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Educational Web SeminarEducational Web Seminar
Adverse Events and Reactions in Adverse Events and Reactions in Cellular TherapyCellular Therapy
Thursday, February 23, 201212:00 Noon 12:00 Noon -- 1:15 PM ET1:15 PM ET
Objectives• Examine how each type of adverse event should be reported for 361, 351, and licensed cell products • Identify adverse events related to cellular therapy product collection, processing and/or infusion • Illustrate the role of the processing laboratory, the PI, and IRB in reporting adverse events
SpeakersKaren Snow, BS(ASCP)BB - Quality Manager
Massachusetts General Hospital Olive Sturtevant, MT(ASCP)SBB, SLS - Quality Assurance Director
Dana Farber Cancer InstituteRobert Lindblad, MD - PACT Coordinating Center PI
The EMMES Corporation
Web seminar presentation slides are available publicly at www.pactgroup.netwww.pactgroup.net
CME Credit and certificates of attendance provided upon request
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the
joint sponsorship of AABB and PACT. AABB is accredited by the ACCME to provide continuing medical education for physicians. In accordance with the ACCME Standards for Commercial
Supportsm, all faculty for this event have signed a conflict of interest form in which they have disclosed any significant financial interests or other relationships with the industry relative to
the topics they will discuss during this program.
Faculty Disclosure Nature of Relationship Manufacturer/Provider
Robert Lindblad, MD None Speaker, PACT staff N/A
Karen Snow None Speaker N/A
Olive Sturtevant None Speaker N/A
Prali Dave NonePlanning Committee
PACT StaffN/A
Lisa Davis NonePlanning Committee
PACT StaffN/A
Karin Quinnan NonePlanning Committee
PACT StaffN/A
David Styers NonePlanning Committee
PACT StaffN/A
Debbie Wood NonePlanning Committee
PACT StaffN/A
Sharon Moffett None AABB Staff N/A
Tiffany Achane None AABB StaffN/A
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PACT WorkshopOctober 22-23, 2012
Manufacturing Cellular Therapy Products: Practical AspectsHost site: Baylor College of Medicine
Center for Cell & Gene TherapyHouston TX
Putting the Pieces Together
Karen Snow BS(ASCP)BBKaren Snow, BS(ASCP)BBQuality Assurance OfficerBone Marrow Transplant ProgramMassachusetts General HospitalBoston, MA
Define adverse event & adverse reaction
Distinguish reporting requirements indifferent circumstancesd e e t c cu sta ces
Explain different reporting systems
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Any undesirable experience associated with the use of a medical product in a patient. Cellular Therapy Products C ll i Collection Processing Infusion
http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm
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A noxious and unintended response suspected or demonstrated
to be caused by the collection or infusion
of a cell therapy productof a cell therapy product or by the product itself.
One type of Adverse Event
FACT CT Stds 4th edition8
Must be documented and reported in accordance with the facility’s policies and/or applicable laws and regulations.
At a minimum, any such event must be At a minimum, any such event must be reported to the patient’s physician and the medical director of the facility that issued the product.
Circular of Information for the Use of Cellular Therapy Products November, 2009
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Who needs to know?o
“Reported in accordance with the
facility’s policies ……”
Collections Processing Clinical Clinical BMT, Cardiac, Neurology, Other
Communication helps to put the pieces together!
