Positron Emission Tomography (PET): Questions and Answers about CGMP Regulations for PET Drugs
1. What did FDA do today?
The Food and Drug Administration (FDA) issued regulations establishing the Current Good Manufacturing Practices (CGMP) for positron emission tomography (PET) drugs. The regulations in new 21 CFR Part 212 apply to the production, quality control, holding, and distribution of PET drugs. The regulations ensure that PET drugs are of the highest quality and will meet the requirements of the Federal Food, Drug, and Cosmetic Act (the Act) regarding safety, identity, strength, quality, and purity. In conjunction with the final rule, we also announced the availability of a guidance entitled PET Drugs — Current Good Manufacturing Practice (CGMP). The guidance provides information about approaches to comply with the regulations.
In 1997, Congress passed the Food and Drug Administration Modernization Act (Public Law 105-115) (the Modernization Act). Section 121 of the Modernization Act directs FDA to establish appropriate approval procedures and CGMP requirements for PET drugs. We are establishing these CGMP requirements for PET drugs under this provision.
2. What is the difference between a rule and guidance?
Rules, also called regulations, generally contain binding requirements that manufacturers and others must follow. They are enforceable in the courts. Guidance describes FDA’s current thinking on an issue that is not binding on FDA or the public. Guidance documents usually recommend approaches to complying with statutory requirements or regulations, but alternative approaches can be used if they meet the statutory and regulatory requirements.
3. What are PET drugs?
PET drugs are radioactive drugs administered to patients so that a special camera, called a PET scanner, can take images of internal body organs and tissues. These images aid in diagnosing disease and assessing specific health concerns. PET images show the chemical functioning of an organ or tissue and are unlike X-ray or MRI images, which show only body structure. PET imaging is useful in 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-lives, (a half-life is defined as the time it takes one-half of the product’s radioactive isotope to decay) they must be administered to patients within a few hours of being produced.
4. Why is FDA regulating PET drugs?
PET drugs were originally developed as a research tool, but in the 1980s and 1990s, they began to be used more widely in clinical practice. FDA determined that like all other drugs, it was necessary for PET drug producers to demonstrate that PET drugs were safe and effective for their intended uses, and that they would be produced in a manner that ensures their identity, strength, quality and purity. In 1997, Congress recognized that FDA should regulate PET drugs when it enacted section 121 of the Food and Drug Administration Modernization Act, which directs FDA to establish appropriate approval procedures and CGMP requirements for PET drugs.
5. What is CGMP?
CGMP stands for Current Good Manufacturing Practices. Federal law requires all drugs to be made according to CGMPs, and FDA has for many years had CGMP regulations for finished pharmaceuticals which may be found at 21 CFR parts 210 and 211. CGMPs are the minimum standards that each manufacturer is to follow when it makes the drug to help ensure a drug remains safe and effective over its labeled shelf-life. CGMP regulations cover nearly all areas of drug processing and handling, including the control of ingredients, methods of processing ingredients to make a finished drug, training and standard operating procedures, recordkeeping and review, testing of materials as well as finished product, and the quality assurance and management control practices to be followed. Because PET drugs have certain unique characteristics including their short half lives and must be produced in close proximity to where they are to be administered, FDA has established CGMP regulations specific to PET drugs. The CGMP regulations for PET drugs are at 21 CFR Part 212.
1. When do PET drug producers have to comply with these regulations?
Section 121 requires that FDA establish approval procedures and CGMP requirements for PET drugs and make those procedures and requirements effective 2 years after they are established. Approval procedures for PET drugs were established previously. The CGMP regulations for PET drugs will go into effect and become mandatory for PET drug production 2 years after the publication of this final rule. Additionally, starting 2 years after publication of this final rule, FDA will also require the submission of a new drug application (NDA) or abbreviated new drug application (ANDA) for any PET drug product marketed for clinical use in the United States.
2. Does the final rule apply to PET dugs used in clinical investigations and non-clinical research?
The final rule at 21 CFR part 212 establishes CGMP regulations for PET drugs produced for routine clinical use (i.e., use in humans not a part of a clinical trial for an unapproved PET drug). PET drugs intended for clinical investigations only or for research only may be produced in accordance with either the CGMP regulations at 21 CFR part 212 or with the current United States Pharmacopeia (USP) general chapter 823 titled “Radiopharmaceuticals for Positron Emission Tomography–Compounding.” This is explained in the Federal Register announcement for the CGMP regulation and in the Guidance.
3. How will FDA inspect PET drug production?
The CGMP regulations announced today will become effective in 2 years. During the next 2 years, producers of PET drugs can expect FDA will continue to perform inspections of selected PET producers using the current standard, USP chapter 823. FDA will also continue to inspect new PET producers, including those producers who apply to make a type of PET drug that has not been previously approved, before FDA grants marketing approval. FDA will not routinely inspect producers of PET drugs intended for use in conducting investigational drug research, but will conduct “for cause” inspections due to reported problems in product quality and adverse events.
