Guidance 
 
PET Drug Applications  Content and 
Format for NDAs and ANDAs 
 
Fludeoxyglucose F 18 Injection 
 
Ammonia N 13 Injection 
 
Sodium Fluoride F 18 Injection  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
August 2011 
Procedural 
   
     
Guidance 
 
PET Drug Applications  Content and 
Format for NDAs and ANDAs 
 
Fludeoxyglucose F 18 Injection  
 
Ammonia N 13 Injection 
 
Sodium Fluoride F 18 Injection  
 
 
For additional copies contact: 
 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave. 
Silver Spring, MD 20993-0003  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
August 2011 
Procedural  
   
    Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  SUMMARY OF PET POLICY.......................................................................................4 
IV.  SHOULD I SUBMIT AN NDA OR AN ANDA?............................................................4 
A.    Submitting an NDA for a PET Drug............................................................................................5 
B.  Submitting an ANDA.....................................................................................................................5 
C.  General Recommendations...........................................................................................................8 
V.  WHAT ELSE SHOULD YOU KNOW ABOUT SUBMITTING AN 
APPLICATION?...............................................................................................................9 
A.  Can I Submit the Application Electronically?............................................................................9 
B.  Labeling........................................................................................................................................11 
C.   Bioequivalence..............................................................................................................................12 
D.  Patents...........................................................................................................................................13 
E.  What is a Drug Master File?.......................................................................................................13 
F.  What About Foreign Documents?..............................................................................................15 
APPENDIX A:  NDAS  WHAT SHOULD YOU INCLUDE IN YOUR NDA?................16 
A.  Application Form.........................................................................................................................16 
B.  Individual Items in the Application Form.................................................................................19 
APPENDIX B:  ANDAS  WHAT SHOULD YOU INCLUDE IN YOUR ANDA?...........28 
A.  Application Form.........................................................................................................................29 
B.  Individual Items in the Application............................................................................................32 
APPENDIX C:  FORMS............................................................................................................46 
 
 
  i 
    Contains Nonbinding Recommendations 
 
1
Guidance
 
PET Drug Applications   
Content and Format for NDAs and ANDAs 
 
Fludeoxyglucose F 18 Injection 
 
Ammonia N 13 Injection 
 
Sodium Fluoride F 18 Injection 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
I.  INTRODUCTION 
 
On December 9, 2009, FDA issued a final current good manufacturing practice (CGMP) 
regulation for the production of positron emission tomography (PET) drugs.2  Under the 
requirements of section 121 of the Food and Drug Administration Modernization Act (FDAMA), 
within two years following this publication date, an NDA or ANDA must be submitted for any 
PET drug marketed for clinical use in the United States.   
 
This guidance is intended to assist applicants in preparing new drug applications (NDAs) or 
abbreviated new drug applications (ANDAs) for fludeoxyglucose F 18 injection, ammonia N 13 
injection, and sodium fluoride F 18 injection used in PET imaging for the indications cited in 
Section III (below).  FDA approval of an NDA or ANDA will make it possible to market these 
PET drugs for clinical use according to the requirements of the Federal Food, Drug, and 
Cosmetic Act (the Act).3   
 
The guidance (1) provides brief background information, (2) makes recommendations to help 
you decide whether you should submit an NDA or an ANDA, (3) includes a description of the 
content and format needed in an NDA and an ANDA, and (4) provides boxed text that you can 
copy or cut and paste into your application.  The content and format sections provide information 
                                                 
1 This guidance has been prepared by the PET Steering Committee in the Center for Drug Evaluation and Research 
(CDER) at the Food and Drug Administration.  
2 The regulation, CGMP guidance, and supportive information, including historical documents are available at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm085783.htm. 
3
 NDAs, including 505(b)(2) applications, are submitted under section 505(b) of the Act.  Section 505(j) of the Act 
applies to ANDAs. 
  1 
    Contains Nonbinding Recommendations 
 
required to submit an NDA or an ANDA for these PET drugs.  Finally, we have developed 
sample formats for the chemistry sections and for the proposed labeling for fludeoxyglucose F 
18 injection, ammonia N 13 injection, and sodium fluoride F 18 injection as well as 356h sample 
forms.  These formats are supplied as separate documents on FDAs web site.4
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements apply.  
The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
Because this guidance discusses in great detail what must be submitted in an NDA (particularly a 
505(b)(2) NDA) or an ANDA (505(j)), the guidance differs from most guidances in that it 
contains extensive mandatory language, especially in the Appendices.  This mandatory language 
is used whenever the Act and/or FDA regulations require the submission of certain information.  
Unlike other documents in which mandatory language is accompanied by the related cite, to 
make the guidance more user friendly and less cumbersome, we do not cite each regulation each 
time we discuss a requirement.   
 
