Drugs

Positron Emission Tomography (PET): Questions and Answers about CGMP Regulations for PET Drugs

[12/9/2009]

BACKGROUND INFORMATION

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. 

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INSPECTIONS/COMPLIANCE

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.
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PET DRUGS AND USER FEES 

1.  What are user fees?
Under sections 735 and 736 of the Federal Food, Drug, and Cosmetic Act (the Act), FDA is authorized to assess and collect three kinds of user fees: 

  • application fees for certain applications for approval of drug and biological products
  • fees for establishments where the products are made
  • fees for the products

User fee rates are established annually and published in the Federal Register.  FDA announced the prescription drug user fee rates for fiscal year 2010 (October 1, 2009 – September 30, 2010) in the Federal Register of August 3, 2009 (74 FR 38451). 

APPLICATION FEES

2.  Will I be required to pay a user fee when I submit a new drug application (NDA) for a PET 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 Act, unless you qualify for a waiver of or exemption from the fees (see answers to questions 5 and 6 below).

3.  Will I be required to pay a user fee if I submit an abbreviated new drug application (ANDA) for a PET product?
No.  Under current law, ANDAs submitted under section 505(j) of the Act are not assessed fees.  At present, you can submit an ANDA for FDG F 18 injection, ammonia N 13 injection, or sodium fluoride F 18 injection because there are NDAs already approved for these products.  However, you must demonstrate that your product is the same as the already approved NDA product.  Until NDAs are approved for other PET products, no ANDAs for these other products can be submitted.

4.  Will I be required to pay a user fee if I submit a supplement to my NDA after my application is approved?
Yes.  You will be assessed fees for any supplement that requires clinical data for approval.

APPLICATION FEES — WAIVERS AND REDUCTIONS

5.  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 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).  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 your PET application fee if your business (including any affiliates) meets the following criteria:

  • You have fewer than 500 employees. 
  • You do not have a drug product that has been approved under a human drug application and introduced or delivered for introduction into interstate commerce. 
  • The NDA must be the first human drug application (e.g., NDA), within the meaning of the Act, that your company or its affiliate has submitted to FDA. (Note that human drug applications include 505(b) applications and certain biological license applications submitted for products licensed under section 351 of the Public Health Service Act (see section 735(1) of the Act for details)).    

You must request the small business waiver from FDA and provide evidence to the Small Business Administration regarding the size of your company.  Waivers must be requested of FDA no later than 180 days after the fees are due (section 736(i) of the Act).  FDA encourages firms to request a waiver at least 90 days in advance of submitting an application so that the request can be evaluated before the fee is due.
(See section 736(d)(1)(D) of the Act.)

  • If your product qualifies under the public health or barrier-to-innovation user fee waiver provision of the Act

The public health waiver and the barrier-to-innovation waiver provisions provide for waivers of application fees (section 736(d)(1)(A) and (B) of the Act).  FDA’s Attachment G Draft Interim Guidance Document for Waivers of and Reductions in User Fees (waiver guidance) sets out the criteria for each of these waivers.  FDA evaluates requests for these waivers on a case-by-case basis.

In the PET Safety and Effectiveness Notice, FDA concluded that certain PET products were considered innovative.  PET products other than FDG F 18 injection, ammonia N 13 injection, or sodium fluoride F 18 injection may be able to show that they are innovative using the PET Safety and Effectiveness Notice as a model.

Part of the basis for granting a public health or barrier-to-innovation waiver is financial:   the assessment of the fee must be a barrier to innovation because of your company’s limited resources or other circumstances.  The statute gives FDA more discretion under the barrier-to-innovation test.  Because the statute does not provide FDA with the ability to consider “other circumstances” when determining whether to grant a public health waiver, a company requesting a public health waiver will have to establish that it has limited resources.  Normally, if your company’s total annual revenues are greater than $10 million, your resources would not be considered limited and you would not be eligible for either a public health or a barrier-to-innovation waiver. 

To obtain a public health or barrier-to-innovation waiver, you should submit a written request for a waiver 90 days before you submit your application (but not later than 180 days after the fee is due).

