APHIS/CDC Form 4- Report of Identification of Select Agent or Toxin Frequently Asked Questions

General
Diagnosis and Verification
Proficiency Testing

General

1. What is the purpose of the APHIS/CDC Form 4A, 4B, and 4C?

   Clinical/Diagnostic Identification (Form 4A)
   Any person or entity, including any clinical or diagnostic laboratory, having identified a select agent or toxin contained in a specimen or sample presented for diagnosis or verification is required by the select agent regulations (7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part 73) to report this identification by submitting a completed and signed APHIS/CDC Form 4A to either APHIS or CDC Select Agent Program. This form can be found at the National Select Agent Registry website (www.selectagents.gov/CDForm.html).

   Proficiency Testing Identification (Form 4B)
   Any person or entity, including any clinical or diagnostic laboratory, having identified a select agent or toxin contained in a specimen or sample presented for proficiency testing is required by the select agent regulations to report this identification by submitting a completed and signed APHIS/CDC Form 4B to either APHIS or CDC Select Agent Program. This form can be found at the National Select Agent Registry website (www.selectagents.gov/CDForm.html).

   Federal Law Enforcement Seizure (Form 4C)
   A Federal law enforcement agency that seizes a select agent or toxin is required by the select agent regulations to report this seizure by submitting a completed and signed APHIS/CDC Form 4C to either APHIS or CDC Select Agent Program . This form can be found at the National Select Agent Registry website (www.selectagents.gov/CDForm.html).

2. Our entity is a diagnostic/clinical laboratory whose activities involving select agents and toxins are limited to diagnosis, verification, and proficiency testing. Do we meet the exemption provisions of Select Agent Regulations?

   Anyone that possesses a select agent or toxin that is contained in a diagnostic or verification specimen or sample is exempt from the requirements of the select agent regulations for that specific select agent or toxin if you do the following:

   • Unless directed otherwise by APHIS or CDC Select Agent Program, within seven (7) calendar days after identification of the select agent or toxin, either transfer the select agent or toxin in accordance with section 16 of the select agent regulations (requires prior approval by APHIS or CDC Select Agent Program) or destroy the specimen on-site by a recognized sterilization or inactivation process.
   • Before transfer or destruction, secure the select agent or toxin to prevent theft, loss, or release.
   • Immediately report the identification of specific select agents and toxins listed in the regulations (See immediate notification list). Additionally, an APHIS/CDC Form 4A should be sent to the CDC or APHIS Select Agent Program within seven (7) calendar days after identification.
   • Maintain copies of all APHIS/CDC Form 4A reports for a period of three (3) years.

   Anyone that possesses a select agent or toxin that is contained in a specimen used as a part of proficiency testing is also exempt from the requirements of the select agent regulations only for that specific specimen and only if you do the following:

   • Unless directed otherwise by APHIS or CDC Select Agent Program, within ninety (90) days of receipt of the sample or specimen used for proficiency testing, either transfer the select agent or toxin in accordance with section 16 of the select agent regulations (includes prior approval by APHIS or CDC Select Agent Program) or destroy the specimen on-site by a recognized sterilization or inactivation process.
   • Before transfer or destruction, secure the select agent or toxin to prevent theft, loss, or release.
   • Send an APHIS/CDC Form 4B to the APHIS or CDC Select Agent Program within ninety (90) days of receipt of the proficiency testing sample or specimen. It is important to note that the ninety (90) days starts from the date you receive the proficiency test and not from the date you identify the select agent.
   • The entity maintains a completed APHIS/CDC Form 4B for a period of three (3) years.

   NOTE: The retention of a diagnostic, verification, or proficiency sample which has been identified as positive for a select agent by an individual or entity that is not registered with either APHIS or CDC Select Agent Program is a violation of Federal law. Such possession would include the retention of a select agent or toxin which had been identified from a diagnostic, verification, or proficiency specimen as a positive control or reference sample.

3. Is there any guidance available to address the day-to-day operations of diagnostic laboratories in human, animal, and plant diagnostic laboratories?

   Recommendations from a CDC-convened, Biosafety Blue Ribbon Panel were published in the Morbidity and Mortality Weekly Report entitled "Guidelines for Safe Work Practices in Human and Animal Medical Diagnostic Laboratories." This document is available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/su6101a1.htm?s_cid=su6101a1_w. Additional information on this topic can be found in the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories manual and the NIH Guidelines for Research Involving Recombinant DNA Molecules. Links to these publications can be found at the National Select Agent Registry website (www.selectagents.gov/Resources.html). Additional reference information for plant diagnostic labs may be found at https://www.npdn.org/login.

Diagnosis and Verification

1. Is a registered entity required to report select agents or toxins identified from clinical/diagnostic specimens?

   Yes. In accordance with Section 9(c) of the select agent regulations, the Responsible Official must report the identification and final disposition of any select agent or toxin contained in a specimen presented for diagnosis or verification. The registered entity does have the option of adding the identified or verified select agent or toxin to their registration.

2. What Form do I complete if I have identified a select agent or toxin in a clinical sample?

   You would complete APHIS/CDC Form 4A reporting the identification of a select agent or toxin from a clinical/diagnostic specimen (section A: Reference Laboratory Information and section B: Select Agent or Toxin Identified from Clinical/Diagnostic Specimen (s)) within seven (7) calendar days of identification of a select agent or toxin as a result of diagnosis or verification. This form can be found at the National Select Agent Registry website (www.selectagents.gov).