 
II.  BACKGROUND 
 
On November 21, 1997, President Clinton signed FDAMA into law (Pub. L. 105-115).  Section 
121(c) of the Modernization Act directed FDA to regulate PET drugs.  Section 121 identified a 
number of tasks for the FDA including:  
 
  Develop appropriate procedures for the approval of PET drugs as well as CGMP 
requirements for such drugs. 
 
  Consult with patient advocacy groups, professional associations, manufacturers, and 
persons licensed to make or use PET drugs in the process of establishing these 
procedures and requirements. 
 
  Do not require the submission of NDAs or ANDAs for compounded PET drugs that are 
not adulterated as described in the Act for a period of four years after the date of 
enactment or 2 years after the date FDA adopts special approval procedures and CGMP 
requirements for PET drugs, whichever is longer.  Nothing prohibits the voluntary 
submission and FDA review of such applications.  
 
Beginning in 1997, FDA took a series of actions, which are summarized here.  
 
  The Agency conducted several public meetings with various representatives of an 
industry trade association, the Academy for Molecular Imaging (formerly the Institute for 
                                                 
4 See http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065015.htm and 
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm241316.htm.   
  2 
    Contains Nonbinding Recommendations 
 
Clinical PET (ICP)), and other interested persons to discuss FDA proposals for PET drug 
approval procedures and CGMP requirements.   
  Because certain PET drugs have been used clinically for a number of years, FDA 
conducted its own review of the published literature5 to evaluate the safety and 
effectiveness of the PET drugs in widespread use for certain indications to facilitate the 
process of submitting applications for these products.  
  The Agency discussed its preliminary findings on the safety and effectiveness of 
fludeoxyglucose F 18 injection (for the assessment of malignancy as well as left 
ventricular myocardial viability) and ammonia N 13 injection (for assessing myocardial 
perfusion) with the ICP and other interested persons at public meetings on November 17, 
1998, and February 18-19, 1999.   
  On June 28-29, 1999, the Agency presented its findings to its Medical Imaging Drugs 
Advisory Committee (Advisory Committee). The Advisory Committee concluded that 
fludeoxyglucose F 18 injection and ammonia N 13 injection can be considered safe and 
effective for these indications, although it recommended some revisions to the wording of 
the indications proposed by FDA.  
  In a notice in the Federal Register in March 2000 (the PET Safety and Effectiveness 
Notice),6 FDA presented its findings of safety and effectiveness for the PET drugs 
studied for certain indications and described the types of applications that can be 
submitted for fludeoxyglucose F 18 injection, ammonia N 13 injection, and sodium 
fluoride F 18 injection used in PET imaging (see Section III).  These findings fulfill the 
requirement to develop appropriate approval procedures for these PET drugs. 
  In April 2002, FDA issued a preliminary draft proposed CGMP regulation and a draft 
guidance on CGMP requirements for public comment; a proposed rule and revised draft 
guidance were issued in September 2005, to solicit additional public input. 
  In December 2009, after carefully considering all public input, FDA published a final 
CGMP regulation, triggering the two-year time period for applicants to submit an NDA 
or ANDA for any PET drug used clinically.   
 
PET drug application submissions must be received by the agency on or before December 12, 
2011. FDA will not grant an extension for submitting applications.  However, applicants may 
continue to use a PET drug while their NDA or ANDA is under review.  FDA intends to exercise 
enforcement discretion regarding unapproved PET drugs while submissions are reviewed.  
However, FDA expects that by December 12, 2015, all PET drugs in commercial clinical use 
(i.e., not used under RDRC or IND) will be used under approved applications and does not 
intend to exercise enforcement discretion beyond that date. 
 
                                                 
5As stated in FDA guidance for industry, Providing Clinical Evidence of Effectiveness for Human Drugs and 
Biological Products, FDA may, in certain circumstances, rely on published literature alone to support the approval 
of a new drug product under section 505 of the Act.
6 65 FR 12999, March 10, 2000.   
  3 
    Contains Nonbinding Recommendations 
 
III.  SUMMARY OF PET POLICY 
 
Based on the findings elucidated in the March 2000 PET Safety and Effectiveness Notice, FDA 
has determined that you are not required to conduct clinical trials or submit new safety and 
effectiveness information to obtain approval for fludeoxyglucose F 18 injection, ammonia N 13 
injection, or sodium fluoride F 18 injection used in PET imaging.  You need only reference in 
your marketing application the published literature and/or FDAs determination of safety and 
effectiveness for these drugs described in the PET Safety and Effectiveness Notice provided that 
you are seeking approval of the following indication(s):    
 
Fludeoxyglucose F 18 Injection                      
 
1.  Fludeoxyglucose F 18 Injection is indicated in PET imaging for assessment of 
abnormal glucose metabolism to assist in the evaluation of malignancy in patients 
with known or suspected abnormalities found by other testing modalities, or in 
patients with an existing diagnosis of cancer. 
 
