Surviving Change in the 21st Century Florida Association of Blood Banks Annual Meeting Richard R. Gammon, MD Medical Director

Learning Objectives Discuss past model of blood center operations Cover current challenges Give an overview of current and future opportunities

Past Model of Blood Center Operations

Ancient Times Prehistoric man Left drawings of himself pierced by arrows Aware of blood Fearful as life flowed red out of body of animal or enemy Cave of Lascaux Rossi’s Principles of Transfusion Medicine. 2009

Blood has Mystical Qualities Romans Fountain of youth Medea prepares cauldron of sacrificed black sheep Gives to Jason’s father Aeson His hair and beard…assumed the blackness of youth…limbs of vigour and robustness Bullfinch’s Mythology

Middle Ages 1492 Pope Innocent VIII on deathbed Physician used blood drawn from three boys 10 years of age to save life All died-no blood received

First Animal-to-Human Transfusion June 15, 1667 Jean Baptiste Denis Blood of lamb administered to 15 year-old boy – less impurities Boy had fever and lethargy Symptoms relieved by transfusion of 9 oz of blood

Denis’ Experience Performed transfusions on 3 additional patients Number 2 survived, but 3 and 4 did not Patient 4 – 34 year-old Anthony du Mauroy Experienced bouts of maniacal behavior Transfused blood of a calf two times

The Fate of Mr. du Mauroy Two months later he began to experience maniacal behavior Wife sought transfusion therapy Transfusion could not be accomplished and patient died the next day Wife tried to extort money from Denis or threatened a malpractice lawsuit Denis refused and an investigation was launched

…and the Answer Is? Madame du Mauroy had poisoned her husband with arsenic Judgment April 17, 1668 Denis was exonerated Madame du Mauroy was held for trial Transfusion should not be performed unless approved by the Physicians of the Parisian Faculty

Death of Washington by Howard Pyle 1700s-Early 1800s Within 10 years transfusion banned from England and France Leeches for phlebotomy common Contributed to death of George Washington Death of Washington by Howard Pyle

The Beginnings Early 1800s James Blundell London obstetrician Noted frequency of death after delivery

The Beginnings Performed 10 transfusions 5 were successful Developed devices to facilitate transfusion Against animal transfusions Blundell’s Gravitator

The Victorian Era Media used for transfusion Milk Cows Goats Human milk Abandoned when saline became available Adler J. 1892

Era of Modern Blood Banking 1900 Karl Landsteiner discovered ABO System 1913 Reuben Ottenberg Describes compatibility testing O as “universal”                                             Dr. Landsteiner

Wars and Technology Anticoagulants Sodium citrate - WW I ACD - WW II Indirect transfusion -- WWII Blood collected now Transfused later Soldier Receives Transfusion

Wars and Technology – WW I Battlefield Blood Bank

Transfusion WW I Blood Brothers- L'Illustration – 11/21/1914

War and Technology-World War II US begins “Plasma for Britain” project Dr. Charles Drew heads project 14 million units collected by war’s end

The Rise of the Community Blood Center 1937 Dr. Bernard Fantus established first blood storage facility Cook County Hospital in Chicago Blood bank Save in one place Obtain as needed

The Rise of the Community Blood Center 1941 Irwin Memorial Blood Bank opens First US community blood bank

Blood Centers The Early Days Donor Room Laboratory

Blood Centers The Early Days

The Creation of Components Move to component therapy/plastics Allows extended storage Multiple products from one donation

Derivative Therapy WW II – Cohn develops cold ethanol method of plasma fractionation Albumin, fibrinogen, globulin become available Clotting factor concentrates 1965 Pool discovered Factor VIII could be harvested from cryoprecipitate Hemophiliacs benefited greatly-reduced disability

Volunteerism 1962 Connection made between paid donations and posttransfusion hepatitis 1970 1970 January designated as National Volunteer Donor Month US moves to all volunteer donor base

The 1980s Discovered that HIV could be transmitted in blood – 20 month infant Up to 1% of single-donor unit transfusions were infected with HIV Public confidence in blood supply at all-time low Concern with slow action by regulatory/professional associations

The late 20th/Early 21st Century Improved testing methods Nucleic Acid Testing Introduced HIV (1999) Hepatitis C (1999) West Nile Virus (2003) Hepatitis B (2012)

2010s Error reduction Emerging pathogens Cellular Therapies Barcodes/RFID iTrace – FDA clearance 05/29/13 Emerging pathogens Hemovigilance Pathogen Inactivation Cellular Therapies Blood management http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm354186.htm 05/13

