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Project Management: Regulatory Affairs and Clinical Trials Class Presentation - Round 2 of Prodcut Development

Project Management: Regulatory Affairs and Clinical Trials Class Presentation - Round 2 of Prodcut Development


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  • 1. Technology: Hematology Lead Product: Blood BackUp
  • 2. BioPharmic to Present Blood Substitute Strategy at RENN Capital Investor Conference Aug 11, 2009 9:00am EDT, Washington D.C.
    • “ Although first generation blood substitutes' have failed due to toxicity problems, the blood substitute technology of BioPharmic’s, Blood BackUp, has the potential to be the first viable blood substitute”.
    • “ In fact on July 29 at an FDA meeting on blood substitutes, the FDA indicated that first generation products were toxic and there was a need for a new generation. The approach used in Blood BackUp was cited by the FDA as a strategy for a new generation product”.
    • “ To help address its global strategy, BioPharmic has recently added to its Scientific Advisory Board, Dr. Roscoe Moore, former US Assistant Surgeon General, who has extensive experience in domestic and global health issues and is assisting the company in further development of Blood BackUp and addressing the global need for a blood substitute”.
  • 3. BioPharmic Announces Results of All Blood BackUp Animal Studies Washington D.C., BUSINESS WIRE, Sep. 16, 2009
    • “ BioPharmic announced today that the company has received all results from animal studies involving Blood BackUp, the blood substitute and therapeutic oxygen carrier the company is developing”.
    • “ The results were in line with expectations based on both screening animal studies the company conducted previously and on published studies with other blood substitutes”.
    • “ The results shows that Blood BackUp is safe, even at doses significantly above those shown to be clinically effective”.
    • “ We are pleased with the outcome which confirms that Blood BackUp is safe and we can begin clinical testing on schedule,” said Dr. Heather Juhan, president and CEO.
  • 4. GRAND Opening
    • The official opening of our first manufacturing plant in Washington D.C.
    • Opening of our manufacturing and distribution plant in Galveston, Texas.
  • 5. Microsoft Office Project
  • 6. Lack of Blood in the U.S.
    • Community Hospital of the Monetary Peninsula CA October 2009 “Blood donations of all types, especially O and A positive, are needed at Community Hospital of the Monterey Peninsula’s Blood Center, and the need is CRITICAL……..”
    • Antelope Valley Hospital 2009 Wyoming “Blood Donor Center is reporting a critical shortage of O-negative blood.
    • Colorado Springs Hospitals are calling for blood.
    • Summer months are traditionally tough on blood blanks, and Memorial and Penrose-St. Francis report that blood is in short supply. 2009
  • 7. Lack of Blood in the U.S.
    • New York Hospital Queens 2009 “National Blood Donor Month and there is a need for eligible donors to roll up their sleeves and contribute a pint of blood for the well-being of communities….. almost 5 million people in the United States receive blood transfusions requiring almost 14 million units of whole blood and red blood cells……..
  • 8. Problems Encountered This Past Round
    • 1) The FDA has determined that Blood BackUp is a biologic and it has to be tested against whole blood and there are safety concerns about the use of expired human blood (viruses and prions).
    • 2) There is instability of the 2 components when they are mixed together.
  • 9. Expired Blood?
    • The use of expired blood is one of the most unique ideas, but perfecting the use of expired blood is not an easy task.
    • There have been concerns about Prions and Viruses in the expired blood.
    • Once again, all expired blood has to be processed or begun the purification process 26 days after the expiration date.
  • 10. Expired Blood?
    • The removal of viruses from expired blood is performed by a process known as Virus Filtration.
    • Virus Filtration is a type of Ultra Filtration that is used for the removal of viruses from protein molecules, such as PrPc which is found on the membranes of cells.
    • For the other types of viruses, a process known as Diafiltration is used.
  • 11. Expired Blood?
    • Diafiltration is a separation process that washes smaller molecules through the filter leaving behind larger molecules without changing the concentration.
    • After the Diafiltration process, which removes any potential prions, the solution is placed in a Glutaraldehyde Polymerization.
    • Patent Number: US 8,877,761 B1 approved on 10/17/09
  • 12.  
  • 13. Stability of Blood BackUp
    • In initial formulation, there was a slight instability with the Erythropoietins and our modified blood.
    • The problem we were facing was the instability of the rHuEPO that was being added after the filtration process.
    • To remedy this problem, our team decided to add the rHuEPO before the filtration process.
    • For the next 1000 units produced, our product showed a significant increase in stability.
  • 14. Stability of Blood BackUp
    • We discovered the problem was that if the Erythropoietin was added after filtration ,the chance of prions modifying was increased.
    • The instable blood was examined and revealed PrP Sc to be present.
