Immunosenescence, Imflammaging, and Influenza: What frontline pharmacists need to know in order to improve health outcomes for the aging population

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1 Immunosenescence, Imflammaging, and Influenza: What frontline pharmacists need to know in order to improve health outcomes for the aging population Evolution of Influenza Vaccines: 1 Presenter Disclosure Presenter s Name: Ajit Johal BCPP, CDE, CTH I have the Relationships with commercial interests: Advisory Board/Speakers Bureau [AA Pharma] Funding (Grants/Honoraria) : [Eli Lily] Speaker/Consulting Fees: [Novartis, Boeringher Engelheim, UBC CPD, Mckesson Canada] Other: Current/past Employee of [UBC Faculty of Pharmaceutical Sciences] Investments: Investments in sponsor organization or entity with product in program Patent in product Speaking Fees for current program: I have received a speaker s fee from [Sanofi Pasteur] for this learning activity 1

2 Commercial Support Disclosure This learning activity has received in-kind support from [Sanofi Pasteur] in the form of [logistical support, educational grants]. Learning Objectives Provide an overview of influenza and influenza vaccines in Canada Understand influenza and the influenza vaccines Provide an overview of High-Dose Vaccine 4 2

3 Overview Introduction: Why do we care? Influenza in Adults over 65: Rationale for a different approach High-Dose Influenza Vaccine: A new option for adults over 65 Conclusions 5 Introduction Influenza.. Why do we care? 6 3

4 COLD vs. FLU SYMPTOMS Coughing, sneezing, runny nose General aches and pains Extreme fatigue Fever Potential complications Adapted from: Public Health Agency of Canada Is it a cold of the flu? Accessed at: 7 Potential Complications of Influenza DIRECT effects: Respiratory INDIRECT effects: Multi-Organ Systems TRIGGER for: Asthma & COPD exacerbations 1 Acute myocardial infraction 2,6, Ischemic heart 4,6 disease, and Cerebrovascular disease 4,6 Ear/Sinus Infection 3,5 EXACERBATION of: Bronchitis & Pneumonia 1,5 Renal disorder 1 and Diabetes 1 References: 1. National Advisory Committee on Immunization (NACI): Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for Public Health Agency Of Canada. (October 18, 2016). Retrieved October 31, 2016 from : 2. Barnes, M. et al. Acute myocardial infarction and influenza: a meta-analysis of case-control studies. Heart. 2015;101(21): Conner, L.A. The Symptomatology and Complications of Influenza. JAMA. 1919;73(5): Glezen WP, Payne AA, Snyder DN, Downs TD. Mortality and influenza. J Infect Dis 1982;146: Jpmh.org. N.p., Web. 4 Apr Jefferson, T. et al. Neuraminidase inhibitors for preventing and treating influenza in health adults: systematic review and meta-analysis. BMJ 2009;399: Udell JA. et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA Oct 23;310(16):

5 As Front-line Pharmacists... BC Pharmacists have demonstrated tremendous value to public health prevention by taking responsibility for immunizing the population against seasonal influenza. Talk to your pharmacist they re your #1 resource this cold and flu season! BCPHA bulletin (1) Did you know that community pharmacies provide the most easily accessible influenza vaccine administration available in BC? BC College of Pharmacists Readlinks (2) In addition to providing convenient vaccination sites, community pharmacies are a major resource during flu season, offering immunization education, and over-the-counter medication to help with flu or cold symptoms. BC College of Pharmacists Readlinks NAME OF PRESENTATION 9 NACI Statement Recommended Recipients of Influenza Vaccine Recommended for everyone 6 months and older without contraindications. To reduce the morbidity and mortality associated with influenza, immunization programs should focus on those at high risk of influenza-related complications An Advisory Committee Statement (ACS) - Statement on Seasonal Influenza Vaccine for

6 NACI Recommendations: People at high risk of influenza-related complications or hospitalization Adults >65 & Nursing home Residents Diabetes Anemia Hemoglobinopathy All Children 6 to 59 Months Healthy Pregnant Women Morbidly obese Aborginals Children (<18) with Neurological conditions Renal Disease Cancer/Immune Compromised Patients Cardiac/Pulmonary Disorders (eg: Asthmatics) NACI Recommendations: People capable of transmitting influenza to those at high risk Health care & other providers Household contacts of those at high-risk Child care giver to kids <59 months Service providers in close proximity to high-risk individuals An Advisory Committee Statement (ACS) - Statement on Seasonal Influenza Vaccine for

