Meeting the Challenges of Blood, Vaccine, and Tissue Safety

Jesse L. Goodman, MD, MPH

Director, Center for Biologics Evaluation and Research (CBER)

Presentation to the FDA Science Board

April 15, 2005

Tragedy to Action

• 13 children in St. Louis died of tetanus after receiving diphtheria antitoxin (1901) from a horse named Jim– “This tragedy convinced

Congress and the public that producing antitoxin or vaccine was not a simple matter like weighing out a dose of a drug on a scale.”

– Margaret Pittman, “The Regulation of Biological Products, 1902-1970”

BIOLOGICS CONTROL ACT 1902• First legislative authorization of regulation of

medical products – “Although the preventive and curative powers of viruses,

serums, toxins, antitoxins, and analogous products has long since been established, certain unfortunate accidents, notably those which recently occurred in St. Louis, Mo., have tended to discredit their use. The extreme value of the preparations in preventing and curing disease renders it of prime importance, therefore, that action be taken to preserve the confidence of the medical profession and of the community generally in them.”

History of Biologics: Miracles, Tragedies, Speed Bumps

Informing Product Development• Vaccination

– Jenner, 1796: Prevention of smallpox - spread of syphilis

– Cutter Incident &Vaccine Induced Polio

• Serologic Therapies – Transmission of Tetanus & Other Infectious Diseases

• Transfusion -Transmission of HIV, hepatitis A-C• Tissue Transplants - Contamination• Successful Gene Therapy - Leukemia

Big Themes and Cultural Issues• Complex products and production• Inherent risks: both predictable and unpredictable • Often given to healthy individuals in large numbers: safety

taken for granted• Conflicting needs for supply• Markets often fragile – sensitive to development costs, yet

also sensitive to problems • Confidence of public health system often at stake• Need to build safety into products/production• Need to anticipate emerging safety issues and respond

before or, rapidly, as they evolve

Current Safety Challenges: No Business as Usual; Examples

• Vaccine Safety (and Availability)

• Blood Safety (and Availability)

• Emerging Infectious Diseases & product safety (e.g., TSE, WNV, SARS, flu, BT etc.)

• Human Tissues, Cell Products and Gene Therapy

• Counterterrorism – rapid assessment, animal efficacy, EUAs, INDs, stockpiling

All present both long-term and day to day safety, risk assessment, management & communication challenges

Counter-Counter- BioterrorismBioterrorism

Overall Approach• Prevention first: guidance and extensive pre-marketing

interactions with sponsors• Manufacturing process controls and oversight

– But improve and modernize per GMP initiative

• Defined Post-marketing Safety Responsibility– Office of Biostatistics and Epidemiology (OBE) which reports to

Center Director: responsible for AE surveillance, analysis, and related research

• Systems Approach: – Routine evaluation of serious AEs for important wide-use products

(e.g. blood, vaccines and tissues)– Undertaking assessment/update of current SOPs and approaches

Overall CBER Approach II.• Collaboration and Communication:

– Internal: • Collaborative approaches to evaluating the data: both epidemiologists

and product/clinical teams • Collaborative work planning and safety studies – both laboratory and

population sciences• Collaborative risk assessment unit

– External:• Rich use of public discussion, advisory committees, interagency partners

(e.g. CDC, NIH, OS)

• Incorporation of risk sciences & modeling into training, regulatory mitigation, public health actions

• Balance risks and benefits in context of intended use/needs• Seek needed data and reassess as new information develops

Biologics: Unique Attributes and Risk Management Issues

– Biologic sources (human/animal diseases)

– Multiple mechanisms of action– Predictors of toxicity not well

established– Complex and/or incompletely

understood manufacturing processes

– Uncertainty- E.g. emerging infectious

disease threats and blood• Cutting-edge technology:

less experience, more controversy & concern (intuitive – and may be right!)

Biologics: Unique Attributes and Risk Management Issues II.