After 2 years, FDA will gradually increase the number of inspections of all PET facilities to verify conformance with the new CGMP regulations at 21 CFR Part 212. FDA investigators will receive special training to perform these inspections, so that they will be familiar with the unique characteristics of PET products, and how to apply Part 212. CDER will continue to assist the investigators and provide oversight to PET drug CGMP inspections and evaluation of any deficiencies that may be identified during an inspection. As with all areas of regulatory oversight, FDA welcomes questions by members of the PET drug community as we develop and implement our regulatory oversight of these products.
4. When will FDA require drug registration and listing of PET firms?
All PET drug producers are required to register within 2 years of finalization of the PET CGMP regulations. Firms are required to submit drug establishment and drug listing information through electronic submissions.
General information about electronic drug registration and listing may be found at the Drug Registration and Listing web page.
Instructions on electronic drug registration and listing submissions are available at: Electronic Drug Registration and Listing Instructions web page.
1. What are prescription drug user fees?
Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the Prescription Drug User Fee Amendments of 2017 (PDUFA VI), FDA is authorized to assess and collect two types of prescription drug user fees:
- application fees for certain applications for the review of human drug and biological products
- prescription drug program fees for certain approved products
User fee rates are established annually and published in the Federal Register. Please refer to the PDUFA User Fee Rates Archive page to find current and historical user fee rates.
2. Will I be required to pay a user fee when I submit a new drug application (NDA) for a PET drug product?
You will be required to pay a user fee if you submit an NDA under either section 505(b)(1) or section 505(b)(2) of the FD&C Act, unless you qualify for a waiver of or exemption from the fees.
APPLICATION FEES — WAIVERS AND REDUCTIONS
3. How can I get a waiver of my PET application fee?
You can apply for a waiver of your application fee in the following circumstances:
- If your application is for FDG F 18 injection, ammonia N 13 injection, or sodium fluoride F 18 injection
FDA will waive the application fee for 505(b)(2) applications for NDAs for FDG 18 injection, ammonia N 13 injection, and sodium fluoride F 18 injection products that are submitted in accordance with the PET Safety and Effectiveness Notice (65 FR 12999, March 10, 2000). The applicant must submit, with its NDA, a statement that it waives any right to market exclusivity to which it may be entitled under the FD&C Act. This waiver is consistent with the congressional goal of promoting the availability of FDA-approved PET drugs.
FDA expects that for 505(b)(2) NDAs that are submitted in accordance with the PET Safety and Effectiveness Notice for FDG F 18 injection, ammonia N 13 injection, or sodium fluoride F 18 injection, the application fee would be waived. If your application proposes indications and usage not in the notice, then the application fee would not be waived.
- If you are a small business submitting your first NDA
You may qualify for a small business waiver of an application fee if you meet all of the following criteria:
o The applicant employs fewer than 500 employees, including employees of affiliates;
o The applicant does not have a drug product that has been approved under a human
drug application and introduced or delivered for introduction into interstate commerce;
o The applicant, including affiliates, is submitting its first human drug application to FDA
For more information on the criteria for a small business waiver and how to submit a waiver request, please see FDA’s guidance for industry User Fee Waivers, Reduction, and Refunds for Drug and Biological Products (Waiver Guidance).
- If your product qualifies under the public health or barrier-to-innovation user fee waiver provision of the FD&C Act
The public health waiver and the barrier-to-innovation waiver provisions provide for waivers or reductions in user fees, including application fees (sections 736(d)(1)(A) and (B) of the FD&C Act, respectively). For more information on the criteria for a public health or barrier-to-innovation waiver and how to submit a waiver request, please see FDA’s Waiver Guidance.
4. Are any other exemptions from or reductions in user fees available for my PET drug application?
Yes, you may be eligible for an exemption from or reduction in the application fee in the following circumstances:
- You are a State or Federal government entity that does not commercially distribute your PET drug product.
An application submitted by a State or Federal government entity for a drug that is not distributed commercially is not considered a human drug application. If the application is not considered a human drug application, application fees would not be assessed. (See section 735(1) of the FD&C Act.)
For the purposes of the State and Federal exemption from user fees under the FD&C Act, “distributed commercially” means any distribution in exchange for financial reimbursement, goods, or services, whether or not the amount of the charge covers the costs associated with the product. Any recovery by the applicant, of all or part of the costs of manufacture or distribution of a product, makes the distribution commercial.
- Your application is for a designated orphan drug or indication.
