Select Toxin Guidance: Regulatory Exemptions

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Product Exemptions

Select agents or toxins or products containing or bearing BSAT are exempt from the SAR provisions if they are cleared, approved, licensed, or registered under certain laws, unless the HHS Secretary issues an order making provisions to protect public health and safety, according to 42 CFR §5(c). These laws include:

The Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 301 et seq.)

Products that are covered under this act that are most likely to involve select toxins are:

  1. Drugs
    1. Prescription drugs (both brand-name and generic)
    2. Non-prescription (over-the-counter drugs)
  2. Biologics
    1. Vaccines
    2. Blood and blood products
    3. Cellular and gene therapy products
    4. Tissue and tissue products
    5. Allergenics
  3. Veterinary products, including:
    1. Livestock feeds
    2. Pet foods
    3. Veterinary drugs and devices

Section 351 of the Public Health Service Act pertaining to biological products (42 U.S.C. § 262)

Products that are covered under this act are:

  1. Any biological product (General Licensing Requirements: The biological product must be safe, pure, and potent; the biological product must comply with applicable Federal Food, Drug, and Cosmetic Act requirements; the manufacturing facility must ensure that the biological product is safe, pure, and potent as determined through inspection of the facility). The term ‘biological product’ includes the following:
    1. Viruses
    2. Therapeutic serums
    3. Toxins
    4. Antitoxins
    5. Vaccines
    6. Blood
    7. Blood component or derivative
    8. Allergenic products, proteins (except any chemically synthesized polypeptide), or analogous products
    9. Arsphenamine or derivatives of arsphenamine (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of a disease or condition of human beings

BOTOX® is licensed under section 351 of the Public Health Service Act pertaining to biological products (42 U.S.C. 262). Currently there are three approved Type A botulinum toxins on the US Market (Botox®/Botox Cosmetic, Dysport®, and Xeomin®) and one Type B Botulinum toxin (Myobloc®). FDA approves the drug making process from the seed stock through the toxin production (from fermenters to purification, formulation, packaging, and labeling) to the final packaged product. FDA approval is based on a medical use. All other product uses (e.g. research or off-label use) fall outside of FDA’s jurisdiction. Many entities will ship the substance to multiple facilities (in multiple states or countries) for manufacturing, processing, and packaging. This is all part of the license and is approved by FDA. The basic research to generate an innovator product that could receive investigational new drug (IND) approval is outside of FDA’s purview. INDs are only applicable for products (both biosimilar and innovator) that will be used in clinical trials and not the basic research that led to the development of the product. The Biologics Price Competition and Innovation Act established a legal pathway for abbreviated development of a biologic based on its similarity to an already marketed product, referred to as biosimilars. The approval pathway for a biosimilar product is under section 351(k) of the Public Health Service act (for an innovator product it is the 351(a) pathway). A product to be licensed using the 351(k) pathway must establish biosimilarity to a product licensed using the 351(a) pathway, (i.e. the reference product must be a US licensed product). Any 351(a) product is eligible to be a reference product for a biosimilar, as long as there is no patent infringement and the reference product is outside the exclusivity period for the 351(a) licensed product.

Competitor products could be part of the biosimilars process; however, if they are doing basic research and development with the competitor product then it would fall outside of FDA purview. For example, if it is part of their process detailed in their license application as their quality assurance/quality control, then it would fall under the FDA’s purview. Any off label use (research and development, practice of medicine) of BOTOX, biosimilars, or competitor products is not regulated by FDA. The manufacturing process from seed stock until BOTOX® is aliquoted into vials is regulated by both FDA and DRSC for different purposes. DRSC regulates BOTOX® as a select agent until it is in its final formulation aliquoted in vials, and ready to be used for medical purposes.

The Virus-Serum-Toxin Act (21 U.S.C. 151-159)

Exemption from the select agent regulations does not amount to exemption from any other USDA law or regulation. Under the Virus-Serum-Toxin Act, the importation or movement of any organism or vector requires a permit issued by the Secretary of Agriculture. Contact the Organism and Vector staff for current regulatory requirements at OV@aphis.usda.gov or (301) 851-3300 option 3.

See the Virus-Serum-Toxin Act (21 U.S.C. §§ 151 – 159) for more information.

The Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. § 136 et seq.)

Please see the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. § 136 et seq.) for more information.

Investigational product exemption requirements for select toxins

An investigational product that is, bears, or contains a select toxin may be exempted from the select agent regulation requirements when such product is being used in an investigation authorized under any Federal Act.

  1. To apply for an exemption, an individual or entity must submit a completed APHIS/CDC Form 5.
  2. A determination regarding the application will be made within 14 calendar days after receipt, provided the application meets all of the requirements of the select agent regulations and the application establishes that the investigation has been properly authorized. A written decision granting or denying the request will be issued.
  3. The applicant must notify CDC or APHIS (depending on who the applicant is registered with) when an authorization for an investigation no longer exists. This exemption automatically terminates when such authorization is no longer in effect.

More information on investigational product exemption requirements can be found at Request for Exemption of Select Agents and Toxins for an Investigational Product on the FSAP website.