Safety and Security Requirements for Select Agent Research

Safety and Security Requirements for Select Agent Research

BioterrorismBioterrorismBioterrorismBioterrorism

DefinitionsDefinitions

• Biological terrorism (BT) – Use of biological agent on a population to deter, hinder, or otherwise slow the productivity of a community.

• Biological warfare (BW) - Use of biological agent to harm or kill an adversary’s military forces, population, food, and livestock.

• Select agents (SA): designated subset of biological agents or toxins identified as having the potential to be used in weapons of mass destruction (WMD’s)

Types of Biological WeaponsTypes of Biological WeaponsTypes of Biological WeaponsTypes of Biological Weapons

• Bacterial agents

• Viral agents

• Biological toxins

Advantages of BTAdvantages of BTAdvantages of BTAdvantages of BT

• Killing efficacy

• Cost effectiveness

• Vehicle

• Relative ease of production

• Interval between dissemination to infection

HistoryHistoryHistoryHistory

• Ancient – 20th century

• 20th century – 1972

• 1972 – today

Does the Siege at Caffa Correlate Does the Siege at Caffa Correlate with the Initiation of Black Death?with the Initiation of Black Death?Does the Siege at Caffa Correlate Does the Siege at Caffa Correlate with the Initiation of Black Death?with the Initiation of Black Death?

1346 - 13521346 - 1352

2020thth Century to 1972 Century to 19722020thth Century to 1972 Century to 1972

• World War I• Glanders and anthrax used on horses

• Geneva Protocol (1925)- 40 violations from 1969-86 of prohibitions of

bioweapons used in war

• World War II- Unit 731, Manchuria, China – weapons tests

on Chinese

2020thth Century to 1972 Century to 1972 2020thth Century to 1972 Century to 1972

• US military bio-weapon program, 1950-72• Ft. Detrick, Maryland

• Pine Bluff Arsenal, Arkansas• 1966, B. subtilis in NYC subway

- Study dissemination patterns

• 1969, Serratia in San Francisco- Study line-source dissemination

• Biological Weapons Convention, 1972• Today, 148 signatories

- India, North Korea, Pakistan, Iran among those not signed

1972 - Today1972 - Today 1972 - Today1972 - Today• 1979, Sverdlovsk, Russia

• 66 fatalities from anthrax release

• For 13 years USSR government tells public it was due to ingestion of contaminated meat.

• 1992, Boris Yeltsin admits a faulty HEPA exhaust filter as the result of the release from Building 19.

• Science, 1994, 266(5188):1202-8.

1972 - Today1972 - Today 1972 - Today1972 - Today

•1992, Aum Shinrikyo cult•Weaponize anthrax

- 10 botched attempts (1992)•Travel to Zaire to find Ebola•Sarin gas attacks in Japan

Where in the World is Safety Bob and what is the public health significance of this place?

The former Shakey’s Pizza where the Bhagwan Shree Rajneesh cult conducted the first known bio agent attack in the US in September 1984, spraying salmonella on the salad

bar to in an attempt to prevent citizens from voting in an upcoming election

The 2001 Anthrax LettersThe 2001 Anthrax LettersThe 2001 Anthrax LettersThe 2001 Anthrax Letters

• 23 reported cases of anthrax • New York City (8), New Jersey (7), D.C. (5), Florida

(2), and Connecticut (1)• 11 inhalation anthrax (5 deaths)• 12 cutaneous anthrax

• 9/11 inhalation anthrax cases are linked to direct exposure to contaminated mail

• 2 cases had no known exposure (61 y.o. woman in NY, 94 y.o. woman in CT)

AnthraxAnthrax AnthraxAnthrax

• Bacillus anthracis

• Gram (+) sporulating rod

• 3 antigens formed• (EF), (LF), (PA)• Presence of (LF) and (PA) = pathogenic

• 3 distinct clinical syndromes• Cutaneous• Inhalational• Gastrointestinal

Inhalational AnthraxInhalational AnthraxInhalational AnthraxInhalational Anthrax

• Infective Dose = 8,000 - 15,000 spores

• Incubation period = 1-6 days

• Duration of illness = 3-5 days

• Diagnostic Hallmark• Widened mediastinum

• Treatment:• Ciprofloxacin: 500mg bid x 4 wk• Doxycycline: 100mg bid x 4 wk

Anthrax - Clinical PresentationsAnthrax - Clinical PresentationsAnthrax - Clinical PresentationsAnthrax - Clinical Presentations