2.  Fludeoxyglucose F 18 Injection is indicated in PET imaging in patients with 
coronary artery disease and left ventricular dysfunction, when used together with 
myocardial perfusion imaging, for the identification of left ventricular 
myocardium with residual glucose metabolism and reversible loss of systolic 
function in patients with coronary artery disease and left ventricular dysfunction, 
when used together with myocardial perfusion imaging. 
 
3.  Fludeoxyglucose F 18 Injection is indicated in PET imaging in patients for the 
identification of regions of abnormal glucose metabolism associated with foci of 
epileptic seizures. 
          
Ammonia N 13 Injection 
 
4.  Ammonia N 13 Injection is indicated for diagnostic PET imaging of the 
myocardium under rest or pharmacologic stress conditions to evaluate myocardial 
perfusion in patients with suspected or existing coronary artery disease. 
 
Sodium Fluoride F 18 Injection 
 
5.  Sodium fluoride F 18 Injection is indicated for diagnostic positron emission 
tomography (PET) imaging of bone to define areas of altered osteogenic activity. 
   
 
IV.  SHOULD I SUBMIT AN NDA OR AN ANDA?  
 
An applicant seeking approval for fludeoxyglucose F 18 injection, ammonia N 13 injection, or 
sodium fluoride F 18 injection may submit an NDA or an ANDA, depending whether or not the 
specific drug product is the same as an already approved drug formulation and the indications for 
which approval is sought.   
  4 
    Contains Nonbinding Recommendations 
 
 
A.    Submitting an NDA for a PET Drug 
 
Generally, you would submit an NDA if your product is not the same as an already approved 
product.  An NDA for the PET drugs discussed in this guidance is of the type described in 
section 505(b)(2) of the Act, which generally relies for approval on (1) references to studies 
conducted by others and for which the applicant does not have a right of reference and/or (2) 
findings of safety and effectiveness for previously approved products and/or (3) published 
literature.  An applicant submitting a 505(b)(2) NDA for a PET drug can rely on FDAs review 
of the literature as described in the PET Safety and Effectiveness Notice and/or on FDAs 
findings with respect to previous approvals of PET drugs for certain indications.7   
 
B.  Submitting an ANDA 
 
1.  Generally 
 
An ANDA is usually submitted for a drug product that is the same as an already approved drug 
(a listed drug).8  When an applicant submits an ANDA based on a listed drug, the previously 
approved drug product on which the ANDA relies is officially known as the reference listed 
9
drug (RLD).   The proposed drug product for which approval is sought in an ANDA submitted 
under section 505(j) of the Act is commonly referred to as a generic drug. 
 
FDA regulations (21 CFR 314.92(a)(1)) define a drug that is the same as a listed drug to mean a 
generic drug that has the identical active ingredient(s), dosage form, strength, route of 
administration, and (with certain exceptions) conditions of use as its RLD.10  Differences in the 
manufacturing processes do not affect whether a product may be approved under an ANDA.  The 
strength is compared based on stated strength at the time of calibration, which for a multi dose 
vial of a PET drug is generally at the end of synthesis (EOS).  EOS is taken to mean at the end of 
manufacturing of the finished drug product.  For unit dose vials, the strength is calibrated to a 
particular time from the end of synthesis of a unit dose (for example see NDA 17-042). Such 
drugs must also be bioequivalent to that RLD.11  Because there are already approved NDAs for 
fludeoxyglucose F 18 injection, sodium fluoride F 18 injection, and ammonia N 13 injection for 
specific indications, you could submit an ANDA  if your product is the same as the approved 
product  and you are seeking approval only for the already approved indications.   
 
                                                 
7 The PET Safety and Effectiveness Notice includes a detailed description of 505(b)(2) NDAs. 
8 A listed drug is defined as a new drug product that has an effective approval under section 505(c) of the Act for 
safety and effectiveness or under section 505(j) of the Act, which has not been withdrawn or suspended under 
section 505(e)(1) through (e)(5) or (j)(5) of the Act, and which has not been withdrawn from sale for what FDA has 
determined are reasons of safety or effectiveness (21 CFR 314.3(b)). 
9 A reference listed drug is defined as the listed drug identified by FDA as the drug product upon which an 
applicant relies in seeking approval of its abbreviated application (21 CFR 314.3(b)).  FDA lists approved drugs that 
may be referenced in an ANDA in the Approved Drug Products With Therapeutic Equivalence Evaluations (the 
Orange Book). The Orange Book is updated by a monthly cumulative supplement.   
10 It should be noted that the comparison is between the generic and RLD finished products.   
11 21 CFR 314.94 and 314.127. 
  5 
    Contains Nonbinding Recommendations 
 
Although drugs approved in ANDAs are generally the same as the RLD, there are differences 
that may be permitted.  If your proposed (test) drug differs from the RLD in certain ways, as 
discussed below, you can still submit an ANDA.  In some cases, though, you must first submit 
and obtain approval of a suitability petition under 21 CFR 314.93.  This process could lengthen 
the time it takes for your application to be approved.   
 