• Products often needed for public health and individual health; multiple partners

• Often no substitute product (e.g. cannot switch to another antihypertensive or hypoglycemic agent)

• Supply/availability as a public health issue and factor in assessment

• Everything has a “worst case scenario”• High public interest• Perceived-real needs for immediate actions

CBER Risk Training• GOALS: Disseminate risk science & communication skills and

approaches. Create shared common understanding across Center. • Four courses launched in FY2004 for CBER product review staff

– “Introduction to Risk Management for Biologic Products”– “Introduction to Risk Assessment for Biologic Products”– “Introduction to Risk Communication for Biologic Products”– “Message Mapping Techniques for Biologic Products”

• Biologic specific case studies to reinforce concepts• Overall course focus on risk reduction tools for:

– Evaluation of risk– Identifying optimal risk management tools & interventions– Addressing and communicating uncertainty– Developing risk communication vehicles that:

• Are specific to type of audience and situation• Contain critical and understandable information

• Participation by ~ 50 review staff to date

Blood Safety: "5 layers"

• Donor eligibility (suitability)• Donor deferral lists • Testing for communicable diseases • Quarantining of unsuitable blood • Investigation of problems and AEs (reporting of

fatalities and product deviations)

All connected with anticipating and tracking emerging ID and other threats

Donor Eligibility: Uniform Donor History Task Force

– Goal: to improve the sensitivity and efficiency of the donor screening process

– Cooperative effort - industry, FDA, CDC, NIH • Logical ordering and wording of questions

• Cognitive evaluation to maximize understanding across demographic strata

TESTING: Implementation of New TESTING: Implementation of New Technologies has Resulted in Declining Technologies has Resulted in Declining

Risk of Viral InfectionsRisk of Viral Infections

Protecting the Blood Supply: AABB Task Force on Domestic Disasters & Terrorism

– Cooperative Industry/Agency/DHHS effort to preserve blood supply and safety in a time of emergency

– Disaster TF Level I members convene by telephone within one hour of event notification (subgroup proactively designs contingency plans for major events, e.g. National Political Conventions)

– FDA Level I participant responsible for designing, vetting, and disseminating regulatory policy in response to crisis.

– FDA has also contributed the design of a major component of the DHHS blood supply emergency monitoring system (TRANS-Net) housed in the Secretary’s Operations Center.

Example of Response toa Potential Threat : vCJD

– 1999: UK donor deferral policies initiated – despite no cases – asked why?• Scientific concerns: prions in lymphoid tissue, scope of epidemic

unclear- precautionary principle • Modeling strategies balanced vs. potential supply impacts– removed ~

87% of UK exposure risk • Removed recall requirements for classical CJD plasma: - epi, lab data• Twice yearly reevaluations through TSEAC

– 2001-2: Deferrals increased and geographically broadened due to concerns of scope of epidemic in Europe and animal studies – modeling ~ 91% total exposure

– 2004-present: 2 human transfusion related cases (UK)• FDA considering deferral of donors transfused in France • Approval of analogous recombinant products made without animal

proteins

vCJD: Other Ongoing Scientific and Public Health Responses

– Periodic review and modification of geographic and prior transfusion recipient donor deferral policies

– Risk assessments ongoing for plasma derivatives

– Develop strategies to validate prion filters

– Facilitate global efforts to establish vCJD reference panels including for validation of blood screening tests

– Studies being encouraged and reviewed on manufacturing clearance of model TSE agents for plasma derivatives

West Nile• In Summer 2002, CDC and FDA identified possible

risk from evolving epidemic, FDA issued alert and then first cases detected and evaluated

• FDA issued challenge to develop screening, held workshop to define pathways, provided standards– Guidances for donor deferral– GenProbe and Roche NAT INDs filed and now BLAs– From 2003 on >1000 WNV + donations intercepted and

removed before transfusion– A major public health success achieved through collaboration

of diagnostics & blood industries, CDC and FDA

Summary of risks of transfusion: 2005010-110-210-310-4 1010-510-610-710-8

HIV

HCVHBV

Mistransfusion

Lung injury

GVHD

Under transfusion

Cardiac

Metabolic risk in neonates

Bacteria

General anesthesia

After S. Dzik, MD Blood Transfusion Service, MGH, Boston

Changing Risks: win/win Regulation and Product Development: 7-Day Platelets

In 1984, 7 day shelf-life of platelets was reduced to 5 days due to increased risk of bacterial contamination.