October 2001: Anthrax Mail Attacks:UTHSC-H ExperienceOctober 2001: Anthrax Mail Attacks:UTHSC-H Experience

Ricin Ricin• Derivative from castor bean plant, Ricinus communis• Protein cytotoxin that inhibits protein synthesis through its 2

polypeptide chains• Marginal toxicity when compared to other biological toxins

• LD50 = 30 μg/kg

• Recent history• 1978 – Bulgarian dissident• 1996 – KC Oncologist intent to use• 1997 – WI resident possession• 2003 – Al Qaeda plot• 2004 – Washington DC letter

Ricin, cont’d Ricin, cont’d

Major clinical presentations:• Inhalation

• Rapid onset (4-8 h) – fever, chest tightness, cough, dyspnea, nausea• Respiratory failure (36-72 h) and pulmonary edema

• Injection• Same onset as inhalation• Local lymphoidal and muscle necrosis, GI hemorrhaging

• Ingestion• Less toxic than above• Onset of symptoms similar time – abdominal pain, vomiting, diarrhea,

progressing to GI hemorrhaging, hepatic, splenic, and renal necrosis• Death 3-5 days – cessation of circulatory system

SmallpoxSmallpoxSmallpoxSmallpox

• Variola major virus• Orthopox virus

• BW threat from aerosolization• Acute stages often confused with Varicella (chickenpox)

• Differentiation:• Smallpox typically evolves distally• Lesions generally all is same stage• Febrile illness prodromal stage

• Eradicated by WHO in 1980• US & UN delay destruction of reserves until 7-02• Delayed longer

• Treatment• No known cure

• Vaccinia Immune globulin• Cidofovir

Smallpox PresentationSmallpox PresentationSmallpox PresentationSmallpox Presentation

Given the Threat – What to Do?Given the Threat – What to Do?Given the Threat – What to Do?Given the Threat – What to Do?

• Preparedness Needs• Detection - Health Surveillance• Rapid Laboratory Diagnosis• Epidemiological Investigations• Implementation of Public Health Control Measures• Communication network• Research and Development

• PPE, respirators• Triage and decontamination methods• Vaccines, prophylaxis

Web ResourcesWeb Resources Web ResourcesWeb Resources

• www.bt.cdc.gov• http://www.osha.gov/SLTC/biologicalagents/

index.html• http://www.usps.com/news/2001/press/

pr01_1010tips.htm• http://www.texasbiosecurity.org/• www.aphl.org• www.defenseofhouston.org• http://www.cdc.gov/od/sap/

The Select Agent RuleThe Select Agent Rule

Foundation for Select Agents Foundation for Select Agents

• Antiterrorism and Effective Death Penalty Act of 1996 (PL 104-132)

• Invoke transport requirements, and prohibited possession as weapons

• USA PATRIOT Act (PL 107-56)• Effective 10/16/01

• Controlled the possession of 49 Select Agents/Toxins for any use: peaceful, research, or intentional

• Outlawed use if a “restricted person”

Public Health Security and Bioterrorism Preparedness and Response Act of 2002Public Health Security and Bioterrorism Preparedness and Response Act of 2002

• (PL 107-188) effective 6/12/02• Covers both human and plant/animal select

agents; joint program between HHS (CDC) and USDA (APHIS)

• 9/10/02 - CDC notification of possession or use of SA by facilities required; negative certification also required

• 12/12/02 – Interim final rule published• 02/14/03 – Interim final rule enacted as law• 03/18/05 – Final Rule released

What is a Select Agent? What is a Select Agent?

• List of agents can be found on the CDC and APHIS websites

http://www.cdc.gov/od/sap/docs/salist.pdf

• Includes infectious agents and biological toxins of WMD concern; often termed “dual use”

• There are some exemptions for certain strains and amounts of toxin per PI

42 CFR 73 – Select Agent Regulations42 CFR 73 – Select Agent Regulations

• 73.7 Registration & related security risk assessment

• 73.9 Responsible Official

• 73.10 Restricting access to Select Agents

• 73.11 Security plan

• 73.12 Biosafety plan

• 73.14 Incident Response

• 73.15 Training

• 73.18 Inspections

• 73.19 Notification for Theft, Loss, or Release

CFR 73.7 - Registration CFR 73.7 - Registration

• You must be registered prior to beginning work• Registration good for 3 years

• Facility must meet CDC/NIH BMBL guidelines in addition to security requirements

CFR 73.7 – Related Security Risk AssessmentCFR 73.7 – Related Security Risk Assessment