Note that the Act also provides for a fees-exceed-the-cost waiver, in which the fees associated with all of an applicant’s submissions are compared with standard costs associated with FDA’s reviews of the submissions and if the fees exceed the costs, the applicant gets a waiver and refund of fees paid. FDA does not believe this provision will provide a basis for waivers for user fees for PET products, but we are mentioning it for completeness. For further information on this waiver, and to see if you qualify for this provision, see the guidance entitled Fees-Exceed-The-Cost Waiver Under the Prescription Drug User Fee Act, which is available on the Internet at the FDA (Drugs) web site under Guidances (Drugs).

6.  Are any other exemptions from or reductions of the fees available for my PET application?
Yes, you might be eligible for a reduction of or exemption from the application fee in the following circumstances:

  • You are a State or Federal government entity that does not commercially distribute your PET 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, then application fees would not be assessed.  (See section 735(1) of the Act.)

For the purposes of the State and Federal exclusion from user fees under the 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 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 Act.)

FDA expects that this exemption would not apply to most PET products, although there may in the future be PET drug products approved for rare diseases that would qualify.

  • Your application does not require clinical data for approval.

If your NDA (application under 505(b)(1) or 505(b)(2) of the Act) does not require clinical data for approval, under section 736(a)(1)(A) of the 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 can be found in FDA’s guidance for industry on Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees (bundling policy) at the FDA (Drugs) web site under Guidances (Drugs).  As explained in the answer to question 5, 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.

PRODUCT AND ESTABLISHMENT FEES

7.   Will I be required to pay any other user fees after my application is approved?
Yes.  You will be assessed annual product and establishment fees for your NDA products.  Fees are not applicable to ANDAs (see the answer to question 3).  In general, applicants are assessed product fees for each prescription drug product that is on the list of products described in section 505(j)(7)(A) of the Act (the Prescription Drug Product List in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, known as Orange Book).  If you are an applicant and your product is assessed a product fee, then you also are responsible for the establishment fee.  Fees are assessed each fiscal year.  However, the establishment fees for PET products are reduced under the Act (see question 8).

8.  As a holder of an approved PET drug application, am I eligible for a reduced establishment fee?
Yes.  Section 736(a)(2)(C) of the Act provides for special rules for the assessment of establishment fees for PET products.

  • If you are named as the applicant in an approved human drug application for a PET drug, you are subject to one-sixth of an annual establishment fee for each establishment identified in the application as producing PET drugs.  In the event the establishment is shared by multiple applicants, the establishment fee is equally divided and assessed among the applicants whose products are manufactured by the establishment during the fiscal year (see 736(a)(2)(A) of the Act).
  • If you are a not-for-profit medical center that has only one establishment for the production of PET drugs, and at least 95 percent of the total doses of each PET drug produced by the establishment will be used within the medical center, you are exempt from an establishment fee.

9.  Are there any special rules for PET drug product fees similar the special rule for establishment fees?
No.  There are no special rules for PET drug product fees. 

10.  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 product fee for my product?
If your product is the same as another approved product (e.g., same active ingredient(s), same dosage form, same route of administration, same strength), then your product would be exempt from a product fee.  Generally, if you have an approved NDA, and FDA approves an ANDA (505(j) application) for a product that is the same as the NDA product, then fees would no longer be assessed to the NDA product as long as your generic competition continues for the entire fiscal year.  If there is no generic competition for any part of the fiscal year, then you would be assessed a product fee. 

11.  If I stop producing and marketing my PET product, will I still be assessed product fees?
If you are no longer producing and marketing your product and you have delisted it under section 510 of the Act, but the product is on the Prescription Drug Product List of the Orange Book, then you should alert the Orange Book Staff so the product can be moved to the Discontinued Drug Product List.  You would still be responsible for the product fee for the fiscal year in which it is discontinued.  In subsequent fiscal years, if the product is not produced and marketed and it remains on the Discontinued Drug Product List for the entire fiscal year, you would not be assessed a product fee.  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.

12.  How can I get a waiver of my PET product and establishment fees
You can apply for a waiver of your PET product and establishment fees in the following circumstance:

  • If your product qualifies under the public health or barrier-to-innovation user fee waiver provision of the Act, you can apply for a waiver of the annual product and establishment fees.