Current Challenges

Paradigm Shift B. Grigsby ABC Meeting 08/11

Hospitals Employ More Than 259,000 Physicians, Up 31% From 2000 Physicians hesitate to make decisions contrary to hospital since many are now employees R Umberstock ABC Meeting 03/13

Adapting to Change

Adapting to Change

More Change…

Affordable Care Act

Seizing Opportunity

Seizing Opportunity

Diversification J Fredericks. ABC Meeting 03/12

Diversification - Transplantation

Diversification – Transfusion Medicine Many blood centers have centralized production and outsourced testing

Opportunities – Current and Future

Role of the Blood Center ABC Webinar 12/08/10

Processing Services

Cord Blood Processing and Banking

The Possibilities

Cumulative Stem Cell Trials Worldwide

Cell therapy companies & their products ~300 therapeutic companies with ~250 cell-based therapies in the market or in some stage of clinical development. These therapies can be roughly broken down into the following stages*: ~110 Phase I ~70 Phase II ~30Phase III ~40 Commercial (marketed in at least one country) Only ~1/3 of the therapies currently marketed (~13) required and received regulatory approval. In contrast, an estimated 90% of the therapies in development are “products” requiring pre-market approval. __________________________________________________________________________________ * Note that these numbers are limited to industry-sponsored trials and may not capture fully products in early-stage trials where industry “sponsorship” is less than transparent. ABC Webinar 0212

Have the fundamentals changed? Cell therapy is here – instances of it being routine clinical practice & commercial There has been incremental success CT is now very much a part of individual, corporate, academic, policy, and financial consciousness CT is now part of routine clinical practice and commercial products Emerging metrics of a maturing industry (e.g., players, orgs, FDA, etc.) On financial sector’s radar Now working on second generation (not first generation) products. Very little of this was true 10 year’s ago.

Today’s Market

Raw Cellular Material Collection

Storage and Logistics

Regulatory

US blood centers: strengths / opportunities In 2011 independent blood centers grew cell therapy business from almost nothing to ~2,000 collections in ~35 sites generating >$3M in revenue on track to do ~$6M in 2012. The growth to-date is exclusively from patient-donor collections. This market is growing rapidly

US blood centers: strengths/opportunities Other cell-based opportunities exist (more-to-less synergistic): Custom allogeneic collections (e.g.., cells from diseased patients) Blood products (e.g.., plasma, etc.) Post-collection minimal manipulation cell processing (separation/isolation) Collection from cell sources such as cord blood, bone marrow Stem cell or tissue banking - cord blood, cord tissue, adult stem cell, tissue Manufacturing Collection/processing of other cell sources such as adipose, cadaveric, tissue Technology (e.g.., device or biologic) development / distribution Out-patient clinics (clinical infusion)

US blood centers: advantages A cohesive independent blood center network: Represents one the largest single network of collection centers in the world Represents the most collection centers with experience collecting for cell therapies Is comprised of centers staffed by personnel accustomed to working in an environment requiring strict regulatory compliance ISBT128-compliant Offers centralized contracting, training, implementation and ongoing central support regarding customer service, data tracking, etc.. Most commercially and technically flexible network of centers

US blood centers: weakness / threats Competitors are hungry for this business. Academic centers (sourcing and manufacturing) American Red Cross (dispersed sourcing and future manufacturing) Fresenius (dispersed sourcing (therapeutic apheresis arm)) HemaCare (dispersed sourcing) AllCells, Inc. (sourcing – single site) Synergy BioSolutions (sourcing – single site) Key Biologics, LLC (sourcing – single site) Lonza (sourcing – single site and manufacturing) PCT (manufacturing – sourcing in future)

Increasing financial pressures on healthcare US blood centers: impact of healthcare trends Increasing financial pressures on healthcare Cell therapy is big business now Core business declining volume & diminishing margins while novel areas represent double-digit CAGR = success will go to the nimble Lines between blood and cells and synthetics are blurring

Key drivers to success? Cohesion. Centralized administration and access for customers. Identifying leading centers for beta implementations / R&D. Having and demonstrating expertise with emerging technologies / systems. Demonstrating commitment to being commercially flexible and service-oriented. Participating in the field’s leadership & executive network

Where Might We Go In 10 years?