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Autologous or Allogeneic
Related (1st or 2nd)or Unrelated
351 or 361 Product
Clinical Trial
Sponsorship (NIH, Industry)
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BMT or Clinical Program Hospital Quality & Safety Committee Outside Facility or Registry (NMDP, CIBMTR) FDA
P i i l I i Principle Investigator Internal Review BoardNational Cancer Institute Clinical Trial Sponsor
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“…and/or applicable laws and regulations”
ClinicalProgramClinicalProgram
CollectionCollection
Quality & Safety
Quality & Safety
ProcessingProcessing
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Safety Issue Related to patient, staff or visitor Event outside of the laboratory Repeated Errors P ti t ID Patient ID Sampling Clerical Deviation from standard procedure
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Related to Core GTPs
Facility ✪ Environmental Controls ✪
Form 3486
Equipment✪ Supplies or Reagents Recovery (collection)
1271.150(b)
Processing & Process Controls Labeling Controls Storage Receipt, Pre-distribution, Shipment and
Di t ib tiDistribution Donor Eligibility Screening & testing
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1271.150(b)
HCT/P Deviation Code Changes:✪ Facilities
Cleaning & sanitation Suitable size, construction
✪ Equipment✪ Equipment Quality control not performed EQ not capable of producing valid results Check FDA website for more details
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Do Not Report as Biological Product Deviation if: No products were distributed Not associated with: Communicable disease transmission Possible product contamination Not Related to core GTP’s Product was released under Urgent Medical Need (Allogeneic)
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Collection Processing Testing Testing Labeling Storage Product administration
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Product safety Purity Potency
Was the product infused?
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Was the product infused? Yes = BPD required No = No BPD required
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“Even if investigation later shows
contamination is a false
A note about product contaminationBPD required when the product is
infused
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contamination is a false positive”
“A deviation report is required if a positive culture is obtained and the product was distributed, “even if it's later determined to be a false positive result.”
Fatal Life Threatening Requires Medical
21CFR 1271.350(a)
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Intervention Involves Transmission of
Communicable Disease Must have been Infused
Is a BPD or Medwatch Form Required?
Fatal or Life Threatening? Yes Required Medical Intervention? Yes Communicable Disease Transmission? No Communicable Disease Transmission? No Was the Product Infused? Yes
Not a Biological Product Deviation All four criteria for Medwatch 3500(A) not met
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Investigational New Drug (IND)I ti ti l D i E ti (IDE)Investigational Device Exemption (IDE)
National Cancer Institute (NCI)
The Cancer Adverse Event Reporting System (caAERS) is an open source software tool that is used to collect, process, and report adverse events that occur during clinical trials..that occur during clinical trials..
http://ctep.cancer.gov/reporting/ NCI criteria differ from FDA
requirements
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Reported by the Principle Investigator when:
SAE (Serious Adverse Event) Adverse event is unexpected Not consistent with investigator brochure No informed consent of possible event Event type has not been observed previously
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Internal Review Board Clinical Trial Sponsor FDA as SAE (Medwatch 3500A) National Cancer Institute National Cancer Institute
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Adverse Reaction is one type of Adverse Event
Determine Who Needs to Know Define the Type of product Review Reporting Requirements
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Questions?
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Adverse Events associated
with Cell Therapy
Products
Olive J Sturtevant, MHP, MT(ASCP)SBB/SLS, CQADirector, Cellular Therapy Quality AssuranceDana Farber Cancer Institute
Objectives
Review the types of Reactions and Adverse Events associated with various Cellular Products and their additives & how we capture data
Discuss some unique case studies of Adverse Events
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Identify process changes to help mitigate the symptoms and/or reduce the frequency of reactions
Discuss the lack of consensus on reaction workup or review
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What Is the true rate?