7 Influenza in Adults over 65: Rationale for a different approach 13 Older Canadians suffer disproportionately from influenza-related morbidity and mortality While adults over 65 represent just 15% of the Canadian population 1...they experience: 70% of influenza-related hospitalizations AND >90% of influenza-related death 2 References: 1. Statistics Canada Population projections: Canada, the provinces and territories, 2013 to Available at: Accessed on October 8, Public Health Agency of Canada (PHAC). FluWatch. May 3 to May 9,

8 BC Overview: Seniors 15 BC Seniors Guide 11 th Edition Published In , hospitalizations caused by influenza A and B were highest among adults over 65 1 Cumulative number of hospitalizations with influenza reported by the participating provinces and territories, Canada, but influenza A, especially H3N2, was by far the leading cause of hospitalization among seniors. Reference: 1. Public Health Agency of Canada (PHAC). FluWatch. August 16 to August 29, Adapted from Public Health Agency of Canada (PHAC). FluWatch

9 Comorbidities Increase Mortality from Influenza amongst Older Adults1 Death rates from influenza and pneumonia among persons 65 years of age: Epidemics in , Deaths per 100,000 population References: 1. Barker WH, Mullooly JP. Arch Intern Med. 1982;142(1): None 1 2 Number of high-risk conditions 17 Influenza Worsens Comorbidities 1-3 Among those without comorbidities, influenza can lead to new infections such as secondary bacterial pneumonia, increase the risk of cardiac complications, etc. Among those with comorbidities, influenza often aggravates existing chronic illness, such as: Congestive heart failure Chronic Obstructive Pulmonary Disease (COPD) Asthma Diabetes Deaths from influenza-related complications are typically attributed to these underlying or secondary illnesses References: 1. CDC. Accessed January 17, CDC. Accessed January 16, Capua I, et al. J Virology 2013;87(1):

10 Hospitalizations attributed to influenza, by most responsible diagnoses Seniors 65+ Average annual admissions Influenzaattributed Pneumonia ( ) 44, Influenza (487) 1, COPD ( ) 22, ARI ( ) 5, Asthma (493) 6, Congestive heart failure (428) 54, Years included in analysis: (Canada) Schanzer et al. (2008) Role of influenza and other respiratory viruses in admissions of adults to Canadian hospitals. Influenza and Other Respiratory Viruses 2(1), Co-morbidities Associated with Influenzaattributed mortality For adults aged 65 years and over, the risk for influenzaattributed death was 1 : 5x 12x Greater among those with chronic heart diseases Greater among those with chronic lung diseases 20x Greater among those with both chronic heart and lung conditions 1.An Advisory Committee Statement (ACS)/National Advisory Committee on Immunization (NACI): Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for Schanzer DL, et al. Co-morbidities associated with influenza-attributed mortality, , Canada. Vaccine. 26 (2008)

11 Influenza Inflammation Potential AMI High-risk Plaque Formation Infections like influenza may result in exacerbation of underlying inflammatory processes of athlerosclerosis The influenza virus has extensive effects on inflammatory and coagulation pathways, which might lead to destabilization of vulnerable atherosclerotic plaques and thus coronary artery occlusion the major cause of acute myocardial infarction (AMI) 3 4 Inflammation Plaque Rupture Coagulation Cascade Acute Coronary Syndrome 3 Severe inflammation during acute infection References: 1.Madjid M. Eur Heart J. 2007;28 (10): Ross R. Nature. 1993;362(6423): Warren-Gash C, et al. Lancet Infect Dis. 2009;9(10): Harskamp RE, van Ginkel MW. Ann Med. 2008;40(2): Phrommintikul A, et al. Eur Heart J. 2011;32(14): Why are Adults 65+ at Greater Risk of Influenza and Related Complications? Immunosenescence is the natural and progressive weakening of the immune system over time. 1 This results in: Higher risk and severity of infectious diseases Lower responsiveness to vaccines 2 Immunosenescence renders vaccines less effective for seniors, making seniors more vulnerable to influenza 22 References 1. FLUZONE High-Dose vaccine. Product Monograph. Sanofi Pasteur Inc.; September Public Health Agency of Canada (PHAC). Canadian Immunization Guide. General Guidelines Accessed December 4,

