Archived - The Canadian Biopharmaceutical Industry Technology Roadmap — Footnotes

¹  One impact of genomics — the study of the human genome — on life sciences is to make every element of the cell into an 'omics specialty, such as proteomics for proteins and metabolomics for cellular fluids. Chapter Two contains a broader discussion of this point. (Return to document) 

²  Statistics Canada, Canadian Trends in Biotechnology, 2nd Edition (2005), Figure 12, p. 25. (Return to document) 

³  One example is the Small Business Industrial Research (SBIR) program designed to enable early-stage companies in strategic sectors to advance to proof-of-principle stage in order to maximize their chances of successful commercialization. (Return to document)

⁴  Computerized techniques for sorting, storing, analyzing, manipulating and mining biological information stored in databases. (Return to document)

⁵  Research to find connections between diseases, molecular targets such as an enzyme or receptor protein implicated in the disease process (biology phase), and drug molecules (chemistry phase) capable of modulating the biological activity of the target. (Return to document)

⁶  Food and Drug Administration, Challenge and Opportunity on the Critical Path to New Medical Products (March 2004). (Return to document)

⁷  J. Hodgson, "ADMET — turning chemicals into drugs," Nature Biotechnology (August 2001), p. 722. (Return to document)

⁸  Christopher Dobson, "Chemical Space and Biology," Nature (December 2004), p. 826. (Return to document)

⁹  U. Betz, "How many genomic targets can a portfolio afford," Drug Discovery Today (Aug. 2005), p. 1059. (Return to document)

¹⁰  In RNAi, a double-stranded RNA segment is introduced into cells or organisms to silence a specific gene by binding to and initiating the degradation of the gene's mRNA. (Return to document)

¹¹  Because each organism lacks some of the characteristics of human physiology, more than one model is necessary for better human predictive ability. (Return to document)

¹²  Metabolic responses, for example, are affected by variables such as proteins, diet, and age that may mask the effects of disease; as well, the number of different metabolites is unknown — estimates range from 2000 to 20 000. (Return to document)

¹³  There is a difference between druggability and biological activity. A protein may be druggable but modulating its function with a small molecule may have limited therapeutic value. On the other hand, a protein may have an important role in the disease process but may not be druggable. (Return to document)

¹⁴  Protein-protein interaction pathways found in apoptosis, the major pathway of programmed cell death (cancerous cells, for example, exhibit unchecked cell growth caused by the lack of apoptosis) have no known druggable targets. This has resulted in the use of an alternate strategy based on antisense apoptosis inducers, but these agents have drug delivery problems. (Return to document)

¹⁵  U. Betz, "How Many Genomics Targets Can a Portfolio Afford," Drug Discovery Today (August 2005), p. 1061. (Return to document)

¹⁶  T. Creavin, "Antigen synthesis opens the door to a broad spectrum AIDS vaccine," Drug Discovery Today (June 2004), pp. 507–508. (Return to document)

¹⁷  P. Palese, "Making Better Influenza Virus Vaccines," www.medscape.com/viewarticle/518514, accessed December 21, 2005. (Return to document)

¹⁸  Manuel J. Rodriguez-Ortega et al., "Characterization and Identification of Vaccine Candidate Proteins through Analysis of the Group A Streptococcus Surface Proteome," Nature Biotechnology (February 2006), p. 191. (Return to document)

¹⁹  Christopher Dobson, "Chemical Space and Biology," Nature (December 2004), p. 827. (Return to document)

²⁰  The synthesis and retesting of analogues to ensure the compound has acceptable pharmaceutical properties in terms of potency, bioavailability, and high affinity and selectivity for the biological target. (Return to document)

²¹  GPCRs must be screened in a cell-based format to mirror the in vivo environment, while screening methodologies for ion channels (the "patch-clamp" technique, which measures ionic currents under a defined membrane voltage) are extremely low throughput, require technically skilled operators, and are difficult to scale up. Ion channel libraries also do not benefit from as wide a chemical diversity and number of known ligands to use as a starting point as GPCRs. (Return to document)

²²  An abnormality of cardiac muscle repolarization, defined as the time from Q wave deflection to the end of T wave on an electrocardiogram. (Return to document)

²³  Because a drug's safety and efficacy often depend on how it is metabolized in the liver and whether toxic or inactive metabolites are generated, assays are based on hepatocytes (liver cells) harvested from cadavers, but human liver tissue is expensive and difficult to obtain. (Return to document)