Before beginning to fulfill the submission requirements for the ANDA, you should determine 
whether your product is the same as the listed drug you reference (RLD).  The following tables 
describe approved PET products.  Generally, your product should be the same as one of the 
RLDs.  (There are multiple RLDs for fludeoxyglucose F18 injection as well as an approved 
suitability petition12).  Certain differences between the generic drug and the RLD are permitted.  
Such differences are addressed below.13
 
Fludeoxyglucose F 18 Injection (NDA 20-306) 
Active ingredient  2-Deoxy-2[18F]fluoro-D-glucose 
Inactive ingredients  Sodium chloride injection, USP (9 mg/mL sodium chloride 
in water for injection (WFI)) 
Dosage form  Injection 
Specific activity  No-carrier added 
Strength (radioconcentration)  4 - 90 mCi/mL at EOS (end of synthesis) 
Osmolality  Isotonic 
pH  5.5 - 7.5 
Route of administration  Intravenous 
 
Fludeoxyglucose F 18 Injection (NDA 21-768) 
Active ingredient  2-Deoxy-2[18F]fluoro-D-glucose 
Inactive ingredients  Sodium chloride (4.5 mg/mL), Citrate (7.2 mg/mL) in water 
for injection (WFI) 
Dosage form  Injection 
Specific activity  No-carrier added 
Strength (radioconcentration)  10-100 mCi/mL at EOS (end of synthesis) 
Osmolality  Isotonic 
pH  5.0  7.5 
Route of administration  Intravenous 
 
Fludeoxyglucose F 18 Injection (NDA 21-870) 
Active ingredient  2-Deoxy-2[18F]fluoro-D-glucose 
Inactive ingredients  Sodium chloride (4.5 mg/mL), Citrate (7.2 mg/mL) in water 
for injection (WFI) 
Dosage form  Injection 
Specific activity  No-carrier added 
Strength (radioconcentration)  20-300 mCi/mL at EOS (end of synthesis) 
Osmolality  Isotonic 
pH  5.5 - 7.5 
Route of administration  Intravenous 
                                                 
12There is an approved ANDA suitability petition for fludeoxyglucose F 18 injection that involves changes in 
strength, including mCi/mL, and total activity from the RLD (Docket No. FDA 2010-P-0444).  
13 The information used to formulate these tables is presented in the Orange Book and the product labeling available 
at  http://dailymed.nlm.nih.gov/dailymed.   
  6 
    Contains Nonbinding Recommendations 
 
 
Sodium Fluoride F 18 Injection (NDA 17-042) 
Active ingredient  Sodium fluoride F 18 
Inactive ingredients  Sodium chloride injection, USP (9 mg / mL sodium 
chloride in  water for injection (WFI)) 
Dosage form  Injection 
Specific activity  No-carrier added 
Strength (radioconcentration)  2 mCi/mL at calibration  
Osmolality  Isotonic 
pH  6  8 
Route of administration  Intravenous 
   
Sodium Fluoride F 18 Injection (NDA 22-494) 
Active ingredient  Sodium fluoride F 18 
Inactive ingredients  Aqueous 0.9% sodium chloride 
Dosage form  Injection 
Specific activity  No-carrier added 
Strength (radioconcentration)  10 - 200 mCi/mL at EOS (end of synthesis) 
Osmolality  Isotonic 
pH  4.5  8.0 
Route of administration  Intravenous 
  
Ammonia N 13 Injection (NDA 22-119) 
Active ingredient  Ammonia N 13 
Inactive ingredients  0.9% aqueous sodium chloride 
Dosage form  Injection 
Specific activity  10-20 mCi dose contains 8.47-16.94 picograms (theoretical 
calculated) of ammonia.  No-carrier added. 
Strength (radioconcentration)  3.75-37.5 mCi/mL (30 mCi-300 mCi/8 mL) at EOS (end of 
synthesis) 
Osmolality  Isotonic 
pH  4.5 - 7.0 
Route of administration  Intravenous 
 
2.  In What Ways May a Generic PET Drug Differ from the RLD? 
 
Generally, the inactive ingredients for generic drug products for parenteral use are allowed to 
differ from those of the RLD only in preservative, buffer, and/or antioxidant.  These excipient 
classes are often referred to as exception excipients.  The differences in exception excipients 
must not affect the safety or effectiveness of the generic drug (see also bioequivalence 
determination criteria in section V.C. below).14  Additional differences in non-exception 
excipients are generally not permitted. 
 