12 Standard-Dose Influenza Vaccine Effectiveness by Age 1 During the influenza seasons shown, the range of vaccine effectiveness was 62% to 76% in persons years of age and 26% to 52% in those 65 years of age Reference: 1. Monto AS, Ansaldi F, Aspinall R, et al. Influenza control in the 21st century: optimizing protection of older adults. Vaccine. 2009;27: High-Dose Influenza Vaccine: A new option for adults over 65 Evolution of Influenza Vaccines: 24 12

13 FLUZONE High-Dose Vaccine: Canadian Regulatory Update FLUZONE High-Dose Vaccine was approved in Canada on September 9, 2015 INDICATION: FLUZONE High-Dose is indicated for active immunization against influenza caused by the specific strains of influenza virus contained in the vaccine in adults 65 years of age and older. HIGHLIGHT: FLUZONE High-Dose vaccine demonstrated superior efficacy compared to FLUZONE in preventing laboratoryconfirmed ILI 25 FLUZONE High-Dose Vaccine 1 Developed in response to requests for a more immunogenic/effective vaccine for seniors 60 mcg hemagglutinin (HA) of each influenza strain per 0.5 ml dose (4 times that of standard-dose influenza vaccines) (15 mcg HA/strain) Trivalent, inactivated, split-virus influenza vaccine No adjuvant, antibiotic, gelatin, or preservative Format: Single-dose, 0.5 ml, prefilled syringe Supplied in packages of 10 prefilled syringes Available in Canada as of Reference: 1. Fluzone High-Dose vaccine Canadian product monograph 26 13

14 FIM12: Post-Licensure Efficacy Trial 1,2 Post-licensure commitment study to compare the clinical efficacy of Fluzone High-Dose vaccine and Fluzone vaccine Randomized and blinded trial ~32,000 participants 65 years of age enrolled in 126 study sites in the US and Canada Trial spanned 2 influenza seasons ( and ) Participants randomized 1:1 to receive 1 dose of Fluzone High-Dose vaccine or Fluzone vaccine and then followed for illness until the end of each season Serious adverse events (SAEs) were collected for 6 months post-vaccination References: 1. Clinicaltrials.gov. Accessed April 13, DiazGranados CA, et al. N Engl J Med. 2014;371(7): FLUZONE High-Dose Efficacy Trial Design (FIM12) RCT 126 centers US & Canada Adults 65 years of age N = 32,000 Intervention / Control 16,000 Fluzone High-Dose 1:1 ratio 16,000 Fluzone Endpoint Influenza No Influenza Influenza No Influenza Time D0 (Sep-Oct) 6-8 months April 30 Study conducted over two influenza seasons Primary endpoint based on influenza caused by any influenza strain associated with a protocol-defined ILI Study powered to identify a sufficient number of laboratory-confirmed influenza cases for the primary endpoint 28 14

15 Primary Analysis: Relative Efficacy (FIM12) Laboratory-confirmed influenza caused by any viral type or subtype (regardless of similarity) a Fluzone High-Dose N=15,892 n (%) Fluzone N=15,911 n (%) Relative Efficacy % (95% CI) Associated with PD ILI b 228 (1.4) 301 (1.9) 24.2 ( ) Lower limit of the 95% CI of relative efficacy = 9.7% Pre-specified lower limit required by FDA to demonstrate superior clinical benefit > 9.1% This is the only analysis for which the study was powered a Per-protocol analysis set b Protocol-defined influenza-like illness DiazGranados et al, N Engl J Med 2014;371: Evolution of Influenza Vaccines: 29 How effective is FLUZONE High-Dose among older seniors? Evolution of Influenza Vaccines: 30 15