3. How long may a non-registered laboratory keep a diagnostic specimen of a presumptive select agent sent to a reference laboratory for confirmation?

   A diagnostic specimen may be kept by the sending non-registered laboratory until the identification of a select agent or toxin. After the identification, the non-registered laboratory must either:
   (1) Destroy the specimens (diagnostic specimen containing the select agent). If the choice is to destroy the select agent or toxin, the date and method of destruction must be indicated on the APHIS/CDC Form 4A; or
   (2) Transfer the specimens (diagnostic specimen containing the select agent) to an entity registered for the select agent(s) or toxin(s). Prior to the transfer, pre-approval must be obtained by submitting APHIS/CDC Form 2 ("Request to Transfer Select Agents and Toxins") to APHIS or CDC Select Agent Program.

4. Is a toxin identified as a result of diagnosis or verification required to be reported on APHIS/CDC Form 4A?

   If the total amount of the toxin in possession by the clinical or diagnostic laboratory does not exceed the amounts identified in Section 3 of select agent regulations , then possession of the toxin would be excluded from the select agent regulations and an APHIS/CDC Form 4 would not be required. Otherwise, you will have to complete APHIS/CDC Form 4A sections A and B within seven (7) calendar days of identification.

   Note:The Federal requirements to register with the select agent program applies at any time the aggregate amount of a select toxin under the control of a clinical or diagnostic laboratory exceeds the aggregate amounts specified (See Section 3 or 4 of the select agent regulations).

5. If a patient produces multiple specimens, do I need to submit a separate APHIS/CDC Form 4A for each sample?

   No. You would complete one APHIS/CDC Form 4A Reporting the identification of a select agent or toxin from a clinical/diagnostic specimen section A: Reference Laboratory Information and section B: Select Agent or Toxin Identified from Clinical/Diagnostic Specimen (s). This information would be listed in Section B and should include the number and type of samples received (e.g., tissue, fluid, urine, etc.), the zip code of the patient’s residence and if additional samples are anticipated.

6. Can I report Coccidioides species instead of Coccidioides posadasii/Coccidioides immitis?

   No. Since Coccidioides posadasii and Coccidioides immitis are the only currently recognized Coccidioides species that can affect humans, the requirement is that you list as "Coccidioides posadasii/Coccidioides immitis " since this is how the fungi is listed as a select agent.

7. After identification, is a laboratory able to retain the isolate that contains a select agent?

   If the laboratory is registered with CDC or APHIS Select Agent Program or the identified select agent(s) and toxin(s), the laboratory may retain the isolate that contains the select agent. Note: The registered laboratory must still account for the new addition in its records in accord with the select agent regulations.

8. How would the registered entity note on the APHIS/CDC Form 4A that it retains the sample?

   In Section B7 of the APHIS/CDC Form 4A, the entity would check "retained" and list the name of the person that took responsibility of the material.

9. Is the APHIS/CDC Form 2 required to transfer select agents or toxins identified from clinical/diagnostic specimens being sent for susceptibility testing?

   Yes, APHIS/CDC Form 2 would be required to request prior authorization for the transfer of the identified select agent(s) or toxin(s). For further guidance regarding requesting a transfer of a select agent or toxin, please refer to: http://www.selectagents.gov/TransferForm.html.

10. What strains of Clostridium would be characterized as being Botulinum neurotoxin producing species of Clostridium?

    Botulinum toxin (serotypes A through G) is produced by Clostridium botulinum (phenotypically classified into 4 Groups -I, II, III, IV) and some isolates of Clostridium baratii (serotype F only), Clostridium butyricum (serotype E only), and Clostridium argentinense (serotype G only). Some strains of C. botulinum have been identified that produce 2 botulinum serotypes (e.g. both A and B).

    Demonstration of the production of botulinum neurotoxin, through a toxin detection test, in a suspect culture is critical to the characterization of a Botulinum neurotoxin producing species of Clostridium. Most isolates of C. baratii, C. butyricum, and some isolates of C. argentinense do not contain the genes necessary to produce botulinum toxin. Some non-toxigenic clostridia species (e.g. C. sporogenes) are phenotypically identical to C. botulinum but may result in an identification of C. botulinum on some rapid biochemical identification methods (i.e., 16sRNA sequencing may misidentify a non-toxin producing clostridia as a C. botulinum, particularly Group II strains).

    If a laboratory detects botulinum neurotoxin from a culture of any suspected Clostridium species (such as C. botulinum, C. baratii, C. butyricum, and some isolates of C. argentinense), the laboratory will need to report the identification of Botulinum neurotoxin producing species of Clostridium by completing Section 1 of the APHIS/CDC Form 4 within seven (7) calendar days of identification. In addition, if the laboratory is not registered with the Federal Select Agent Program for possession of Botulinum neurotoxin producing species of Clostridium, the laboratory must destroy or transfer the isolate within seven (7) calendar days after identification.

Proficiency Testing

1. Does the sender/sponsor need an APHIS/CDC Form 2 when sending a specimen for proficiency testing that contains a select agent or toxin?

   No. A select agent or toxin that is contained in a specimen for proficiency testing may be transferred without prior authorization from APHIS or CDC provided that, at least seven (7) calendar days prior to the transfer, the sponsor/sender provides information to APHIS or CDC Select Agent Program the select agent or toxin to be transferred and the name and address of the recipient.

2. What section do I complete if I have identified a select agent or toxin in a proficiency test?

   You would complete APHIS/CDC Form 4B Reporting the identification of a select agent or toxin: Proficiency testing report within ninety (90) days of receipt.