See Appendix B for a more detailed description of permissible differences between a generic 
PET drug and the RLD. 
 
                                                 
14 See 21 CFR 314.94(a)(9)(ii) and (iii). 
  7 
    Contains Nonbinding Recommendations 
 
3.  What is a Suitability Petition? 
 
If your drug differs from the RLD in strength, route of administration, or dosage form, you can 
still submit an ANDA, but you must first submit a suitability petition to obtain permission to file 
an ANDA with such a change (21 CFR 314.93).  For example, a change in the specific 
concentration (in mCi/mL), and/or in the amount of active ingredient is considered a change of 
strength and may be permitted in an ANDA with approval of a suitability petition.  The 
suitability petition must be approved before the ANDA is filed.  As noted above, this process 
could lengthen the time it takes for your application to be approved. 
 
You will have to demonstrate in the suitability petition that, among other things, clinical 
investigations will not be required to establish the safety or effectiveness of the petitioned 
product.  If your proposed version of one of the PET RLDs listed above differs from the RLD in 
dosage form, strength, or route of administration, and you decide that you do not wish to submit 
an ANDA suitability petition, you still have the option of submitting a 505(b)(2) NDA. 
   
After an ANDA suitability petition is approved for a change to a product, any applicant (not just 
the applicant who submitted the suitability petition) may refer to that petition as the basis for 
submission of an ANDA.  When the ANDA is submitted, you should refer in your ANDA to the 
appropriate petition docket number and include a copy of the letter approving the suitability 
petition in the ANDA submission.  Section IV.B.1., describing approved PET drug products, 
notes applicable approved suitability petitions that may be referred to in an ANDA.15  Once an 
application is approved for a product that is the same as the subject of an approved suitability 
petition, that drug product will be a listed drug.  Thereafter, generally, you should refer to that 
listed drug and not to the petition as the basis for submission of an ANDA.  
 
If you have any questions about submitting an ANDA or about suitability petitions, please 
contact the Office of Generic Drugs.  
 
C.  General Recommendations 
 
FDA recommends the following application types for each of the three PET drugs discussed in 
this guidance.16  
 
1.  Fludeoxyglucose F 18 injection  
 
Three NDAs have been approved for fludeoxyglucose F18 injection, for a total of three 
different indications.  FDA expects that applicants will seek approval of fludeoxyglucose 
F 18 injection for three approved indications, using either the 505(b)(2) NDA route to 
approval or the ANDA approval route as appropriate.   
 
                                                 
15 See footnote 13. 
16 Because NDAs are subject to user fees while ANDAs are not, an applicant seeking to reduce its user fee liability 
could consider modifying its product so that it is eligible for approval under an ANDA. 
  8 
    Contains Nonbinding Recommendations 
 
2.  Ammonia N 13 injection 
 
There is an approved NDA for ammonia N 13 injection.  We expect that applicants will 
seek approval of ammonia N 13 injection for the approved indication using either the 
505(b)(2) NDA route to approval or the ANDA approval route as appropriate.  Although 
Ammonia N13 injection is covered by new chemical entity exclusivity, the NDA holder 
has waived the exclusivity and therefore applications may be submitted at this time.   
 
3.  Sodium fluoride F 18 injection 
 
There are two approved NDAs for sodium fluoride F 18 injection (NDA 17-042 and 
NDA 22-494).  Both are listed in the Discontinued Drug Product List section of the 
Orange Book.  However, FDA has determined that neither drug was withdrawn from sale 
for reasons of safety or effectiveness, and therefore they may be referenced in marketing 
applications.  Accordingly, you can submit an ANDA for sodium fluoride F 18 if your 
product is the same as either RLD.  You can also submit a 505(b)(2) NDA if your 
product formulation differs from the RLD in certain ways and the proposed changes do 
not affect previous findings of safety and effectiveness (see Section V.C. and Appendix 
B). 
 
If you have any questions about the type of application you should submit or about application 
requirements for other PET drugs or for other possible indications for the three PET drugs 
discussed in this guidance, please contact the Division of Medical Imaging Products (DMIP) in 
the Center for Drug Evaluation and Research (CDER). 
 