16 Relative Efficacy against Confirmed a Influenza of FLUZONE High-Dose to Standard Dose FLUZONE Vaccine: By Age All participants: 65 years of age and older Fluzone High-Dose N=15,990 n (%) Associated with PD ILI b 228 (1.43) 301 (1.88) 24.2 (9.7; 36.5) Participants 65 through 74 years of age Fluzone High-Dose N=10,581 Fluzone N=10,563 Relative Efficacy Associated with PD ILI b 156 (1.47) 194 (1.84) 19.7 (0.4; 35.4) Participants 75 years of age and older Fluzone High-Dose N=5409 Fluzone N=15,993 n (%) Fluzone N=5430 Relative Efficacy % (95% CI) Relative Efficacy Associated with PD ILI b 72 (1.33) 107 (1.97) 32.4 (8.1; 50.6) a Laboratory-confirmed influenza caused by any viral type or subtype (regardless of similarity); full analysis set (subjects categorized as randomized). b Protocol-defined influenza-like illness Reference: 1. DiazGranados et al, Vaccine 2015; 33: , Table 2 31 How effective is FLUZONE High-Dose among Frail Seniors or those with co-morbidities? Evolution of Influenza Vaccines: 32 16

17 Relative Efficacy against Confirmed a Influenza of FLUZONE High-Dose to Standard Dose FLUZONE Vaccine: By Number of Baseline Frailty Conditions Associated with PD ILI b No Frailty Condition One Frailty Condition 2 Frailty Conditions 3 Frailty Conditions Fluzone High-Dose n/n (%) Fluzone n/n (%) Relative Efficacy % (95% CI) 29/2129 (1.36) 44/2132 (2.06) 34.0 (-7.9; 60.2) 71/4988 (1.42) 96/4893 (1.96) 27.5 (0.4; 47.4) 56/3970 (1.41) 75/4046 (1.85) 23.9 (-9.0; 47.2) 72/4903 (1.47) 86/4922 (1.75) 16.0 (-16.3;39.4) a Laboratory-confirmed influenza caused by any viral type or subtype (regardless of similarity); full analysis set (subjects categorized as randomized). b Protocol-defined influenza-like illness Reference: 1. DiazGranados et al, Vaccine 2015; 33: , Table 2 33 Relative Efficacy against Confirmed a Influenza of FLUZONE High-Dose to Standard Dose FLUZONE Vaccine: By Baseline Co-Morbidity Associated with PD ILI b No High-Risk Comorbidities One High-Risk Comorbidity 2 High-Risk Comorbidities 1 High-Risk Comorbidities Fluzone High-Dose n/n (%) Fluzone n/n (%) Relative Efficacy % (95% CI) 66/5240 (1.26) 93/5241 (1.77) 29.0 (1.6; 49) 82/5365 (1.53) 103/5349 (1.93) 20.6 (-7.1; 41.3) 80/5385 (1.49) 105/5403 (1.94) 23.6 (-3.2; 43.6) 162/10,750 (1.51) 208/10,752 (1.93) 22.1 (3.9; 37.0) a Laboratory-confirmed influenza caused by any viral type or subtype (regardless of similarity); full analysis set (subjects categorized as randomized). b Protocol-defined influenza-like illness Reference: 1. DiazGranados et al, Vaccine 2015; 33: , Table

18 How might FLUZONE High-Dose Perform in an A-strain mismatch year? Evolution of Influenza Vaccines: 35 Relative Efficacy against Confirmed a Influenza of FLUZONE High-Dose to Standard Dose FLUZONE Vaccine: By Study Year Low Activity; High Match High-Activity; Low Match HD N=7253 n (%) Year 1 Year 2 SD N=7244 n (%) Associated with PD ILI b 32 (0.32) 42 (0.58) Relative Efficacy % (95% CI) ( ) HD N=8737 n (%) SD N=8749 n (%) 205 (2.35) 259 (2.96) Relative Efficacy % (95% CI) ( ) a. PD-ILI: Protocol-Defined Influenza-like Illness The authors concluded that this, finding provides reassurance that the benefit of [High-Dose vaccine] persists despite varying seasonal conditions. 1 References: 1. DiazGranados CA, et al. N Engl J Med. 2014;371(7):