On March 15, 2005 FDA cleared the Gambro collection container for 7 day storage of apheresis platelets when coupled with 100% screening for bacteria using BacT/ALERT Microbial Detection System according to the Gambro package insert.

Gambro has committed to perform a post marketing study to further characterize the sensitivity of the BacT/ALERT device as used, and to estimate the residual risk of bacterial contamination of a day-7 platelet product.

Blood Safety: Post Marketing Surveillance

• Device performance– Lot release– Assay and reagent development for product testing and

standardization• e.g. RNA reference panels for HIV subtypes; West Nile Virus panels

• Blood, plasma and transfusion– Biological Product Deviation Reporting– Fatality and Serious AE Reporting and Investigation

Biological Product Deviation Reports

– Required self-reporting– Deviation or event that may affect safety, purity,

potency – Report within 45 days of discovery– Similar provisions for HCT/P but limited to

communicable disease & core GTP

BPD – Why?• Early Warning System

– Informs CBER of manufacturing problems

• Indicator of potential problems / recalls– Information shared or investigated as appropriate

• Surveillance– Uniform tracking system for trending

• 2004: 38,162 reports – 21, 550 (57%) received electronically – continuing increase over

previous years– Annual reports and summaries available at

http://www.fda.gov/cber/biodev/reports.htm • Helps direct training, outreach and guidance – both for FDA & industry,

including development and implementation of preventive steps

Fatality Reports• Required reporting of transfusion or collection related

fatalities • Preliminary & 7-day follow-up information - further

investigation requested as appropriate• Data monitored for trends & priorities• 2004: 82 reports

– 28 (34%) – hemolytic transfusion rxn (HTR), red cell antibody rxn, bacterial contamination

– 21 (26%) – TRALI– 13 (16%) – other– 14 (17%) – not related to transfusion– 8 (10%) – donor deaths

Serious Non-Fatal AEs

• Non-fatal AEs must be investigated by facilities and are currently reviewed during FDA establishment inspections, at least every 2 years.

• Under a proposed reporting Rule change, facilities would be required to submit a written report to CBER within 45 calendar days.

Safety Reporting Requirements for Human Drug and Biological Products Proposed Rule - Federal Register: March 14, 2003 (Vol 68, No. 50)] [Pg 12405-12497]

Blood Safety- 2005 Priorities• Reducing the Risk of Donor Mismatch• Reducing the Risk of Bacterial Contamination• Evaluation of TRALI - workshop• Evaluation and approval of West Nile virus

(WNV) screening• Other EID (e.g. Chagas, malaria, leishmania,

CT)• Inactivation technologies-identification and

assessment• Evaluation of candidate tests and

manufacturing improvements to address transmissible spongiform encephalopathies (TSEs)

Vaccine Post-marketing Safety Approaches and Systems

– Safety group collaboration with OVRR reviewers on Phase IV study designs and pharmacovigilance plans

– AE: VAERS, co-managed by FDA and CDC• Individual case review, case series • Electronic reporting

– Vaccine Safety Datalink• Healthcare databases: examples of negative studies –rubella

and arthritis, measles and autoimmunity, diabetes and vaccines. Ongoing study: thimerosol and neurodevelopment

• CDC lead w/ FDA Collaboration

– Clinical Immunization Safety Assessment Centers– CMS & healthcare databases (pilots, e.g. flu and GBS)

VAERS Review Process• All licensed vaccines assigned to specific DE/VSB

medical officer• 15 day and direct reports of serious adverse events

or deaths forwarded by VAERS contractor to DE/VSB Medical Officers within 1 business day– ~ 15,000/year

• Reviewed daily for unexpected events• Follow up with reporters • Weekly meeting to discuss new concerns• Periodic reports/PSURs reviewed when submitted

