceptibility, disease etiology and individualized preventive therapies.

Epidemiological data aggregated over time and consisting of genetic and treatment information about individuals generate medical insights. These insights can be acted upon to design more targeted therapeutics, more informative diagnostics, and more specific treatments to cure and prevent disease. The fast growth of diverse genotypic and phenotypic patient data is expected to continue, based on new scientific advances and the growing recognition of the need to invest in national health-care IT infrastructures.

Information-based medicine can leverage this growing wealth of available information to support pharmacogenomics and the delivery of new, targeted, personalized treatments and therapies that will ultimately increase the quality and reduce the cost of health care.

Canadian Project Initiatives

An interdisciplinary approach that brings stakeholders together to transform health care toward personalized medicine is the key to implementing the vision of information-based medicine. Early leaders are emerging in many parts of world, and Canada is playing a very active part.
Along with prestigious medical institutions at the leading edge of medical research and clinical practice (such as Mayo Clinic in the U.S. and Karolinska Institute in Sweden), the James Hogg iCAPTURE Centre (Vancouver, B.C.) has moved to the forefront of information-based medicine in the important therapeutic areas of cardiovascular and lung disease. Similarly, the Ste-Justine Hospital Pediatric Research Centre, a university teaching hospital affiliated with the University of Montreal (Montreal, QC), is focusing on a clinical genomics approach to cancer research and patient care.

It was the vision of Dr. James Hogg, PhD to make the iCAPTURE centre a leader in understanding and eliminating heart, lung, and blood vessel diseases. The name “iCAPTURE” is an acronym that reflects strategies and approaches for reaching this vision: imaging, cell analysis, and phenotyping towards understanding responsive, reparative, regenerative, and recombinant events. iCAPTURE is focused on the discovery and implementation of information-based medicine solutions for heart, lung, and blood vessel diseases, and on creating a working environment that attracts and supports top talent. The ultimate goal is improved patient care and outcomes, hence the emphasis on “translation” of research into clinical practice. iCAPTURE’s six strategic goals are to:

1.     discover: conduct first-class medical research;
2.     translate: from discoveries to the clinic, and the community;
3.     synergize: focus on multi-disciplinary and trans-disciplinary research;
4.     attract: be the premier centre for trainees and scientists committed to the elimination of heart, lung, and blood vessel diseases;
5.     communicate: to educate and promote awareness to inspire support and better health for all;
6.     sustain: link knowledge and experience with responsible financial practices to create organizational sustainability.

iCAPTURE has built a reputation for successfully integrating genetic, biological, clinical and computational approaches. In co-operation with IBM, iCAPTURE has created a clinical genomics infrastructure based on the acquisition, integration, management and analysis of phenotypic and genotypic data. iCAPTURE's research excellence—supported by Canadian partners such as Providence Health Care, the University of British Columbia (Vancouver, BC), the Canada Foundation for Innovation (Ottawa, ON), BC Knowledge Development Fund, BC Lung Association (Vancouver, BC), Heart and Stroke Foundation of BC and Yukon (Vancouver, BC), the Michael Smith Foundation for Health Research (Vancouver, BC)—is attracting the interest of the research-based biopharmaceutical industry.

Two large iCAPTURE projects illustrate its transdisciplinary nature and advancing pathway to transdisciplinary training. One of these projects relates to establishing haplotypes of numerous genes involved in immune responses, inflammatory processes, and wound repair that pertain to atherosclerosis, asthma, chronic obstructive pulmonary disorder, systemic inflammatory response syndrome, and aortic valve stenosis. This project, led by Dr. Peter Paré and several co-investigators is predicated on daily interactions between clinicians, biologists, computational scientists, geneticists, and patients. Early results suggest some markers of importance to patient and disease prognosis.

Similarly, another program called Biomarkers in Transplantation, led by Dr. Bruce McManus, PhD and funded by Genome Canada (Ottawa, ON), aims to establish non-invasive, affordable, and widely useable markers that predict and allow definition of prognosis or diagnosis that is patient-specific and immediate. The project relies on a full range of disciplines including clinicians, biologists, geneticists, statisticians, informaticians, technology gurus and ethicists.

Another project worth mentioning is CardioSHARE, which is focused on access to external information resources. Mark Wilkinson, PhD and McManus are leading the development of the first-ever integrated and complete ontology for ischemic heart disease called Cardiovascular Semantic Health and Research Environment (CardioSHARE). Through this endeavour, these two researchers, along with an international team of collaborators, are constructing a novel computational environment where heart research data and clinical data will be “captured” together with their contextual meanings. Heart researchers will be able to browse and query data more intuitively, and the underlying computational framework will enable improved query and analysis of biological questions.

At St. Justine Hospital Pediatric Research Centre in Montreal, an advanced clinical genomics solution is giving medical researchers real-time access to a body of quality data, in a view that is compatible with their needs. Clinical data that used to be manually extracted from the hospital patient file are now electronically transmitted and merged with genomic data to create a Medical Information Repository (MIR) populated with longitudinal records. By combining MIR with flexible software tools, data query processes are reduced from days to minutes, thereby enabling researchers to optimize their work and develop therapies that will take into account the unique genetic profile of individual patients.

Initial research will focus on acute lymphoblastic leukemia, which represents 25 per cent of all childhood cancers. Although 80 per cent of current cases are cured with existing treatments, patients suffer significant long-term side-effects even into adulthood. The Pediatric Research Centre at Ste-Justine Hospital will be able to improve the data entry and setup validation processes, integrate various basic and clinical research databases as well as information from the clinical systems of different hospitals. All research projects will be supported from a single database and integrated infrastructure.

According to Daniel Sinnett, PhD—an associate professor at the University of Montreal and head of the leukemia-cancer section at the research centre—the goal of this clinical genomics project is similar to that of iCAPTURE's: medical discoveries that translate to patient care and improve outcomes.

Advanced clinical genomics systems like those implemented at iCAPTURE and St. Justine are examples of leading-edge, information-based medicine initiatives in Canada. They are attracting the interest of commercial developers of drugs and diagnostics, and they are serving as early pilots for the future transformation of health-care systems.

Michael Hehenberger, PhD is the global leader for IBM Corp.'s Life Sciences/Pharma Transformation Solutions. Guido Roumans is the Southwest European Life Sciences/Pharma R&D leader for IBM Global Business Services.