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Positron Emission Tomography (PET) Drugs: Proposed CGMP Rule and Draft Guidance: Questions and Answers


1. What did FDA do today?

The FDA published for comment a proposed rule to establish current good manufacturing practices for positron emission tomography (PET) drugs (21 CFR, part 212). In conjunction with the proposed rule, we are issuing for public comment a revised draft guidance "PET Drug Products – Current Good Manufacturing Practice (CGMP)." The draft guidance provides additional information about approaches to comply with the proposed regulations, when they become final. Neither the proposed rule nor the draft guidance are final at this time. This means the proposed rule is not binding or effective. After FDA evaluates the comments received on the rule and the guidance, we expect to publish final versions of both documents.

2. What are PET Drugs?

PET drugs are radioactive drugs injected into patients that create images that can be read with a special camera called a PET scanner. PET images show the chemical functioning of an organ or tissue, unlike X-ray, or MRI images that show only body structure. PET imaging is useful for patients with certain conditions affecting the brain and the heart as well as in patients with certain types of cancer. PET drugs contain a very small amount of radioactive material, similar to the material used in other diagnostic procedures. One of the distinctive properties of PET drugs is that, because of their short half-life, they must be administered to patients within minutes or hours of being produced.

3. Why is FDA regulating PET drugs?

PET drugs were originally developed as a research tool. Although PET drugs are generally subject to all of the requirements of the Federal Food, Drug, and Cosmetic Act (the Act) that apply to other drugs, historically they were not a great priority for FDA. However, our (FDA's) regulatory interest in them grew in the mid-1990’s when they began to be used in clinical practice. Because of the short half-life of the radioactive material contained in PET drugs and their method of production, PET drug products pose special issues with regard to production and distribution. Both FDA and PET drug producers felt that certain provisions of the current good manufacturing practice regulations applicable to other types of drugs were inappropriate for PET drugs. In 1997, Congress passed the Food and Drug Administration Modernization Act (Public Law 105-115). Section 121 of the Modernization Act directs us to establish appropriate approval procedures and CGMP requirements for PET drugs. Section 121 also provides that FDA cannot require the submission of a new drug application (NDA) or abbreviated new drug application (ANDA) for a PET drug product until 2 years after we publish appropriate approval procedures and a final rule establishing CGMP requirements for PET drug products.

4. What is the difference between a rule and a guidance?

Rules state binding requirements and are enforceable in the courts. A guidance describes FDA’s current thinking on an issue, recommending approaches which, if followed by industry, would in our judgment meet the requirements set forth in the regulations. Guidances do not establish legally enforceable rights or responsibilities. They do not legally bind the public or FDA.

5. What is CGMP?

Current good manufacturing practice is a minimum manufacturing/production standard that ensures the drug meets the requirements of safety and has the identity strength, quality, and purity it is supposed to have. CGMP covers items such as control of ingredients used to make drugs, production procedures and controls, recordkeeping, quality system, and product testing. 21 CFR parts 210 and 211 contain the CGMP for non-PET drugs, while proposed 21 CFR part 212 will contain CGMP requirements for PET drugs.

6. Do the proposed rule and draft guidance apply to PET dugs used in clinical investigations and basic research?

INDs are used to allow investigation of new drugs in order to provide evidence of the drugs’ safety and effectiveness (see 21 CFR, part 312). The proposed regulations and draft guidance apply to all PET drugs, but draw a distinction for PET drugs that are produced under an IND or with the approval of a Radioactive Drug Research Committee (see 21 CFR § 361.1) and used in basic research. The proposed regulation provides that for investigational and research PET drugs, CGMP would be met by producing PET drugs in accordance with Chapter of the 2004 version of the United States Pharmacopeia, "Radiopharmaceuticals for Positron Emission Tomography–Compounding." All other PET drugs would have to comply with the new regulations proposed for Part 212.

7. How many PET facilities are there?

At the time the proposed rule was drafted, there were slightly more than 100 PET facilities. However, the number of PET facilities has been growing rapidly.

8. In what types of establishments are PET drug facilities located?

PET drugs may be produced in hospitals, academic institutions, and independent commercial facilities.

9. What is FDA doing about developing special approval procedures for PET drugs?

FDA previously issued a draft guidance on the content and format of NDAs and ANDAs for the following PET drugs:

  • Fludeoxyglucose F 18 Injection

  • Ammonia N 13 Injection

  • Sodium Fluoride F 18 Injection.

We solicited public comment on this guidance and we are now preparing a final version of this guidance which we plan to issue soon.

In addition, we greatly simplified the submission of applications for these PET drugs by conducting an evaluation of the literature on the safety and efficacy of these drugs for certain uses and publishing those findings in the Federal Register of March 10, 2000 (65 FR 12999). As a result, applications for these drugs for these uses do not need to provide new clinical data to support approval of the application.

We believe these actions have greatly simplified the procedures for obtaining approval for the vast majority of PET drugs that are currently in use in clinical practice.

10. Were PET drug producers and the public given an opportunity to comment on CGMP for PET drugs before the proposed rule and revised draft guidance were prepared?

We worked closely with the PET community in developing the proposed regulations and guidance. We provided many opportunities for public input including the following:

  • We presented our initial tentative approach to PET drug CGMP requirements and responded to numerous questions and comments about that approach at a public meeting on February 19, 1999.

  • We announced the availability of preliminary draft regulations on PET drug CGMP requirements in the September 21, 1999, issue of the Federal Register (64 FR 51274).

  • We held a public meeting to discuss the preliminary draft regulations on September 28, 1999.

  • After considering the comments on the preliminary draft regulations, we announced the availability of a preliminary draft proposed rule on PET drug CGMP requirements in the April 1, 2002, issue of the Federal Register (67 FR 15344).

  • We also announced the availability of a draft guidance on “PET Drug Products--Current Good Manufacturing Practice for Positron Emission Tomography” on April 1, 2002 (67 FR 15404).

  • We held a public meeting to discuss the preliminary draft proposed rule and draft guidance on May 21, 2002.

  • After considering the comments on the preliminary draft proposed rule and the previous draft guidance we are now issuing a proposed rule and a revised draft guidance on PET drug CGMP requirements, and we are again seeking public comment.

11. How can I comment on the proposed rule?

You may submit written or electronic comments on the proposed rule and draft guidance until [insert 90 days after date of publication in the FEDERAL REGISTER]. Written comments should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Electronic comments should be submitted to http://www.fda.gov/dockets/comments. Comments should be identified with the docket number found in brackets in the heading of the proposed rule or the notice of availability, as appropriate.

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