    • Addition of Erythropoietin before the filtration was important because a pathogenic agent, g55, encoded by the env gene was present in the blood.
    • The problem is that g55 mimics and binds to the Epo receptor.
    • If g55 binds to the Epo receptor, it promotes proliferation instead of differentiation as EPO does.
  • 15.  
  • 16. Scale-Up
    • Shortened cycle to full-scale production
    • Competitive advantage
    • Cost Savings
    • Potential problems with all areas were addressed:
      • Asepsis
      • Construction
      • Validation
      • Processes
  • 17. Scale-Up
    • Aseptic Rooms, State of the Art
  • 18. Scale-Up
    • Our own PVC bag forming machine
  • 19. Scale-Up
    • The problems that we had encountered during scale-up:
      • The processes were not precise for the workers which lead to slower production rates.
      • SOP’s had to be updated for each of the processes.
      • The amount of blood being supplied varied greatly.
  • 20. Animal Studies Demonstrating Safety and Effectiveness
    • Summary of Study
    • We had 2 groups of 10 dogs each. The first group was given donated red blood cells, and the other group was given BloodBackUp.
    • Blood was withdrawn from each dog to the point that their bodies were deprived of oxygen, and blood transfusion was required.
    • The first group was given donated red blood cells, and the other group was given Blood BackUp.
    • The Blood BackUp was able to restore oxygen to the bodies of the dogs safely and effectively just as the donated red blood with no adverse events.
  • 21. PRECLINICAL/ANIMAL STUDIES CONT.
    • TITLE: Intravenous administration of Blood BackUp to assess the safety, toxicity, and effectiveness.
    • DESIGN OF STUDY:
    • Purpose of Study : To confirm that BloodBack Up is safe, non-toxic, and effective.
  • 22. PRECLINICAL/ANIMAL STUDIES
    • Test Animals: 72 Blood hounds were divided into 3 groups of 24 dogs each.
    • Groups:
      • Group 1 : Banked red blood cells (stored for 2 weeks),
      • Group 2 : Fresh Blood
      • Group 3 : HBOC (HBOC-Hemoglobin Based Oxygen Carriers + Recombinant Human Erythropoietin (rHuEPO) Blood Back Up .
  • 23. PRECLINICAL/ANIMAL STUDIES CONT.
    • Methods: Blood was withdrawn from each dog to the point that their bodies were deprived of oxygen, and blood transfusion was required.
    • Dosage Form: Injectable
    • Route of Administration: Intravenous
    • Dosage Used: Dependant of the amount of blood withdrawn.
  • 24. PRECLINICAL/ANIMAL STUDIES CONT.
    • Test Duration: 48hrs
    • Observation: Dogs were monitored after 72 hours to still check for any unusual reaction.
    • Pertinent Parameters: Skeletal muscle oxygen tension immediately following administration.
  • 25. RESULTS
    • SAFETY AND TOXICITY
    • 8 dogs were sacrificed from each test group to evaluate safety and toxicity, after 48 hours of treatment. There were no adverse events following treatment .
    • Blood and Tissue samples were collected from these sacrifices, they included: bone marrow, brains, heart, lungs, and kidneys. There were no unusual clinical observations of the body/organs comparable to the controls, showing safeness and no toxicity.
  • 26. RESULTS CONT.
    • 72 hours later this same procedure was done (4 dogs were sacrificed this time) and there were no unusual clinical observations of the body/organs comparable to the controls, also showing safeness and no toxicity.
  • 27. RESULTS CONT.
    • EFFECTIVENESS
    • Tests were run on the Blood BackUp group to measure the oxygen levels (using an oximeter) to verify that Blood BackUp was successfully transporting oxygen and carbon dioxide in out of the body respectively. Hemoglobin Plasma Levels were also measured to see if Erythropoietin was increasing the amount of red bloods cells. Measurements showed that all these indications were successfully done by Blood BackUp.
  • 28. RESULTS CONT.
    • PHARMCOKINECTICS
    • This study was done in order to check what Blood BackUp does to the body. Blood BackUp is biodegradable and this is measured by the amount of oxygen Blood BackUp consumes (oximeter). This process was done on 8 dogs from the study. Blood BackUp remained in the dogs bodies until their oxygen levels started to decline. Based on the measurements Blood BackUp has a terminal half life of 24hrs.
  • 29. RESULTS CONT.
  • 30. IND APPLICATION SUMMARY
    •    INTRODUCTION             
    • Investigational Agent: Blood BackUp  
    •             
    • Dose and Exposure: Depending on Circumstance
    •              
    • Overview of Previous Human Experience: There were other HBOCs with serious cardiovascular adverse events.              
    • Overview of Preclinical Data: Animals Studies Results             
    •      
  • 31. IND APPLICATION SUMMARY CONT.