 
V.  WHAT ELSE SHOULD YOU KNOW ABOUT SUBMITTING AN 
APPLICATION? 
 
It is important to become familiar with the application form, Form FDA 356h.  A sample format 
for Form FDA 356h is included on our web site for each PET drug addressed in this guidance.17  
This form may be used for both NDAs and ANDAs.18  Appendices A and B walk you through 
Form FDA 356h section by section for an NDA and ANDA, respectively.  
   
This section describes briefly some of the documents you will be asked about in Form FDA 356h 
and provides some additional information you may find useful.  
 
A.  Can I Submit the Application Electronically? 
 
                                                 
17 See CMC Sample Formats at:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078743.pdf.  
18  Form FDA 356h is available on FDAs web site at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/default.htm. 
  9 
    Contains Nonbinding Recommendations 
 
NDAs and ANDAs may be submitted either electronically or in paper format. However, 
electronic submissions are preferred because they facilitate FDAs review of the application.19  
Therefore, we recommend that electronic submissions use the Common Technical Document 
(CTD) format.  A paper format may prove most feasible if you lack the technical support to 
develop an electronic submission. 
 
If you proceed to develop an electronic submission, we encourage you to obtain a pre-assigned 
application number and a secure email account with FDA, as described at the following web site:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electr
onicSubmissions/ucm114027.htm
 
The CTD format is designed to minimize the potential for omission of critical information 
through the use of five components (Modules 1 through 5) that contain information applicable to 
the items listed on page 2 of Form FDA 356h.20   The following will be useful in explaining 
expectations for the CTD format: 
 
  Guidance Submitting Marketing Applications According to the ICH/CTD Format: 
General Considerations 
  Guidance ICH M2 EWG:  Electronic Common Technical Document Specification  
  Guidance ICH M4: Organization of the CTD 
  Submit a sample eCTD to help verify the technical feasibility of your plans:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequi
rements/ElectronicSubmissions/ucm174459.htm. 
  
 
If you decide to submit your application electronically, please note that FDA will consider as 
technically deficient and not received any electronic application that is not submitted in an 
electronic format that can be processed, reviewed, and archived.21   
 
We anticipate an NDA or ANDA will contain predominantly chemistry, manufacturing, and 
controls (drug quality) information.  Within the CTD, the drug quality information is provided in 
Module 3.  Information to include in this module is described in the guidance document titled, 
M4Q: The CTD  Quality.22
 
Submission of the sample eCTD should help minimize the potential for technical deficiencies 
and provide an opportunity for you to obtain feedback from the FDA technical review staff. 
 
                                                 
19 For more on electronic submissions, see guidance for industry Providing Regulatory Submissions in Electronic 
FormatHuman Pharmaceutical Applications and Related Submissions Using the eCTD Specifications 
 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163556.pdf.
20 The sample formats have been kept in the old Office of Generic Drugs format to avoid confusion for the three 
commonly used drugs which are the subject of this guidance.  You may organize the application in the CTD format 
and keep the CMC sections (module 3 of the CTD format) for these drugs in the format indicated in the sample 
formats.  Alternatively, you can organize the application, including CMC, in CTD format.  Module 3 is essentially 
the same for both NDAs and ANDAs.   
21 See http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072385.pdf
22 See http://www.fda.gov/RegulatoryInformation/Guidances/ucm129901.htm. 
  10 
    Contains Nonbinding Recommendations 
 
Questions regarding the electronic submission process may be directed to esub@fda.hhs.gov. 
 
 
B.  Labeling 
 
Whether submitting an NDA or ANDA, you will be required to submit labeling for the drug 
product to FDA.  Labeling is a collective term and for PET drug products consists of: 
 
  Prescribing Information (which contains a summary of the essential information 
needed for the safe and effective use of the product); 
  Label for the drug vial; and 
  Label for the lead storage container. 
 
When submitting the NDA or ANDA, the content of the drug labeling must be submitted to FDA 
electronically using the Structured Product Labeling (SPL) format.  For the three drugs discussed 
in this guidance, FDA has provided labeling templates in SPL on our website that you can use 
whether you are submitting an NDA or ANDA.23  The templates contain most of the required 
labeling information and cannot be modified.  You may reference these templates in your 
application but must separately provide required information in SPL that is specific to your 
products (e.g., name and address of manufacturer).  Further instructions and information on SPL 
and free software that may be used to submit information in SPL is available on FDAs 
website.24   
 
  Ammonia N 13 injection and fludeoxyglucose F 18 injection labeling templates are 
consistent with the 2006 final rule concerning the new requirements for prescribing 
information for drug and biological products.25  These regulations revised the content and 
format of the prescribing information of new drugs to make information more accessible 
and easier to read and use.     
 