Summary

Provenge - Background Harm et al. ASFA meeting 2012 Study conducted at University of Pittsburg and ITxM Harm et al. ASFA meeting 2012

PROVENGE Processing Process repeated three times Full course is typically completed in one month

Mechanism of Action

Mononuclear Cell Collection

Patient Demographics

Results: Scheduling

Scheduling

Results: Collections

Conclusions University of Pittsburg and ITxM

Sports Medicine- Hope or Hype? Claims by athletes and doctors that increased popularity of PRP began winter of 2009 Two leading football players Recovered quickly and went on to play in the Super Bowl   Troy Polamalu USA Today 06/29/11 NY Times09/07/11 Hines Ward

More Questions Than Answers Testimonials from athletes and their doctors are not credible evidence Most injuries eventually recover on their own, so if a patient has a treatment and then gets better, would the person have recovered at the same time anyway? Or did the treatment actually slow the healing process? There is no way to know without a study that compares patients who were randomly assigned to have a treatment with a matched control

Costs Hundreds to thousands of dollars per injection Fails to heal, doctors often inject again and again Insurers usually do not pay, so patients pay out of their own pocket

Transfusion Medicine Reviews 2010; 24: 218-24 Current Studies Contradicting data are available in the literature with regards to PRP in wound healing Reported that the PRP injection in patient with Achilles tendinopathy did not result in greater improvement in pain and activity as compared to placebo injected with saline Transfusion Medicine Reviews 2010; 24: 218-24 JAMA 2010; 303: 144-49

Current Studies – New Zealand 53 adults (mean age 49, 53% men) with symptoms of unilateral mid-portion Achilles tendinopathy for at least three months. Participants were excluded if they had a history of previous Achilles tendon rupture or surgery or had undergone previous adjuvant treatments such as injectable therapies, glycerol trinitrate patches, or extracorporeal shockwave therapy BMJ 2013;346:f2310 doi: 10.1136/bmj.f2310 041813

Results 26 participants were randomly assigned to the treatment group 27 to the control group 50 (94%) completed the six month study, with 25 in each group Clear and clinically worthwhile improvements in the VISA-A score were evident at six months in both the treatment (change in score 18.7, 95% confidence interval 12.3 to 25.1) and control (19.9, 13.6 to 26.2) groups.

Results Overall effect of treatment was not significant (P=0.689) and the 95% confidence intervals at all points precluded clinically meaningful benefit or harm There was no significant difference between groups in secondary outcomes or in the levels of compliance with the eccentric calf strengthening program . No adverse events were reported.

Conclusions The administration of two unguided peritendinous autologous blood injections one month apart, in addition to a standardized eccentric training program , provides no additional benefit in the treatment of mid-portion Achilles tendinopathy.

Current Studies Activity of platelet-derived factors present in PRP could depend upon Quality of the PRP Quality of wound Type of wound Physiologic conditions of the patients (age) Other comorbidities Use of prescription drugs

Conclusions Premature to conclude that the variable results obtained using PRP are due to its inefficacy A large number of randomized clinical trials are essential to establish the importance and role of PRP under diverse conditions

Conclusions Clinicians and patients often want a magic bullet, and autologous blood products seem to satisfy many requirements of different parties They are easy to obtain and prepare, they seem to be safe and ethically and socially acceptable They are not doping, they are hyped by the media, and they allow large profit margins. Editorial Nicola Maffuli from Italy- Orthopedic surgeon editorial BMJ 2013;346:f2979 doi: 10.1136/bmj.f2979 (Published 10 May 2013)

Conclusions But do they actually work? Despite the findings of well conducted studies that suggest that they probably do not, it seems likely that they will continue to be widely used

Blood Center Approach Could be opportunity Proceed with caution Ensure you have protocol Establish way to recoup costs

Other Opportunities Mononuclear cells for in vitro use HPC collection and processing NMDP and private facilities T. Foster – Webinar 04/23/13

Phase III Clinical Trials Refractory angina and chronic myocardial ischemia Renal cell carcinoma Multiple sclerosis Prostate cancer Similar to Provenge but with some important variations

Phase III Clinical Trials Glioblastoma Recurrent glioblastoma Alzheimer’s disease Utilize plasma exchange for treatment

Cell Therapy Opportunities

Blood Management Program Evolution S. Benitez- Santana. Blood Management Summit 11/10

Cost of Allogeneic Blood Englewood Hospital Medical Center, Rhode Island Hospital, Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland), and General Hospital Linz (AKH; Linz, Austria), All major process steps, staff, and consumables to provide red blood cell (RBC) transfusions to surgical patients, including usage frequencies, and direct and indirect overhead costs contributed to per-RBC-unit costs between $522 and $1183 (mean,$761 $294). These exceed previously reported estimates and were 3.2- to 4.8-fold higher than blood product acquisition costs. Annual expenditures on blood and transfusion-related activities, limited to surgical patients, ranged from $1.62 to $6.03 million per hospital and were largely related to the transfusion rate. Mean per-unit acquisition costs included units that were wasted and additional services provided (e.g.., irradiation, washing, cytomegalovirus testing) as described in the text. Transfusion 2010; 50: 753-65

