Regulations - Radiopharmaceuticals

  1. In 1963 the FDA started regulating the clinical efficacy of all radiopharmaceuticals.  
    1. Prior to that the Atomic Energy Commission (AEC) was responsible
    2. The AEC later became the NRC
    3. In general, state agencies regulate cyclotron-produced radio-compounds
  2. Process and approval for new drugs that come to market (radio or non-radio)
    1. Investigational New Drug ( IND)
      1. Initially any new drug under investigation must be filled with the FDA
        1. Forms to be filled are 1571 and 1572
        2. Data includes:   names/credentials of the investigators, define the project, manufacturing and toxicological data, technical details, and clinical protocol
      2. Written consent for must be completed by every patient under its investigation
      3. Institutional Review Board (IRB) is established in most institutions
        1. Reviews, evaluates, and regulates all research endeavors which includes INDs
        2. Approved by the FDA
      4. Usually an IND is sponsored by a radiopharmaceutical company
      5. IND can only run for a specific or limited amount of time
      6. Any adverse reactions must be reported to the FDA immediately
      7. Annual reports must be sent to the FDA
    2. Once a drug is clinically investigated there are different phases it must go through to the final approval process
      1. Phase I - limited number of patients with specific goals being achieved:   pharmacologic distribution, metabolism, excretion, toxicity, optimum dosage, and any adverse reactions
      2. Phase II - small number of patients are evaluated that a specific disease which should be targeted by the radiopharmaceutical
      3. Phase III - Large population of patients are evaluated that involve the disease in question.   Aspects of the drug must be further defined:   safety, efficacy, dosage required for treating or diagnosing.   Usually multicenter trials generate statistical analysis proving the previous sentence
    3. After completion of data the manufacturer sends applies for a New Drug Application (NDA) which is sent to the FDA for approval
      1. FDA evaluates data and if it believes that all the necessary safety and efficacy issues have been satisfied then it approves the NDA.
      2. FDA then requires specific information to be placed in the package insert which includes:   precautions, route of administration, compounding, dosimetry, clinical pharmacological data, specific indications and contraindications
    4. Radioactive Drug Research Committee (RDRC)
      1. Hospitals and medical centers may have a RDRC
      2. It acts like a mini-FDA
      3. The intent is to expedite investigation of new radiopharmaceuticals (phase I)
      4. Member specific
      5. Committee cannot evaluate a radioactive drug for diagnostic or therapeutic means, but is allowed to evaluate its pharmacokinetics
      6. Radioactive dose maybe no more than 3 rem to the critical organ per dose an nothing greater than 5 rem
      7. Maximum patients that can be evaluated is thirty
  3. PET radiopharmaceuticals
    1. In section 121 of the Food and Drug Modernization Act (FDAMA) guidelines have been proposed by the FDA that defined current good manufacturing practice (CGMP) for PET radiopharmaceuticals
      1. Standards for this requirement include:   safety, identity, strength, quality, and purity of the radiopharmaceutical
      2. Must be documented and validated
      3. PET center must have trained personnel
    2. In PET the FDA considered any positron agent a new drug
      1. Methods of manufacturing vary and therefore require an abbreviated NDA (ANDA)
      2. Drugs currently approved are:   Na 18F, 13N-ammonia, and 18FDG
      3. Application for a ANDA usually be based on (and is preferred) other manufacturer protocol that have been approved
  4. Licensure
    1. Agreement State
      1. Means that a state has entered into an agreement in which the state assumes the regulatory responsible normally controlled by the NRC
      2. This maybe limited to just cyclotron agents or may also include by-product materials
      3. Rules and regulations mandated by the State must be at least equal to that of the NRC regulation
    2. NRC license
      1. General domestic license
        1. Given usually for the invitro use of by-product material in animals and humans
        2. Quantities are limited
      2. Specific license (by-product material)
        1. One category goes to the manufacturer who distributes the radiopharmaceutical
        2. End user is the other specific license
          1. Broad scope license
            1. Type A - given to large medical centers with allowable limits of radioactive in the Ci ranges.  
            2. Type B - is usually given to private practice group or a specific physician with all users identified on the license.   A list of approved radiopharmaceuticals   are noted on 10CRF33.100, Schedule A, Column I
            3. Type C - Limited quantity given a specific individual or under his/her supervision.   Type of by-product materials are found in 10CRF33.100, Schedule A, Column II.   Any physician handling these agents must meet training standard set in 10CFR33.15

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