DOCUMENTATION REACTIONNOTED
JUST SIGNS & SYMPTOMS RPT
NO 1027 47
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NFO 60 7
YES 123 NA
# INFUSIONS
RATE BASED ON UNEXPECTED ADE
RATE BASEDON “RX YES”
RATE BASEDON “RX YES AND S&S”
1210 0.03%4/1210
10.2%123/1210
14.6%177/1210
CIBMTR Form 2600 rev2 35
Reactions to Cell Therapy Products
Mild (7% - 50%)
Expected
Febrile, Allergic, Volume Overload, DMSO
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Severe 0.04% (5/1410)
Unanticipated
Neurologic, Leukostatic, Anaphylactic, Cardiac
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Reactions Based on HPC Product Types 21% reaction rate to autologous products
96% of the reactions are related to DMSO
2% Febrile
15% reaction rate to allogeneic products
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ABO compatible – 13%
ABO incompatible – 22%
64% Febrile
17% Allergic
Reaction Types
FebrileAllergic /
AnaphalyticHemolytic
TRALI / TACO Embolic Events /
StrokeSepsis bacterial
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yCardiovascular /
CHFPulmonary / SOB,
CoughingVolume overload
pcontamination
Other
Symptoms Frequently Reported
Symptoms Reported
#Infusions # RX
1210 177
Nausea 82 7% 46%
Vomiting 49 4% 28%
Abdominal Pain 2 0% 1%
Chills 19 2% 11%
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Chills 19 2% 11%
Fever 5 0% 3%
Rash / Hives 7 1% 4%
Flushing 31 3% 18%
SOB/Coughing/Dyspnea 21 2% 12%
Chest Tightness 3 0% 2%
Jittery Legs 4 0% 2%
Hematuria 0 0% 0%
Other 84 7% 47%
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WHAT’S IN THE BAG? HPC (Cord, Marrow,
Apheresis)
TC - Cardiac, MSC, Tumor, CTL, Islets, etc
Additives
Other Additives
Anticoagulants
Hetastarch
Ficoll
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Additives
(buffer, HSA, FBS, etc)
DMSO
Cellular debris
DNAse
Cytokines
Antibiotics
Study additives
Cellular Content 41
DMSO- Dimethyl Sulfoxide7.5% or 10% DMSO used as a cryoprotectant
The daily administration of <l g/kg of DMSO
96% of reactions to Auto HPC products are related to DMSO
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Symptoms: Strong associations to amount of cryopreserved
granulocytes GI, Respiratory Epileptic seizure Skin reaction and breath odor (garlic) Systemic Side Effects of DMSO include some sedative
headache, nausea, and dizziness
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DMSO Rx and TIAo Patient with Hodgkin Lymphoma underwent Autologous SCT
o During the infusion of the HPC-A , patient developed symptoms of Facial Droop, Numbness , Embolic dysarthria
o Patient’s symptoms resolved within minutes from the TIA (transient ischemic attack)
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(transient ischemic attack)
o Patient was scanned for brain mass, hemorrhage, clots,
o Carotids were scanned and a bubble ECHO performed
o No clots, bleeds or masses seen.
o Carotids were unremarkable for arteriolosclerosis
o Bubble study revealed patent foramen ovale
Bacterial Contamination Incidence of contamination HPC-A 1.2 % to 1.6%
Contaminating organisms
Skin flora (SCN, P acnes)
Line or blood (SCN, Salmonella )
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Reaction Symptoms:
Fever, rigors, tachypnea, chest pain, hyper /hypotension decreased urine output,
DIC , renal failure , death
Impact on outcome
None to death
ADE with Contaminated Marrow
BMT on a young male with CML
Half way through infusion Patient developed fever, rigors
P i d DIC d l f il
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Patient progressed to DIC and renal failure
Sterility cultures positive approximately the same time patient first exhibited symptoms (4 hours )
Grams stain - GPRods (ID - B cereus)
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Hemolytic Events Incidence is low
Immediate: Immunological
Fever, back pain, dark urine, dyspnea chest pain nausea and
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dyspnea, chest pain, nausea and vomiting
Anemia, increased LFTs
Free Hemoglobin
ABO Incompatible Transplants
Occurrence - ~20%
Major ABO incompatibilityRBC reduction if Recipients titer >1:16
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Or if RBC volume equals ?Practice 15 – 40 mL of RBC in 24 hour period
Minor ABO incompatibility –Plasma reduction if donor plasma titer >
1:128Or if volume is >125 mL
ADE due to Free Hemoglobin In two cases with ABO-identical grafts, infusion of free
hemoglobin contributed to clinical manifestations of a hemolytic reaction: hemoglobinuria, back pain, chest pain, nausea, and vomiting.