²⁴  More accurate algorithms that consider the flexibility in the torsion angles in both the protein and small molecule will better predict how the two will interact. More rapid algorithms and more computing power are needed if large libraries are to be screened in a reasonable time. Present scoring functions cannot rank subtle differences between ligands or model side effects properly. (Return to document)

²⁵  X-ray crystallography, nuclear magnetic resonance or homology modelling are used to calculate the 3-D structure of a target protein. Computer algorithms are then employed to calculate the likely binding sites for molecules and to select compounds from a database with appropriate molecular shapes and functions. These compounds are positioned into regions of the protein structure and ranked based on their electrostatic interactions with the target site to alter the protein's biological activity. (Return to document)

²⁶  Advances include the use of liquid handling dispensing robots, the ability to dispense protein nanodroplets (which has led to more rapid appearance of crystals), the availability of much more intense synchrotron beam lines suitable for analysing these very small crystals, and crystal mounting and alignment robots enabling unattended collection of X-ray data 24 hours a day. (Return to document)

²⁷  A.M. Aronov, "Predictive in silico modeling for hERG channel blockers," Drug Discovery Today (January 2005), pp. 149–156. (Return to document)

²⁸   Sidec Technologies. (www.sidec.com/). (Return to document)

²⁹  D. Filnore, "Crystallography on Drugs," Today's Chemist at Work, American Chemical Society (January 2004), p. 32. (Return to document)

³⁰  Susan B. Fowler et al., "Rational design of aggregation-resistant bioactive peptides," Proceedings of the National Academy of Sciences (July 19, 2005), pp. 10105–10110. Similar work is being undertaken at the SWITCH Laboratory at the University of Brussels. (Return to document)

³¹  Nanotechnology is the manipulation and interaction of materials measuring 100 nanometers (nm) or less in at least one dimension. One nm is one billionth of a meter; the diameter of a human hair is 50,000 nm, red blood cells 7,000 nm, a bacterium around 1000 nm, viruses roughly 100 nm, receptors about 5 nm in diameter, quantum dots 2  to 9 nm, DNA 2.5 nm, an aspirin molecule 1 nm, a water molecule almost 0.3 nm across, and a typical bond between two atoms 0.15 nm long. The properties of materials can be different at the nanoscale because of their relatively larger surface area and because quantum effects begin to dominate the behaviour of matter affecting optical, electrical, and magnetic properties. (Return to document)

³²  Signalling occurs both when the AFM tip contacts the surface (creates strain) and when it is withdrawn. (Return to document)

³³  Clinical trial sizes to confirm safety are much larger for vaccines. Two new rotovirus vaccine candidates enrolled and monitored more than 60 000 infants, making these the largest trials conducted to evaluated vaccine safety. (Return to document)

³⁴  J. DiMasi et al., "The price of innovation: new estimates of drug development costs," Journal of Health Economics, 22 (2003), p. 177. (Return to document)

³⁵  I. Kola and J. Landis, "Can the pharmaceutical industry reduce attrition rates," Nature Reviews Drug Discovery (August 2004), p. 711. (Return to document)

³⁶  Albert Pi Li, "An integrated, multidisciplinary approach for drug safety assessment," Drug Discovery Today (August 16, 2004), pp. 687–88. (Return to document)

³⁷  Dr. L. Crawford, Acting FDA Commissioner, Speech before the Mayo Alliance for Clinical Trials Conference (August 26, 2004). (Return to document)

³⁸  J. Kaper et al., "Vaccine Development: Current Status and Future Needs," Report from the American Academy of Microbiology (March 2005). (Return to document)

³⁹  Decision Resources Inc., Drug Discovery and Design, Vol. 1, Toxicogenomics (January 2003). (Return to document)

⁴⁰  Ian Wilding and Angus Bell, "Improved early clinical development through human microdosing studies", Drug Discovery Today, July 2005, p. 890. (Return to document)

⁴¹  Richard Frank and Richard Hargreaves, "Clinical Biomarkers in Drug Discovery & Development," Nature Reviews (July 2003), pp. 566–67. (Return to document)

⁴²  Jeffrey Ross et al., The Integration of Molecular Diagnostics with Therapeutics, Feb. 14, 2003, accessed December 12, 2004. (Return to document)