Beneficiaries of Blood Management Ordering of appropriate blood components Distribution, handling, and dispensing of blood components Administration of blood components Monitoring effects of blood components on patients Guidelines for Patient Blood Management. AABB Press 2011

Sample Collection Surprisingly high proportion of pretransfusion testing specimens are mislabeled or contain blood from a patient other than the one identified on the specimen label 1 in 165 samples being mislabeled 1 in 1986 samples with wrong blood in tube errors The samples with labeling errors or omissions are 40-times more likely to be of a different ABO type than the intended recipient

Blood Administration Practice Institutional policies and procedures must list the steps that should be taken before the initiation of a transfusion Physician’s order for the component and any special instructions regarding its preparation or administration Informed consent Patient identification Unit identification (number, product type, blood type, product modifications, and expiration date) Confirmation of correct association of unit to patient

Blood Administration Practice The risk of death as a result of mistransfusion from labeling or omission errors exceeds that of hepatitis C or human immunodeficiency virus (HIV) J. Carson. Ann Int Med 03/26/12

Blood Administration Practice Comprehensive “systems” approach is applied to all aspects of patient, sample, and unit identification to minimize risk of errors Advocate the use of routine audits to monitor the effectiveness of processes to ensure appropriate and accurate labeling and identification 3% patients have serological findings that require further investigation One recent study showed that 21 (7%) of the 309 patients scheduled for elective surgery did not have the type-and-screen sample tested before surgery TRANSFUSION 2011;51:2500-2509 www.blogszebra.com 06/13

Evaluating and Reporting Adverse Effects of Transfusion System to track and identify trends in adverse transfusion reactions and to ensure periodic auditing of such reactions Allows for proper evaluation of trends 2009 NBCUS

The Transfusion Committee AABB Audioconference 05/19/10

Peer Review Assess whether deviations from the transfusion guidelines are clinically justified Reveal practice patterns of over- and under-use that may benefit from an intervention to improve practice Concern with repeated patterns, not isolated incidents

Peer Review May lead the transfusion committee to question whether the guidelines are appropriate or should be modified Effective system of detecting new problems Any detected problems should be reported to the transfusion committee for further exploration

One Center’s Approach Cleveland Clinic Noted continuing high blood product utilization Transfusion of 2+ units of PRBCs common for patients with Hgb>10 g/dL Unreliable blood product usage data Difficult to assign blood product orders to specific physicians to identify usage Implemented CPOE inpatient data (Epic) Revised blood order practice Parker B. Blood Management Summit 11/10

Track By Hospital

Track by Department

Track By Physician

Blood Waste Management

Wastage Examined and tracked Involve a minimal number of components Most often involves products with shelf-lives of 24 hours or less Temperature-controlled containers outside of the blood bank Monitored for proper storage conditions 2009 NBCUS

Conclusions Blood management and utilization is a comprehensive program in transfusion therapy Based on the concept of continuous improvement and centered on the patient

Conclusions Consideration of many factors Patient’s status Laboratory results Evidence-based criteria Defined outcomes Physician and facility history Key to the development of a blood management strategy Improves quality and advances patient safety

A Donor Center: Attracting Donors Who Do Not Wish To See Blood The Cardeza Foundation for Hematologic Research, Thomas Jefferson University in Philadelphia, Pennsylvania, was formally incorporated in 1941 with an endowment from the Cardeza family. Thus a blood bank was established in the Cardeza Foundation. At that time blood was collected in glass bottles by a technician and a physician as shown in the figure (upper right). Universal precautions did not exist: no gloves were used, blood was collected in a hand-held glass bottle, the technician is set up for mouth suction, and the amount of blood to be collected appears to be determined by sight. Once the donor center was established, many donors were available but they were set aback by the sight of blood. The solution to the problem was to partition the donor center in such a way that the donor will not see blood and will not see other donors. Privacy might have been another reason for the partition. This practice continued to the late 1940s or early 1950s. Partitions to separate donors from collectors, rather than from each other, were introduced by Russia in the 1930s and were used in the USSR for many years. Moreover, the practice of donating blood through a window was used by the French in 1939 as was previously described in a transfusion medicine illustrated article. We are not aware, however, whether this practice was used somewhere else in the United States in addition to Philadelphia. Transfusion 2013; 53: 13

Richard.Gammon@oneblood.org 407-248-5097 direct line The End…Questions Richard.Gammon@oneblood.org 407-248-5097 direct line