    • Chemistry and Manufacturing             
    • General Method of Preparation and packaging : Produce our own IV bags that are PVC-free          
    • Drug Components and Drug Product: Produced by using expired human blood obtained from blood banks and hospitals with addition of Recombinant Human Erythropoietin
    •        
    •   Placebo Product: Fresh Blood and Stored Blood                      
    • Labeling :   
    •   At h VN 2235/05.H6
    • P/N: 80.332 L/N: 060-00032
    • Store at Room Temperature
    • Caution: New Biologic-Limited by United States
    • Law to investigational use
    • Blood BackUp
    •          
  • 32. APPROVED APPROVED APPROVED FOR PHASE 1 CLINICAL STUDIES
  • 33. Clinical Trials PHASE I & II METHODS
    • The principal objectives of this study were:
      • Evaluate the effectiveness of Blood BackUp as a blood substitute in acute trauma and emergent surgery.
      • To compare directly the therapeutic benefit of Blood BackUp with that of allogeneic red blood cells (RBCs) in the treatment of acute blood loss.
      • To characterize safety and tolerability.
      • To determine the side effects associated with increasing doses of Blood BackUp.
  • 34. STUDY DESIGN
    • The study was conducted at Denver Health Medical Center and American College of Surgeon certified Level I adult trauma center.
    • The protocol was reviewed and approved by the Colorado Multiple Institutional Review Board.
    • Informed consent of the potential risks and benefits associated with this study was obtained from either the patient or appropriate surrogate in all enrollments.
    • The study was a prospective, non-randomized, open-label trial.
    • All patients were under the care of a Health Professional.
    • Male and female patients of at least 18 years of age were eligible for the study.
  • 35. STUDY DESIGN
    • The inclusion criteria included the following:
      • Blood loss due to acute trauma or urgent surgery.
      • Clinical decision for urgent transfusion in anticipation of low Hb.
      • Systolic blood pressure less than 100 mmHg due to blood loss.
    • The exclusion criteria included the following:
      • Sever head injury.
      • Lack of acute blood loss.
      • Signs or symptoms of preexisting organ dysfunction.
      • Clinically determined pregnancy.
  • 36. STUDY DESIGN
    • When a clinical decision was made to initiate transfusion, Blood BackUp was infused in lieu of allogeneic blood.
    • All infusions were supervised by the study coordinator to observe for any unexpected events in the course of the patient’s therapy.
    • The first 10 patients were eligible to receive 1 unit, 20 patients were eligible to receive up to 3 units, and the last 9 were eligible to receive up to 6 units of Blood BackUp.
    • The goal was adjusted as the study was proceeded to identify those patients who were likely to receive the maximum allowable dose.
    • After receiving the maximum eligible dosage of Blood BackUp, all patients completed any further necessary transfusion therapy with red cells transfusions as indicated. Infusion were given preoperatively, intraoperatively, and postoperatively; to both awake and anesthetized patients.
  • 37. MEASUREMENTS
    • Samples were obtained at pre-infusion, end of infusion, 12 hours, Day 1, Day 2, and Day 3.
    • Vital signs (temperature, blood pressure, heart rate)
    • Liver function (AST, ALT, bilirub)
    • Amylase
    • Renal function (creatinine clearance, creatinine) were measured.
    • Hematocrit, total hemoglobin, red cells hemoglobin, and plasma hemoglobin concentrations were determined using a Coulter JT and an IL CO-Oximeter Model 482.
  • 38. STATISTICAL METHODS
    • Results were compared at each stage of the study to the pre-infusion data using a paired t- test, or an unpaired t-test for the O 2 utilization data, and statistical significance was assessed at the p<0.05 level.
    • All data are expressed as mean +/- standard deviation.
  • 39. RESULTS
    • The 39 patients ranged in age between 19 and 83 years.
    • The 28 male and 11 female recipients represented all racial and ethnic backgrounds.
    • Twenty-two patients sustained blunt and penetrating trauma.
    • And 17 patients underwent non-trauma related surgery (aortic aneurysm, hepatic resection, portosystemic shunt, and hip replacement).
  • 40. BLOOD BACK-UP INFUSION
    • Infusion rates ranged from 1 unit in 175 minutes to 6 units (300mg) in 20 minutes, depending on the urgency of the situation.
    • Infusion were administered preoperatively (n=3), intraoperatively (n=23), and postoperatively (n=13) to both awake and anesthetized patients.
    • 39 patients received 1 (n=14), 2 (n=2), 3 (n = 15), 6 (n=8) units of Blood BackUp instead of stored red blood cells as part of their initial resuscitation after acute blood loss.
    • Three complaints of labile blood pressure or chills were documented, but subsequently re-occured with further administration of other blood products.
    • There were no significant safety issues or adverse events related to the infusion of Blood BackUp.