Case 1, an ABO-identical cryopreserved HPC-A product
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Case 1, an ABO identical cryopreserved HPC A product
Product contained 55 mL of hemolyzed red cells
Case 2, an ABO-identical fresh unit of HPC-M with prolonged time from harvest to infusion
Product contained 478 mL of hemolyzed red cells.
Following onset of symptoms, the product infusion was halted. The remaining product was returned and washed
Product was subsequently infused without further symptoms.
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Febrile Non Hemolytic
Temperature rise ≥1C
Fever mild to severe
Non-hemolytic febrile reactions are thought to stem from the release of cytokines during
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stem from the release of cytokines during storage
Leukoagglutinins or platelet agglutinins
Seldom proceeds to hypotension or respiratory distress
Allergic ReactionsReactions can be mild or severe.
Seen in 3% of Allogeneic InfusionsAccounts for 17% of Allogeneic
Symptoms can include:
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Hives, rash, flushingAnxiety Chest and/or back pain Trouble breathing Fever, chills, flushing, and clammy skin A quick pulse or low blood pressure Nausea Anaphylactic
Infusion Record51
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Reaction Work-up
Not standard across centers Range is from no workup to a serological
workup similar to a blood reaction (DAT, ABO, etc.)
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UnitGram stain and cultureEndotoxinHLA?
RecipientCulture, DAT, free hemoglobin, UA, DIC workup, LFTsScans
Reduce Reactions
Reduce RBCs in both fresh and cryopreserved products
Reduce cellular debris (granulocytes, platelets etc)
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platelets, etc)
Reduce removed unnecessary additives (DMSO, Albumin, FBS, etc)
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Thank you & Questions
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Safety Reporting In Cell Safety Reporting In Cell Therapy Clinical TrialsTherapy Clinical TrialsTherapy Clinical TrialsTherapy Clinical Trials
Robert Lindblad, MDChief Medical Officer
Principle InvestigatorPACT Coordinating Center
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Safety ReportingSafety Reporting
Regulatory Agency
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ManufacturingFacility
Clinical SiteFacility
Product Use
Is this and IND study? Have you met with the clinical team?
Does the clinical team Does the clinical team understand your need to know about infusion reactions?
Do you understand the need to inform the clinical team of manufacturing issues?
For IND StudiesFor IND Studies
Who is the IND Sponsor?Who is the IND Sponsor?◦ Clinical Investigator◦ Manufacturing Investigator◦ Independent Companyp p y
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Clinical Trial Team (Sponsor)Clinical Trial Team (Sponsor) Develop a research question Develop the measurements to answer that
question Develop a protocol
Develop safety reporting strategies
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Develop safety reporting strategies Develop stopping rules Identify research sites Conduct the trial per protocol Review reported safety events Report the trial results
Clinical SiteClinical Site
Provide medical care Take medical history Conduct physical exam
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Evaluate medical events Prescribe treatment Report adverse events
Manufacturing FacilityManufacturing Facility
Maintain GMP and GTP procedures Assess for Product Deviations
• Collection, processing and infusion
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Microbial contamination Suspected disease transmission During or after product administration
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Regulatory AgencyRegulatory Agency
Identify safety risks Review protocol for safety reporting
parameters Review manufacturing deviations
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g Review all adverse events in annual
report Review expedited reports when
submitted Evaluate reported adverse events
Safety ReportingSafety ReportingWhere is the Critical Piece?Where is the Critical Piece?
Regulatory
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g yAgency
ManufacturingFacility
Clinical SiteFacility
Regulatory
Safety ReportingSafety ReportingWhere is the Critical Piece?Where is the Critical Piece?
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g yAgency
ManufacturingFacility
Clinical SiteFacility
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Regulatory
Safety ReportingSafety ReportingWhere is the Critical Piece?Where is the Critical Piece?
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g yAgency
ManufacturingFacility
Clinical SiteFacility
Communication between the Manufacturing Facility and the Clinical Site is critical to maintain the regulatory obligations of the IND
New FDA Regulations for Safety New FDA Regulations for Safety Reporting in INDs Reporting in INDs -- BackgroundBackground March 14, 2003 - FDA issued proposed rule to revise
its regulations governing pre and post marketingsafety reporting for human drugs and biological products.