• Registration information required to be submitted so that Attorney General may perform risk assessment of work at institution with Select Agents

CFR 73.9 – Responsible Official CFR 73.9 – Responsible Official

• Responsible Official (RO) and an Alternate Responsible Official (ARO) must be designated

• This individual must have resources available to ensure compliance

CFR 73.10 – Restricting Access CFR 73.10 – Restricting Access

• Must be an authorized person to have unrestricted, unsupervised access to Select Agents

-training & experience required

-must be approved by Attorney General

• Authorization granted for a period of five years

Statement of Eligibility Statement of Eligibility

• Denied SA possession if ‘Yes’ to any of following:• Jail >1 year• Fugitive from justice• Controlled substance use• Citizen of one of UN recognized terrorist countries• Committed to a mental institution• Dishonorably discharged

CFR 73.11 – Security CFR 73.11 – Security

• Inventory Control Measures• Physical Security

- Looking for at least 3 levels

• Cyber Security• Provisions for visitors, housekeeping, and

maintenance• Procedures for lost passwords, keys, IDs,

personnel leaving, unauthorized personnel

CFR 73.12 - Biosafety Plan CFR 73.12 - Biosafety Plan

• Biosafety and containment procedures set forth following BMBL and NIH rDNA Guidelines

• i.e. entry protocols; PPE; general and special practices and procedures

• Plan must be tested at least annually using drills to evaluate the effectiveness of plan or after any incident

CFR 73.14 - Incident Response CFR 73.14 - Incident Response

• Do you have an institutional Emergency Situations Response Plan (ESRP)? Where is it located?

• Planning and coordination with outside parties

• What are the emergency hazards associated with select agent?• Oral, Contact (dermal), Inhalational hazards

• What are the hazards associated with response that could lead to the spread of select agent?

• Do you have appropriate site security and control during emergency?

• Where do you find information about the specific hazards associated with the select agent?

• Biosafety Plan

CFR 73.15 - RecordsCFR 73.15 - Records

• Current, accurate list of individuals approved for access to select agent

• Current, accurate inventory of select agent• Name, characteristics, and source data• Quantity acquired and date of acquisition• Quantity destroyed and date of destruction• Quantity transferred, date of transfer, and to whom it was transferred

(EA-101)

• Records of APHIS/CDC Form 2 (EA-101) transfers

• Access to area where select agent is used or stored

CFR 73.19 – Notification for Theft, Loss, or ReleaseCFR 73.19 – Notification for Theft, Loss, or Release

• Must have a procedure for any of the above events

• Must complete report to USDA or CDC using APHIS/CDC Form 3

PenaltiesPenalties

• 42 CFR 1003 imposes strict penalties for violations of 42 CFR Part 73

• Imprisonment of up to 5 years• “….. $250,000 in the case of an individual”• “……$500,000 in the case of any other person”

• Failure to completely comply also carries significant reputational risk

Foreseeable TrendsForeseeable Trends

• Increasing regulatory requirements, inspections, scrutiny

• Opportunities for research• The FY03 budget for Department of Homeland

Security was $37,450,000,000

CommentaryCommentary• Additional bureaucratic controls for select agents are

imminent

• These rules will not always be based on sound science

• Incompatibilities with universities: • Designed as traditionally open environments• Internationally diverse populations• Population eschews being told what to do• Openly shares information

• But the work is important –so an infrastructure is needed to support this type of activity

Commentary (con’t)Commentary (con’t)

• When looking at positions, suggest asking about the support infrastructure in place - specifically:

Who does EH&S report to?

Who is the designated “responsible official”?

Is “select agent” work currently underway?

What facilities exist and are planned?

Summary Summary

• Biosafety is much more than just research protocol reviews or bloodborne pathogens

• Risk assessment process the key to properly classifying and reviewing research with infectious agents or rDNA

• Safety department must rely on the expertise of the committee for assistance

• Select agent work is highly regulated and scrutinized

References References

•42 CFR 73 (CDC) http://www.cdc.gov/od/sap/42_cfr_73_final_rule.pdf

•7 CFR 331 and 9 CFR 121 (APHIS) http://a257.g.akamaitech.net/7/257/2422/01jan20051800/edocket.access.gpo.gov/2005/pdf/05-5063.pdf

•Biosafety in Microbiological and Biomedical Laboratories, 4th ed. CDC/NIH 1999

•Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) April 2002

•Health Canada MSDS for Biological Agents

http://www.phac-aspc.gc.ca/msds-ftss/index.html#menu?