19 Was there any impact on other outcomes during the RCT? Evolution of Influenza Vaccines: 37 Hospitalization and Cardio-Respiratory Serious Events FLUZONE High-Dose vs FLUZONE Vaccine (FIM12) Affected Subjects (Rates a ) rve% (95%CI) IIV-HD (N = 15,990) IIV-SD (N = 15,993) Both Seasons Combined All-cause hospitalization 1530 (95.68) 1643 (102.73) 6.9 (0.5; 12.8) Serious cardio-respiratory events 428 (26.77) 520 (32.51) 17.7 (6.6; 27.4) Pneumonia events 71 (4.44) 118 (7.38) 39.8 (19.3; 55.1) Asthma/COPD/bronchial events 74 (4.63) 75 (4.69) 1.3 (-36.0; 28.4) Influenza events b 4 (0.25) 6 (0.38) 33.3 (-136.2; 81.2) Coronary artery events 121 (7.57) 124 (7.75) 2.4 (-25.3; 24.0) Congestive heart failure 57 (3.56) 75 (4.69) 24.0 (-7.2; 46.1) Cerebrovascular events 72 (4.50) 77 (4.81) 6.5 (-28.9; 32.1) Other respiratory events 31 (1.94) 47 (2.94) 34.0 (-3.8; 58.1) a. Events per 1000 participant-seasons. b. Serious laboratory-confirmed influenza diagnosed outside study procedures by participant's health-care provider. Ref: 1. DiazGranados et al, Vaccine 2015;33: ; data from Tables 1 and

20 Safety Profile Evolution of Influenza Vaccines: 39 Safety: Frequency of Solicited Injection-site Reactions, 0-7 Days Post-vaccination (FIM05) 1, Pain Erythema Swelling References: 1. FLUZONE High-Dose Influenza Virus Vaccine Trivalent Types A and B (Split Virion) Product Monograph. Date of Approval: September Falsey A, et al. J Infect Dis. 2009;200(2):

21 Safety: Frequency of Solicited Systemic Reactions, 0-7 Days Post-vaccination (FIM05) 1, Myalgia Malaise Headache Fever References: 1. FLUZONE High-Dose Influenza Virus Vaccine Trivalent Types A and B (Split Virion) Product Monograph. Date of Approval: September Falsey A, et al. J Infect Dis. 2009;200(2): FLUZONE High-Dose Vaccine Safety Data (FIM12): Safety Results, Entire Study Period a Fluzone High-Dose (N=15,992) Fluzone (N=15,991) Subjects experiencing at least one: n % n % SAE Related SAE 3 b AE of Special Interest (AESI) 3 c d 0.04 SAE leading to study discontinuation Death (any cause) a Full analysis set (subjects categorized by vaccine received) b Related SAEs: Fluzone High-Dose group: left cranial nerve VI palsy (Day 1), hypovolemic shock with diarrhea (Day 1), and acute disseminated encephalomyelitis (ADEM; Day 117) c AESI: Fluzone High-Dose group: Bell s palsy, ADEM, and Stevens-Johnson Syndrome (Days 53, 117, and 166) d AESI: Fluzone group: 5 cases of Bell s palsy (Days 9 through 204) and 1 case of Guillain-Barré Syndrome (Day 95) 42 21

22 US Experience with Fluzone High-Dose Fluzone High-Dose has been licensed in the US since 2009 By the influenza season, 50 million Approximate number of doses of Fluzone High- Dose distributed in the US since % of adults 65+ in the US who receive an influenza vaccine will be vaccinated with Fluzone High-Dose References 1.Sanofi Pasteur Inc. Data on file. Fluzone High-Dose. Doses Distributed Izurieta et al: Effectiveness of Fluzone High-Dose Vaccine Among US Medicare Recipients, FDA, CDC, and CMS Study: Identified Medicare beneficiaries 65 years of age who were immunized at community pharmacies during the season The study included 929,730 Fluzone High-Dose recipients and 1,615,545 standarddose influenza vaccine recipients 22% more effective in preventing probable influenza, based on rapid influenza test and oseltamivir Rx 22% more effective in preventing influenza inpatient hospital admission or emergency department visit 1. Izurieta HS et al. Lancet Infect Dis 2015;15: , Figure 3 22