Qualitative Analysis of Surveillance

• Describe characteristics and look for patterns of reports to detect “signals” of adverse events plausibly linked to a vaccine– Unexpected clinical or demographic clustering – “positive rechallenge” reports

• Signals detected through analysis of surveillance data almost always require confirmation through a controlled study

Analysis of Surveillance Data:Quantitative Methods

– Reporting rates vs. background rates– “Data mining” - Identify events reported more commonly

for one product than others through periodic use of semi-automated statistical analysis

• Now being applied to routine surveillance:– Examples: retrospective -early detection RV intussusception (Niu et al

Vaccine, 2001); prospective-possible allergic rxns to typhoid vaccine (Begier et al, CID, 2004)

– These methods don’t account for medical knowledge or reporting biases–expert judgment

– Signal’s impact and follow-up depend on: • Plausibility, data quality, health impact (seriousness, size of effected

population), possibility of intervention, effective intervention

Challenges

• Scientific: – low incidence of vaccine AEs and few unvaccinated

children– Poor understanding of normal population incidences of

diseases

• Epidemiologic: – reliance on passive surveillance– resources and tools needed to develop/support advanced

approaches e.g. healthcare databases, active reporting

• Political, cultural, communications

Strengths• Strong physician-epidemiologist staff• Interagency relationships and collaboration• Passive surveillance data can be utilized in a

systematic and useful manner, as feasible– All serious VAERS reports reviewed by MD

– Safety reviews of new vaccines communicated to physicians in peer-reviewed journals

• E.g. documentation of safety profiles of Prevnar and FluMist

– Focused reviews of special issues

Successful Detection of a Rare Vaccine AE: Rhesus Rotavirus Vaccine

– Rotavirus: • nearly a million deaths in developing countries, U.S.20-40, 50,000

hospitalizations

– Pre-licensure clinical trials: vaccine highly effective– RotashieldTM Vaccine: intussusception

» pre-licensure ~10,000 vaccinees : 2/8240 receiving vaccine, 1/4633 receiving placebo, 3/2000 w/other formulations

– Intussusception reported not to be associated with wild type rotavirus infection ( Rennels et al, Pediatrics, 1998) but.....

– August 1998: Rotavirus vaccine licensed – based on above• Original product label included intussusception• Post marketing studies required• IS prospectively included as term in VAERS database

Post-licensure Findings: "be prepared"– Early May 1999: VAERS signal

• 6 intussusception cases: discussed at CBER’s weekly vaccine safety surveillance meeting

– Mid May 1999• 9 total cases , case-control study initiated

– July 1999 • 15 intussusception cases in VAERS (11 observed during first week after

vaccination vs. 14-16 expected). • Population-based studies suggest higher IS rates after vaccination (not

statistically significant) • CDC and AAP recommend temporarily suspension of use

– October 1999: • Population-based studies: elevated risk of intussusception after vaccination • Wyeth Lederle voluntarily withdraws vaccine

Preemptive Action: Thimerosal– Concern over health effects of human exposure to

mercury in general – reduction in exposure limits– Increase in number of routine vaccines recommended for

routine use in infants – thimerosal used as preservative– FDAMA 1997 – review of mercury in pharmaceuticals – CBER/OVRR&OBE joint assessment

• Some infants may exceed some recommended exposure limits • No direct evidence of harm but mercury known neurotoxin• Desire to reduce total mercury exposure in general• Confidence in vaccines critical for public health• Adequate vaccine supply critical for public health

Actions Taken: Balancing Risks• PHS policy and FDA letters to manufacturers (7/99 and

5/00) stating goal to reduce thimerosal in vaccines as a precautionary measure

• PHS workshop on thimerosal in vaccines (8/99) • CBER expedited approval of thimerosal-free or -

reduced vaccines • Institute of Medicine review 10/01 - agreed with FDA

risk assessment and risk management decision to remove thimerosal

• All current routinely recommended childhood vaccines available in thimerosol free or reduced formulation– Flu vaccine supply in transition, increasing availability of

single dose vials

• Epidemiologic studies ongoing

Tissue Safety– Increasing number and diversity of procedures, increasing concerns