  • 41. HEMOGLOBIN DATA
    • The data for Hb was determined according to the following relationship:
      • Total Hb = RBC Hb + Blood BackUp Hb.
    • Each 50-gram, single-unit infusion of Blood BackUp raised the plasma hemoglobin approximately 1 g/dL, as shown in Table 1, maintaining total Hb as the RBC Hb fell as a result of progressive hemorrhage shown in Figure 1.
    Blood Back-up plasma Table 1. Hemoglobin concentration (g/dL) in study patients Blood Back-Up Figure 1. Data for total [Hb] and RBC [Hb] before and after Poly SFH-P infusion.
  • 42. OXYGEN UTILIZATION
    • The data for O 2 loading and unloading, and percent O 2 utilization at the end of Blood BackUp infusion is shown in Table 2. The mean RBC Hb was 7.2 +/-2.7 g/dL, and the Blood BackUp level was 2.4 +/- 1.4 g/dL.
    • The O 2 utilization from Blood BackUp injection was increased compared with the O 2 utilization from the red cells (p <0.05).
    Blood Back-up Table 2. O2 loading/unloading
  • 43. SAFETY
    • The data for temperature, mean arterial pressure (MAP), heart rate, and creatinine clearance are shown in Fig. 2, 3, 4, and 5.
    • There were no significant changes in any of these parameters, documenting the absence of any vasoactive properties of Blood BackUp.
  • 44. SAFETY Figure 5. Data for creatinine clearance before and after Blood BackUp infusion. Figure 3. Data for heart rate before and after Blood BackUp infusion. Figure 4. Data for mean arterial pressure before and after Blood BackUp infusion. Figure 2. Data for temperature before and after Blood BackUp infusion.
  • 45. SAFETY
    • The data for creatinine, AST, ALT, total bilirubin, and amylase are shown in Table 3 and 4.
    • There is a large variance in these parameters resulting from the many abnormal starting values due to the injuries.
    • Table 4 shows the data excluding those individuals who had abnormal preinfusion values, to assess the influence of Blood BackUp in the absence of preexisting pathologic condition.
    • The results indicate the lack of any change in these values after the infusion of Blood BackUp.
    • Acid-base status was assessed by an end-infusion arterial blood gas:
      • pH = 7.36 +/- 0.1 and PCO 2 = 35.9 +/-.
      • Lactic acid measurements were not done.
  • 46. SAFETY Table 3. Organ function for the entire population. Table 4. Organ function after excluding patients with abnormal pre-infusion values.
  • 47. BLOOD UTILIZATION
    • During the initial 24-hour period after blood loss and Blood BackUp infusion, 23 (59%) of the 39 patients avoided allogeneic blood exposure and were infused exclusively with Blood BackUp as the oxygen carrier.
    • The distribution of allogeneic transfusions during this 24 hour period is illustrated in Figure 3.
  • 48. CONCLUSION
    • Although, RBC Hb fell to 2.9+/- 0.2 g percent, the total Hb was maintained at 7.5+/- 0.2 g percent with Blood BackUp.
    • With respect to safety, patient’s temperature, mean arterial pressure, heart rate, and creatinine clearance did not change during the 72 hrs study period.
    • Liver function tests and amylase varied substantially because of patient’s injuries.
  • 49. CONCLUSION
    • There were no serious or unexpected adverse events related to Blood BackUp. An adverse event seen in one patient was rash which was usual for the patients who had previous numerous reactions to vaccines.
    • The tolerated dose of Blood BackUp is determined by the health care professional administering Blood BackUp to the patient.
    • Blood BackUp is safe and tolerated by all individuals involved in the study as it is compatible to all blood types.
    • Increase or decrease in dosage administered to patients by health professional had no side effects.
    • In summary, this report illustrates the ability of Blood BackUp to safely and adequately maintain circulating hemoglobin levels at a therapeutic level without the infusion of red cells after acute blood loss, while effectively loading and unloading oxygen. This protocol tested Blood BackUp in the most relevant setting of urgent hemorrhage and suggested a benefit to the patient by reducing the need for allogeneic transfusion therapy. Although this was a nonrandomized open-label study, the results document the initial evidence of clinical utility of Blood BackUp as a blood substitute in this setting.
  • 50. Financial
    • Asking for 16 million
    • Offering 2 million shares
    • Stock price = $8.00
    • Government Grant from the NIH for research in stability of erythropoietin, including Darbopoietin Alpha, when mixed with blood and modified blood.
    • Awarded $5 million
  • 51. Financial
    • Funds are being used to
      • Buy blood from New Sources along with the previous sources
      • Transportation costs
      • Opening of new centers
      • Conducting clinical trials
      • Increase production
      • Advertising to hospitals and medical personnel