110 comments received from Manufacturers, Trade R i CRO U i i i
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Representatives, CROs, Universities, etc. September 29, 2010 - FDA published a final rule
amending safety reporting requirements for INDs and Bioavailability/Bioequivalence (BA/BE) Studies.
September 2010 - Draft Guidance issued to address rule changes
March 28, 2011- Final rule became effective September 28,2011 Final rule enforced
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FDA New Regulation/GuidanceFDA New Regulation/GuidanceClinical Trial Safety ReportingClinical Trial Safety Reporting
Major principles◦ Quit submitting useless individual safety
reports◦ Quit calling things related unless there is
evidence
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evidence◦ Quit dumping all adverse events into
investigator brochures◦ Sponsors need to think – make decision
regarding expedited reporting◦ Protocol development of creative safety
plans and reporting strategies
DefinitionsDefinitions Adverse event
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
Suspected adverse reaction Suspected adverse reaction means any adverse
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Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there
is evidenceto suggest a causal relationship between the drug and the adverse event.
Adverse Reaction◦ Any adverse event caused by the drug
FDA New Regulation/GuidanceFDA New Regulation/Guidance
New TermsAdverse EventSuspected Adverse ReactionAdverse Reaction
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Adverse Events
Adverse Reactions
Suspected Adverse Reactions
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Investigator BrochureInvestigator Brochure
Only include adverse events for which a causal relationship is suspected or confirmed
Update the IB as new information becomes available
Continue to report as unexpected until IB is d t d
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updated
Previous – Lists any and all AEs reportedNew – List only Suspected Adverse
Reactions
Expedited ReportingExpedited Reporting
The adverse event meets all three of the definitions contained in the requirement: ◦ Suspected adverse reaction
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◦ Serious ◦ Unexpected
If the adverse event does not meet all three of the definitions, it should not be submittedas an expedited IND safety report.
This has always been a balance for expedited reporting!
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Related Unexpected
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Only sponsor can make this determination if it meets the definition of expedited reporting
Sponsor OR Investigator determines SERIOUSNESS
Sponsor decides RELATIONSHIP
Expedited ReportingExpedited Reporting
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p Sponsor decides EXPECTDEDNESS Sponsor will investigate and document its
decisions Timeline starts when there is adequate
information to determine relationship and expectedness
Operational IssuesOperational IssuesGuidance DocumentGuidance Document
Unblinding◦ Any event that requires expedited reporting ◦ If in Placebo group-would not be reported as an
expedited report◦ If in Treatment group-would be reported as an
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◦ If in Treatment group-would be reported as an expedited report◦ If unblinding individual events would
compromise the study an alternative method can be proposed by the sponsor
MedDRA CodingMedDRA Coding
MedDRA - the Medical Dictionary for Regulatory Activities◦ medical terminology used to classify adverse
event ◦ coding allows health authorities and the
bi h i l i d dil
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biopharmaceutical industry to more readily exchange and analyze data related to the safe use of medical products.
MedDRA was developed by the International Conference on Harmonisation (ICH)
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MedDRA Coding MedDRA Coding
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Regulatory Agency
In SummaryIn Summary--
•Know the new Regulations and Guidance documents
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Agency
ManufacturingFacility
Clinical SiteFacility
•Communication between the Manufacturing Facility and the Clinical Site is critical to maintain the regulatory obligations of the IND
Importance of Safety Importance of Safety ReportingReporting
814th Annual Meeting of the Age-Related Eye Disease Study 2: April 2009
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Importance of Safety Importance of Safety ReportingReporting
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Adverse Events and Reactions in Adverse Events and Reactions in Cellular TherapyCellular Therapy
Speaker Contact EmailSpeaker Contact EmailKaren Snow
Olive SturtevantOlive [email protected]
Robert [email protected]
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