• > 1 million tissue transplants year• Some cases of serious infection transmission

– New Risk Based Tissue Safety Framework• Requires registration and listing, donor eligibility/testing, good tissue practices, and

reporting of adverse reactions and product deviations related to communicable disease

• Adverse Event reports (AERS) and analysis• Active surveillance one ultimate goal• Training, outreach, inspection and compliance

– Tissue Safety Team formed (including OCTGT, OCBQ, OBE, OCTMA, OBRR and IOD)

• SOPs to facilitate reporting/receipt/investigation of AEs • Development of shared databases • Liaison with ORA, CDC, HRSA and CMS

Example of Response to a Potential Safety Problem

• Investigation of possible transmission of bacteria (Peptostreptococcus) through tissue allografts– 3 recipients developed knee infections following allograft

transplants; all with same bacteria; all tissues from same tissue bank

– TST mobilizes; contacts CDC and State DOH

– OBE contacts hospital

– OCBQ contacts tissue bank; directed facility inspection

– State DOH does epidemiologic investigation

– CDC cultures remaining tissue—no growth

– Conclusion: No evidence that tissues were source

Strengths of Current Systems– Tiered, risk-based approach– Requires control of tissue bank operations and

quality programs– Team approach provides for efficient communication,

analysis, follow-up, and documentation of adverse reactions reported from many sources

– Creation of adverse reaction database for real-time communication within CBER allows rapid analysis, follow-up

– Inspectional, compliance and training programs, actions/remedies established and used

– System provides for review/analysis of adverse reactions to make recommendations for prevention and control of future morbidity/mortality

Challenges• Education/Outreach

– FDA investigators– Industry– Users (health care providers and tissue recipients)– Rule and guidance writing

• Inspections – workload and quality• Achieving broad and active AE surveillance• Dynamic learning and reassessment from new and ongoing experience,

new products, to allow development and sharing of best practices• Supporting science to reduce risk/improve quality• All resource intensive

• MedSun: CDRH active surveillance program in ~350 hospitals to identify adverse events associated with medical devices

• Tissue pilot now in development at several hospitals • Collect data (frequency, types) on any AEs or near-

misses related to Tissues-Cells• Identify root causes • Assist hospitals (and other JCAHO accredited

organizations) with JCAHO compliance for tissue program

Leveraging: CBER-CDRH MedSUN Tissue-Cell Transplant Pilot Project

Progress Report and Challenges• Assuring the safety of vaccines, blood, tissues, (and cell &

gene therapies) provides unique scientific and public health challenges, also many common underlying principles and needs among these and with other medical products– Automated methods to screen databases for potential concerns –

progress made– Increased availability/use of computerized health care databases –

easier said than done and expensive– New programs in science-based risk assessment, management and

communication to inform policy & the public in face of uncertainties - implementing

– Better science base for product safety and quality including population, manufacturing and laboratory sciences – lots of opportunities

• While our current systems & organizational interactions have functioned well, they are at or beyond capacity & largely operating on 20th century technologies

• Meanwhile, responsibilities and expectations are increasing (e.g. new industries, novel products, high information and safety expectations, demand for rapid access to promising technologies, medical countermeasure)

• New approaches are needed and, while such innovation is underway, require serious planning and long term collaborative investments in science, methodologies, training, infrastructure and implementation

Progress and Challenges II.

A Constructive Role for FDA in Patient Protection and Innovation• Vigorous, yet thoughtful and collaborative approaches to safety

are critical and can help innovative products with appropriate risk/benefit come to market and keep needed public health measures safe and available

• For products such as blood, vaccines, tissues, and cell and gene therapies, expectations are very high and innovation is sensitive to both risks and costs.

• Information technology and modern biological and physical sciences can help revolutionize safety, and get more bang for the buck

• Best practices, tools and resources can be developed collaboratively, and shared across FDA and with industry and the public

• Communication and transparency are critical

Thanks!