  NDA 17-042 for sodium fluoride F 18 injection was approved prior to implementation of 
the final rule on the new requirements for prescribing information, and the labeling has 
not been updated to address dosage and usage information.  On our website, we provide 
both the older approved labeling as well as newer formatted text.  If you intend to submit 
an ANDA referencing NDA 17-042, you should use the older approved labeling.  If you 
submit an NDA or an ANDA referencing NDA 22-494, you should use the newer 
labeling template which has information presented in the new required format.  We will 
recommend any necessary changes during our review.  Labeling for NDA 22-494, 
Sodium Fluoride F-18 Injection, is consistent with the 2006 final rule on prescribing 
information and can be found at Drugs@FDA.26   
 
                                                 
23 See http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm241316.htm.   
24 See http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. 
25 See 21 CFR 201.56 and 201.57 
26 See http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022494Orig1s000lbl.pdf.   
  11 
    Contains Nonbinding Recommendations 
 
Additional information regarding the content and format of the prescribing information is 
available on the FDA website: New Requirements for Prescribing Information.27   
 
If you are submitting an ANDA, your labeling will be the same as the NDA RLD labeling.  If, 
for example, you intend to propose different pediatric dosing, you would have to submit studies 
to justify the change.  This type of change could not be made in an ANDA and would require 
submission of a 505(b)(2) application. 
 
FDA recognizes that PET drugs are frequently distributed outside the normal channels of 
distribution for drugs.  However, PET producers are responsible for distributing labeling to the 
end user.  At this time, we recommend that the labeling be made available at some specific 
location or website to which the end user may be referred.   
 
C.   Bioequivalence 
 
If your proposed PET drug product is the same Qualitatively (Q1 = same ingredients) and 
Quantitatively (Q2 = same amounts of the inactive ingredients with a + or  5% difference), you 
can request a waiver under 21 CFR 320.22 of any requirement for evidence of in vivo 
bioequivalence (BE). Specific language to request a waiver is provided in the ANDA (generic 
drug) section of this guidance.  
 
If the proposed product is not Q1 and Q2 the same (as discussed above), the products 
bioequivalence must be demonstrated in accordance with 21 CFR 320.24.  For intravenously 
administered PET drug products, in accordance with 21 CFR 320.24(b)(6), FDA has determined 
that bioequivalence has been demonstrated in cases where differences in the inactive ingredients 
are sufficiently small that they will not significantly affect the physical and chemical properties 
of the drug product and where such ingredients have been previously used in the same or greater 
quantities in an approved drug product for the same route of administration.  
 
Examples of situations where FDA has determined that a bioequivalence study is not necessary 
to demonstrate bioequivalence include: 
 
  Presence of or absence of a preservative, buffer or an antioxidant (see 21 CFR 314.94(a) 
(9)(iii)) in the proposed PET drug product, where such ingredients and their amounts 
have been previously approved in a drug product and their amounts do not affect physical 
or chemical properties (e.g., specific gravity, viscosity, pH) in relation to the RLD.  
 
   Presence of or absence of a preservative, buffer or an antioxidant (see 21 CFR 314.94(a) 
(9)(iii)) in the proposed PET drug product, where such a change does not affect tonicity 
(osmolality) of the solution in relation to the RLD or the applicant has established that 
the change in tonicity will not affect safety or effectiveness of the product. 
 
                                                 
27 See http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm  
 
  12 
    Contains Nonbinding Recommendations 
 
To demonstrate bioequivalence under 21 CFR 320.24(b)(6), the application should include a 
discussion with supportive evidence, usually from the FDA list of inactive ingredients in 
previously approved products, to support that the proposed product differences from the RLD are 
not likely to affect the safety or efficacy of the product.28
 
D.  Patents 
 
If you submit an NDA for a PET drug product (including a 505(b)(2) NDA), you must also 
submit information on each patent that claims the drug or a method of using the drug (that is the 
subject of the NDA).  Such patents consist of drug substance (active ingredient) patents, drug 
product (formulation and composition) patents, and method of use patents.29
 
FDA has created two forms to facilitate the listing of patents in the Orange Book, FDA form 
3542a and FDA form 3542.  FDA form 3542a must be submitted in an original NDA to alert the 
Agency to your intent to list patents for your product.  Form 3542 must be submitted within 30 
days of the approval of an NDA.  Form 3542 will be used by the Orange Book staff to list any 
patents for your approved product.  Both of these forms have a checkbox to indicate when an 
applicant does not intend to list any patents.  Therefore, these forms should be submitted even if 
you have no patents to list.   
 