If your application is for a prescription drug product that has been designated as a drug for a rare disease or condition under section 526 of the FD&C Act (an orphan drug), you could be eligible for an exception to the application fee. If your application includes an indication for other than a rare disease or condition, it would not be exempt from the application fee. In other words, orphan only applications would be exempt from the application fee. If your application includes both orphan and non-orphan indications, a fee would be assessed unless the fee is waived or exempted for another reason. (See section 736(a)(1)(F) of the FD&C Act.) For more information on the criteria for an orphan exemption and how to submit an exemption request, please see FDA’s Waiver Guidance.
- Your application does not require clinical data for approval.
If your NDA (application under 505(b)(1) or 505(b)(2) of the FD&C Act) does not require clinical data for approval, under section 736(a)(1)(A) of the FD&C Act, the application fee is reduced by half. Bioavailability and bioequivalence data are not considered clinical data for purposes of assessing user fees. The definition of clinical data and additional information can be found in FDA’s guidance for industry Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees. As explained above, if your NDA for FDG 18 injection, ammonia N 13 injection, or sodium fluoride F 18 injection complies with the PET Safety and Effectiveness Notice (i.e., the applications would not require clinical data for approval other than that noted in the notice), your application fee would be waived.
PRESCRIPTION DRUG PROGRAM FEES
5. Will I be required to pay any other user fees after my application is approved?
Yes. You will be assessed annual prescription drug program fees for your NDA products. In general, applicants are assessed program fees for each prescription drug product that is on the list of products described in section 505(j)(7)(A) of the FD&C Act (the Prescription Drug Product List in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book). Prescription drug program fees are assessed each fiscal year. Each fiscal year begins on October 1st and ends on September 30th.
6. Are there any special rules for prescription drug program fees for my PET drug product?
No. There are no special rules for prescription drug program fees for PET drug products.
7. If my PET product is approved under an NDA and a generic version of the same PET product is subsequently approved, do I continue to pay a prescription drug program fee for my product?
If your product is the same as another approved product, then your product would be excepted from a prescription drug program fee. (Please see the “same product” provision in section 736(a)(2)(B)(ii) of the FD&C Act.)
8. If I stop producing and marketing my PET drug product, will I still be assessed prescription drug program fees?
If you are no longer producing and marketing your product but the product is on the “Prescription Drug Product List” of the Orange Book, you should alert the Orange Book Staff (OrangeBook@fda.hhs.gov) so the product can be moved to the “Discontinued Drug Product List.” Your product is not assessed a prescription drug program fee for a fiscal year if it is in the discontinued section of the Orange Book on the date prescription drug program fees are assessed. If your product remains on the “Prescription Drug Product List” of the Orange Book as of October 1st, you may be assessed a prescription drug program fee for the product even if it is not being marketed. Conversely, if you plan to resume marketing your drug product and it is on the “Discontinued Drug Product List,” you should also notify the Orange Book Staff so the drug product can be moved to the “Prescription Drug Product List.”
9. How can I get a waiver of prescription drug program fees for my PET drug product?
If your product qualifies under the public health or barrier-to-innovation user fee waiver provisions of the FD&C Act (sections 736(d)(1)(A) and (B), respectively), you can apply for a waiver of the annual prescription drug program fees. For more information on the criteria for a public health or barrier-to-innovation waiver and how to submit a waiver request, please see FDA’s Waiver Guidance.
10. Are any other exemptions from or reductions in the prescription drug program fee available for PET drug products?
Yes, you might be eligible for an exemption from or reduction in prescription drug program fees in the following circumstances:
- You are a State or Federal government entity that does not commercially distribute your PET drug product.
An application submitted by a State or Federal Government entity for a drug that is not distributed commercially is not considered a human drug application (see answer to question 4). If the application is not considered a human drug application, then prescription drug program fees would not apply. (See section 735(1) of the FD&C Act.)
- Your approved PET drug product qualifies as an orphan drug product.
If your drug product is designated under section 526 of the FD&C Act for a rare disease or condition and approved under section 505 of the FD&C Act or section 351 of the Public Health Service Act, it shall be exempt from prescription drug program fees if the drug meets the following conditions:
o the drug meets the public health requirements that are applied to
requests for waivers for prescription drug program fees, and
o the drug is owned or licensed and is marketed by a company (including
its affiliates) that had less than $50 million in gross worldwide revenue
during the year preceding the request for exemption. (See section
736(k) of the FD&C Act.)
For more information on the criteria for an orphan exemption and how to submit an exemption request, please see FDA’s Waiver Guidance.
USER FEE CONTACT
11. If I have additional questions regarding user fees for PET products, who should I contact?
If you have additional questions regarding user fees for PET products, contact the PDUFA User Fee Staff:
PDUFA User Fee Staff
Office of Management
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Avenue
Hillandale Building, Room 2185
Silver Spring, MD 20993-0002
Additional information can be found on FDA’s Prescription Drug User Fee web page.