The public health waiver and the barrier-to-innovation waiver provisions provide for waivers of annual product and establishment fees for companies that meet the statutory criteria (see section 736(d)(1)(A) and (B) of the Act).   FDA’s Attachment G Draft Interim Guidance Document for Waivers of and Reductions in User Fees (waiver guidance) sets out the criteria for each of these waivers (at the FDA (Drugs) web site under Guidances (Drugs)).   FDA evaluates requests for these waivers on a case-by-case basis.

In the PET Safety and Effectiveness Notice, FDA concluded that certain PET products were considered innovative.  PET products other than FDG F 18 injection, ammonia N 13 injection, or sodium fluoride F 18 injection may be able to show that they are innovative using the PET Safety and Effectiveness Notice as a model.

Part of the basis for granting a public health or barrier-to-innovation waiver is financial:   the assessment of the fee must be a barrier to innovation because of your company’s limited resources or other circumstances. The statute gives FDA more discretion under the barrier-to-innovation test.  Normally, if your company’s total annual revenues are greater than $10 million, your resources would not be considered limited and you would not be eligible for either a public health or a barrier-to-innovation waiver.

To obtain a public health or barrier-to-innovation waiver for product and/or establishment fees, you may submit a written request for a waiver 90 days before the fee is due, but not later than 180 days after the fee is due.

13.  Are any other exemptions from or reductions of the fee available for PET product and establishment fees?
Yes, you might be eligible for a reduction of or exemption from product or establishment fees in the following circumstances:

  • You are a State or Federal government entity that does not commercially distribute your PET 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 6).  If the application is not considered a human drug application, then product and establishment fees would not apply.  (See section 735(1) of the Act.)

  • Your approved PET product qualifies as an orphan drug product.

If your drug product is designated under section 526 of the Act for a rare disease or condition and approved under section 505 of the Act or section 351 of the Public Health Service Act, you could be eligible for an exemption from the product and establishment fees.  

Your drug product must meet the public health requirements contained in the Act as such requirements are applied to requests for waivers of product and establishment fees.  In addition, your company must have less than $50 million in gross worldwide revenue during the year preceding your request for exemption.  You should submit a certification that your gross annual revenues did not exceed $50 million for the 12 months before your request for exemption. (See section 736(k) of the Act.)

INFORMATION ON AND REQUESTS FOR USER FEE WAIVERS AND REDUCTIONS

14.  If I want to request a waiver, reduction, or refund, or if I have any other questions on user fees, who should I contact?
Contact the Prescription Drug User Fee Staff in CDER’s Office of Management. Contact information is as follows:

Prescription Drug User Fee (PDUFA) Staff
Food and Drug Administration
10903 New Hampshire Ave, Building 51, Room 6257
Silver Spring, MD 20993-0002
Phone: 1-301-796-7900
Email: CDER-PDUFA@fda.hhs.gov
Fax: 1-301-847-8711

Additional information can be found on FDA’s Prescription Drug User Fee web page. 

15.  If I want to request a waiver, what should I include in my request?
To qualify for consideration, you must submit a written request for a waiver, reduction, or refund not later than 180 days after the fee is due (section 736(i) of the Act).  You can submit the request before the fees are due.

Your written request should include the following information:

  • the name and address of the entity, including the company name, and the name and telephone number of the contact person for the fee waiver or reduction request
  • identification of the specific fee for which a waiver, refund, or reduction is requested
  • for an application or supplement fee:  the application or supplement number for which the waiver, refund, or reduction is requested, the date the application was submitted, and whether the application requires clinical data for approval
  • for product fees:  the name of the product (generic and brand names), the application number, the name of the applicant, the specific strength or potency of the product, the dosage form, the invoice number, and the invoice date
  • for establishment fees:  the name and address of the establishment for which the waiver or reduction is requested, the establishment number as listed on the invoice, the invoice number, and the invoice date
  • the statutory provision under which the waiver or reduction is requested information and analyses demonstrating that the criteria for the waiver, refund, or reduction of fees are met
  • date on which payment was or will be made to FDA of the fee for which a waiver or reduction is requested

 

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