⁴³  Genentech's monoclonal antibody Herceptin^TM, which targets the 25 to 30 percent of breast cancer patients that overexpress the HER2/neu antigen, was the first targeted therapy linked to mandatory testing of a specific biomarker. Other examples include Gleevec^TM (chronic myeloid leukemia) and Erbitux^TM (advanced colorectal cancer). (Return to document)

⁴⁴  AstraZeneca's non-small cell lung cancer drug Iressa^TM, for example, was approved on the basis of 50 percent tumour shrinkage lasting at least one month but had to be pulled from the U.S. market after it was discovered there was no significant increase in survival, a large percentage of non-responders, and a statistically high incidence of interstitial lung disease. (Return to document)

⁴⁵  Tumours recur in many early-stage colorectal cancer patients, for example, due to missing pieces of chromosomes 8 and 18. An assay that could measure this imbalance in the clinic would be useful. (Return to document)

⁴⁶  Jeffery Matthews, New Renal Transplant Registry Targets Immune Tolerance, July 29, 2004. Document accessed August 5, 2004. (Return to document)

⁴⁷  Homer Oien et al., "Using Imaging Biomarkers to Accelerate Drug Development and Clinical Trials," Drug Discovery Today (February 2005), p. 260. (Return to document)

⁴⁸  It has recently been discovered that beta amyloid proteins that form plaques in the brains of Alzheimer's patients are also present in the eye lens. Instead of imaging the brain, an infrared laser is directed into the lens and the back-scattered light reveals the amount of protein present. (Return to document)

⁴⁹  The CYP3A group, for example, metabolizes almost 50 percent of approved drugs (for example, HIV protease inhibitors, immunosuppressants, calcium channel blockers, cancer drugs), while the CYP2D6 family metabolizes 25 percent to 30 percent (beta blockers, anti-arrhythmics, antidepressants, morphine derivatives, and anti-psychotics). (Return to document)

⁵⁰  For example, liver size and blood flow to the liver generally decrease in older people, affecting drug clearance. Renal clearance also declines with age. (Return to document)

⁵¹  These include immunohistochemical (IHC) and fluorescent in situ hybridization (FISH) assays for selection of breast cancer patients eligible for Herceptin^TM and an IHC assay for selecting colorectal patients for Erbitux^TM therapy. (Return to document)

⁵²  In addition to Roche's AmpliChip CYP450 assay, other examples include a test for mutations in the metabolizing enzyme thiopurine methytransferase due to risk of haematopoietic toxicity in leukemia patients taking mercaptopurine therapy and an assay to detect variations in the gene UGT1A1 that affects the metabolism of the chemotherapy drug irinotecan used in colorectal cancer treatment. (Return to document)

⁵³  The first companion test for Genentech's Herceptin^TM was immunohistochemistry-based. (Return to document)

⁵⁴  SELDI-TOF-MS, for example, is very sensitive to every step in the analytical process, sequencing technologies need to drop dramatically in speed and price, or proteomic patterns lack discriminatory power (for example, peaks may not necessarily originate from tumour-specific proteins). (Return to document)

⁵⁵  An example was the FDA's use of Pharsight's quantitative modelling and simulation software to help optimize the Phase II and Phase III clinical trial design for an anti-HIV drug. (Return to document)

⁵⁶  This is a trade name owned by Belgium-based Ablynx. NRC is collaborating with Ablynx, which owns the dominant patent position in the field of nanobodies, initially for applications in Alzheimer's. (Return to document)

⁵⁷  Lea Ann Dailey et al., "The role of branched polyesters and their modifications in the development of modern drug delivery vehicles," Journal of Controlled Release (November 2004),  137. (Return to document)

⁵⁸  A. Wack and R. Rappuoli, "Vaccinology at the beginning of the 21st century," Current Opinion in Immunology, Vol. 17 (2005), p. 414. (Return to document)

⁵⁹  Vaccine is spray-dried using a sugar syrup, which then hardens to form microscopic glass spheres that are then suspended in perfluorocarbon, an inert liquid. For combination vaccines, each component can be coated before being combined, ensuring they cannot interfere with each other, and the glass spheres can be made to dissolve at different rates, allowing booster doses to be given in the same injection as the initial vaccine. (Return to document)

⁶⁰  K. Carlson, "Flexibility — Guiding principle for antibody manufacturing," Nature Biotechnology (Sept. 2005), p. 1057. (Return to document)

⁶¹  R. Werner, "The Development and Production of Biopharmaceuticals," Trends in Integrated Biomanufacturing, Special Supplement of BioProcess International (Sept. 2005), p. 11. (Return to document)