23 2016/2017 NACI Seasonal Influenza Statement Based on the available evidence, NACI concludes that there is evidence that high dose TIV should provide superior protection compared with standard dose TIV for adults 65 years of age. This superior relative protection compared to standard dose TIV appears to increase with increasing age over 65 years. A similar conclusion has not been reached for adjuvanted TIV. Considering the burden of disease associated with influenza A(H3N2) and the evidence of superior efficacy of high dose TIV compared to standard dose TIV, it appears that high dose TIV would provide the greatest benefit to the 65 years age group. Reference 1.An Advisory Committee Statement (ACS)/National Advisory Committee on Immunization (NACI): Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for FLUZONE High-Dose Vaccine Evidence for Immunization of Adults over 65 FAVOURABLE SAFETY PROFILE: Demonstrated safety in multicenter, double-blind clinical trials (pre- and post-licensure in the US; some higher reported local and systemic AEs; lower SAEs than SD. SUPERIOR EFFICACY RELATIVE TO STANDARD-DOSE TIV: 24.2% more efficacious compared with Fluzone in older adults >65 years of age regardless of antigenic similarity to vaccine strains Evidence of consistent levels of relative efficacy across age, frailty and comorbidities Lower rates of serious events (Hospitalization and Cardio-Respiratory Serious Events) PUBLIC HEALTH IMPACT and REAL-WORLD EXPERIENCE: Comparative effectiveness studies support Fluzone High-Dose s impact on adult over 65 Available in the U.S. over 5 years; broadly reimbursed since licensure in 2009 ~50M doses distributed since 2009; ~50% of immunized persons 65 years of age and older received Fluzone High-Dose vaccine last year in the U.S. ( ) Cost-savings demonstrated through head-to-head piggy-back trial analysis (mainly from reductions in hospitalizations relative to standard-dose vaccine)

24 Take Home Message to Improve the Health of your patients! 1. Education: Immunosenesence, Comorbidities, Inflamaging and the domino effect Seriousness of influenza -> pneumonia and influenza are only second to CVA & CHF in terms of significant impact on ADL and loss of independence.* Vaccines are available both in funded programs and as a private option**. 2. Establish an efficient patient oriented plan. Optimize existing access opportunities, rework intake sheets, preplan 3. Partnership in the concept of healthy aging: Healthy aging versus vulnerability & frailty -> new choices & how to manage risks Acknowledge fear of loss of independence and empower by educating**. NAME OF PRESENTATION 47 Approved But Non Funded Vaccines The greatest need is to change the widespread perception that vaccines should be publicly funded or ignored. The long-standing and total dominance of population over individual considerations for vaccines needs to end or the potential benefits of some vaccines will not be realized, to the detriment of those at risk. It is a form of discrimination against vaccines compared with (preventive) drugs that urgently needs to be corrected 24

25 Cost-Effectiveness of Canadian Vaccine Programs 1 Fluzone HD expected to be dominant (cost-saving and more effective) compared to the SD TIV in adults 65+ *QALY: Quality-adjusted Life Years NR: Not reported D: Dominant: The intervention costs less and is at least as effective as the comparator. Cost-effectiveness: defined by Canada s implicit threshold of $20,000/QALY 100,000/QALY 3 Categories of cost-effectiveness Cost-effective: <$20,000 CAD/QALY Probably cost-effective: $20,000 CAD/QALY $100,000 CAD/QALY Not cost-effective: >$100,000 CAD/QALY. References 1. Chit A, Lee JK, Shim M, Nguyen VH, Grootendorst P, Wu J, Van Exan R, Langley JM. Economic Evaluation of Vaccines in Canada: A Systematic Review. Human vaccines & immunotherapeutics Feb 1 2. Chit A. et al., High-Dose Inactivated Influenza Vaccine is Associated with Cost Savings and Better Outcomes Compared to Standard-Dose Inactivacted Influenza Vaccine in Seniors, ISPOR, Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ 1992;146(4): Note: The intervention described in the 2011 Hepatitis B study involved the screening of immigrants arriving at Canada for chronic Hepatitis B, followed by treatment or vaccination Cost-Effectiveness of Recently Reimbursed Prescription Drugs in Canada (updated May 2016) References: 1. Canadian Agency for Drugs and Technologies in Health (CADTH). CADTH Common Drug Review (CDR) Reports. Accessed May 01, Canadian Agency for Drugs and Technologies in Health (CADTH). CADTH pan-canadian Oncology Drug Review (pcodr) Reports. Accessed May 01,

26 Be Proactive with your local community! NAME OF PRESENTATION 51 Thank You! 26