⁶²  See www.ciphergen.com for a description of this technology. (Return to document)

⁶³  Vladimir Mironov et al., "Organ Printing: computer-aided jet based 3D tissue engineering," Trends in Biotechnology (April 2003). (Return to document)

⁶⁴  R. Kneller, "National origin of new drugs," Letter to the Editor, Nature Biotechnology (June 2005), p. 655. The number differs from Figure 1 as it includes standard NMEs and NBEs. (Return to document)

⁶⁵  Ibid. (Return to document)

⁶⁶  Roger Coronini et al., "Decoding the literature on genetic variation: survey of the scientific and patent literature on single nucleotide variants," Nature Biotechnology (January 2003), pp. 21–29. (Return to document)

⁶⁷  Biopharmaceuticals in Canada  — Benchmarking of Canadian Biopharmaceutical Science and Technology, report prepared for Industry Canada (March 2003). (Return to document)

⁶⁸  Roger Coronini et al., "Decoding the literature on genetic variation:survey of the scientific and patent literature on single nucleotide variants," Nature Biotechnology (January 2003), pp. 21–29. (Return to document)

⁶⁹  Huang, Zan et al., "Longitudinal Patent Analysis for Nanoscale Science and Engineering: Country, Institution, and Technology Field," Journal of Nanoparticle Research (2003), Vol. 5, Issue 3–4, p. 45. (Return to document)

⁷⁰  C. Riddle, Taking Stock of R&D across Three Sectors, ACST Preliminary Report (June 2003). (Return to document)

⁷¹  Statistics Canada, Total Spending on Research and Development in Canada 1990–2005, Catalogue 88-001-XIE, Vol. 29, No. 8 (December 2005). (Return to document)

⁷²  OECD Science, Technology and Industry Scoreboard 2005 — Towards a knowledge-based economy.  (Return to document)

⁷³  Statistics Canada, Estimates of Total Expenditures on Research and Development in the Health Field in Canada, 1988 to 2004, 88-001-XIE, Vol. 29, No. 5 (July 2005). (Return to document)

⁷⁴  Statistics Canada, Biotechnology Scientific Activities in Federal Government Departments and Agencies, 2004–2005, 88-001-XIE, Vol. 30, No. 2 (March 2006), Table 2 and Table 3A. (Return to document)

⁷⁵  The new funding followed on reports by national advisory committees about the current status and potential of the industry, for example, Leading in the New Millennium, (1998) Sixth Report of the National Biotechnology Advisory Committee. (Return to document)

⁷⁶  Ibid. See also Kathryn Howard, Director General, Life Sciences Branch, Industry Canada, Presentation to BioteCanada Conference 2003: Adapting to the Times (29 May, 2003), slides 3–7. (Return to document)

⁷⁷   NCE Annual Report 2004–2005, available at: www.nce.gc.ca/annualreport2004_2005/Eng/2_3/2_3_3.asp#2_5_6.  (Return to document)

⁷⁸  Industry Canada; 14 chairs are Tier One ($1.4 million over 7 years) and 16 are Tier Two ($0.5 million over 5 years). (Return to document)

⁷⁹  Report of the (Ontario) BioCouncil (March 2002), especially Chapter Two. (Return to document)

⁸⁰  KPMG (2006), Competitive Alternatives: KPMG's Guide to International Business Costs, Executive Summary and Vol. 1, tables. (Return to document)

⁸¹  Canadian approval times appear in Health Canada (2004) Regulatory Review of Pharmaceuticals, Biologics and Medical Devices, Annual Summary of Performance, pp. 24–25. United States approval times are given in United States Health and Human Services, Food and Drug Administration (2004) Report to the Nation, Improving Public Health Through Human Drugs, Chapter 1, Drug Review, pp. 14–16; E.U. times are in the European Medicine Agency (2004) Tenth Annual Report of the European Medicine Area 2004, EMEA/61492/2005/EN/FINAL, pp. 31–32. Note that the United Kingdom scientific review of new active substances is now 40 days; see Medicines and Health Care Regulatory Agency Annual Report and Accounts 2004/05, p. 30. Comparisons are difficult because rates depend on application rates and types of application. Biologics generally require longer approval times. (Return to document)

⁸²  Canadian Biotechnology Strategy: Public Opinion Research into Biotechnology Issues — Fifth Wave, (December 2001). (Return to document)

⁸³  Canada's Research-Based Pharmaceutical Pharmaceutical Companies estimates that it costs $1.3 billion to bring a new drug to market. From the "Facts you should know" section of their website. (Return to document)

⁸⁴  Joseph Cortwright and Heike Mayer, Signs of Life: The Growth of Biotechnology Centres in the United States, The Brookings Institution Center on Urban and Metropolitan Policy (2002), p. 5, Executive Summary. (Return to document)

⁸⁵  Ernst & Young, Beyond Borders (2005), Top Biotechnology Centres. (Return to document)

⁸⁶  Biopharmaceutical Sector Competitiveness Framework, Industry Technology Roadmap Initiative, Preliminary Work, Industry Canada (May 2000). (Return to document)

⁸⁷  "Converging Science and Leadership: The Key to the Future," Canadian Biotechnology Human Resource Study (2004). (Return to document)

⁸⁸  U.S. Food and Drug Administration, Introduction or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products - March 2004. (March 2004).  (Return to document)

⁸⁹  "Public Investments in University Research: Reaping the Benefits," ACST (1999).  (Return to document)

⁹⁰  B.P. Clayman and J.A. Holbrook, The Survival of University Spin-offs and Their Relevance to Regional Development (2004). Centre for Policy Research on Science and Technology (CPROST), Simon Fraser University, 515 West Hastings Street, Vancouver, B.C. V6B 5K3 Canada. See also www.sfu.ca/cprost/docs/CFI%20spinoffs%20March2.doc  (Return to document)

⁹¹  Association of University Technology Managers, Technology Transfer at Canadian Universities: Fiscal Year 2001 Update (May 2003).  (Return to document)

⁹²  Biopharmaceuticals in Canada — Benchmarking of Canadian Biopharmaceutical Science and Technology, internal study prepared for Industry Canada (March 2003).  (Return to document)

⁹³  Dr. Chris Riddle, Commercialization Strategies of Canadian Universities and Colleges, Advisory Council on Science and Technology (March 2004). For a comprehensive study of university licensing practices in biotechnology, see Mark G. Edwards, Fiona Murray & Robert Yu, "Value Creation and Sharing among Universities, Biotechnology and Pharma", Nature Biotechnology, 21, (June 6, 2003) pp. 618–622. For data on licensing trends, especially the value difference between earlyand late-stage agreements, see the Recap website.  (Return to document)

⁹⁴  MacDonald & Associates Ltd., Where Does Biotech Fit? (2004).  (Return to document)

⁹⁵  Bruce Rassmusen, Alliance Opportunities for Australian Biotechnology, Pharmaceutical Industry Project Working Paper Series, No. 23, Centre for Strategic Economic Studies, Victoria University of Technology, Melbourne Australia (2004), p. 6, figure 3, citing Recap data.  (Return to document)

⁹⁶  See, for example, Leading in the Next Millennium, National Biotechnology Advisory Committee, Sixth Report, 1998, particularly Chapter Two and Appendix 1, Recommendations.  (Return to document)

⁹⁷  Kathryn Howard, Director General, Life Sciences Branch, Industry Canada, Presentation to BioteCanada Conference 2003: Adapting to the Times (May 29, 2003), slides 8–11.  (Return to document)

⁹⁸  Science and Technology Statistical Compendium, Science and Innovation Policy: Key Challenges and Opportunities, Meeting of OECD Committee for Scientific and Technological Policy at the Ministerial Level, (January 2004).  (Return to document)

⁹⁹  SECOR Consulting, From Research to Marketing: Conditions for the Maturation of University Research in the Life Sciences, report to BioQuebec (February 2005).  (Return to document)

¹⁰⁰  Roundtable on Seed/Pre-Seed Stage Venture Capital Financing and on Commercialization Skills, ACST Secretariat (March 2004).  (Return to document)

¹⁰¹  Ernst & Young, Beyond Borders (2003), p. 5.  (Return to document)

¹⁰²  A Schincariol, President and CEO, Viventia Biotech, Barriers to Success: Access to Financial and Human Resources, CEO Roundtable (11 April, 2003), Toronto, slide 17.  (Return to document)

¹⁰³  Harrison, op.cit., slide 11.  (Return to document)

¹⁰⁴  One example is the Small Business Industrial Research (SBIR) program designed to enable early-stage companies in strategic sectors to advance to proof-of-principle stages in order to maximize chances of successful commercialization.  (Return to document)