If you submit an NDA under 505(b)(2) of the Act or an ANDA, you must provide a certification 
with respect to each patent that is listed in the Orange Book, which claims the RLD.30  For each 
such patent, you must provide the patent number and certify one of the following circumstances: 
 
  That the patent information has not been submitted to FDA (Paragraph I 
Certification); 
  That the patent has expired (Paragraph II Certification); 
  The date on which the patent will expire (Paragraph III Certification); or  
  That the patent is invalid, unenforceable, or will not be infringed by the 
manufacture, use, or sale of the drug product for which the application is 
submitted (Paragraph IV Certification). 
 
Please see the Appendices for further information about patents and patent certifications.  
Information about patents claiming drugs that have been approved is available in the Approved 
Drug Products with Therapeutic Equivalence Evaluations (Orange Book) at 
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.   
 
E.  What is a Drug Master File?31
 
                                                 
28 See http://www.fda.gov/Drugs/InformationOnDrugs/ucm113978.htm  
29 See 21 CFR 314.53. 
30 See 21 CFR 314.54(a)(1)(vi) and 314.94(a)(12).  
31 For additional information about DMFs, see the Guideline for Drug Master Files available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/ucm073164.htm and the 
DMF web page available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/default.htm.   
  13 
    Contains Nonbinding Recommendations 
 
A drug master file, also known as a DMF, is a file that usually contains information about a drug 
substance, a component, or a container/closure system that is proprietary (i.e., belongs to 
someone else).  This information may not be available to you,32 but you may need it as part of 
your NDA or ANDA.  Rather than providing the information directly to you and to everyone 
who uses their product, the manufacturer may choose to hold a DMF.  The DMF holder provides 
the information directly to FDA.   
 
If a manufacturer holds a DMF that you would like to reference, you should ask them to provide 
you with a letter of authorization (see below), which you must include with (and reference in) 
your application and list on your Form FDA 356h. 
 
A DMF could contain information required in an application about the following areas:  
 
  Drug substance, drug substance intermediate, and materials used in their preparation, 
or drug product (Type II); 
  Packaging materials (Type III); 
  Excipient, colorant, flavor, essence, or materials used in their preparation (Type IV); 
or   
  FDA accepted reference information (Type V).  
 
If you intend to reference a DMF, we will need a letter of authorization from the DMF holder 
granting FDA authorization to refer to information in its DMF during the review of your 
application.  The letter of authorization should be on the DMF holders letterhead and dated and 
signed with an original signature.  The letter should cite the DMF holders name, drug name, and 
DMF number.   
 
If, for example, you want to rely on DMF information concerning the bulk drug substance, the 
authorization must be granted by the holder of the DMF for each source of bulk drug substance.  
If the letter of authorization is made by a third party (i.e., another corporate entity, agent, or 
supplier), the DMF holder should provide the authorization to the third party giving the authority 
to grant referrals to the DMF.   
 
For PET drugs, the manufacturers of automated synthesis equipment may submit a Type V DMF 
that addresses the following: 
 
  Equipment description and principle of operation 
  Equipment specifications 
  Quality system information 
  Design Controls 
  Performance standards essential requirements 
  Design verification testing including programming logic / software testing 
  Safety margin testing 
  Equipment shelf-life 
                                                 
32  The regulatory requirements for a DMF are found in 21 CFR 314.420. 
  14 
    Contains Nonbinding Recommendations 
 
  Risk assessment including Failure Mode, Effects and Criticality Analysis (FMECA) 
  Functional and electrical testing 
  Bench testing including extraneous environment testing. 
  Data for performance verification studies 
  Results of USP extractable study per chapter <381> and USP biological reactivity as per 
chapter <87> and chapter <88> on elastomeric components that come in contact with the 
drug 
 
F.  What About Foreign Documents? 
 
Foreign publications or documents can be submitted to FDA as part of your application (e.g., as 
part of your chemistry section).  If you submit foreign publications or documents, you must also 
provide English translations of this information with the application.33   
                                                 
33 See 21 CFR 314.50(g). 
 
  15 
    Contains Nonbinding Recommendations 
 
APPENDIX A:  NDAS  WHAT SHOULD YOU INCLUDE IN YOUR NDA? 
 
This Appendix is based extensively on section 505(b) of the Act and regulations in 21 CFR part 
314.  As a result, this section contains extensive mandatory language.  This mandatory language 
is used whenever FDA regulations require the submission of certain information.  Unlike other 
guidance documents in which mandatory language is typically accompanied by the related cite, 
to make the guidance more user friendly and less cumbersome, we do not cite each regulation 
each time we discuss a requirement.  
 
Once you have decided to submit an NDA, you must fill out application Form FDA 356h and 
provide the Agency with a variety of information on your product.  The information published in 
the PET Safety and Effectiveness Notice will form the basis for approval of 505(b)(2) NDAs for 
the three PET products discussed in this guidance. 
 
After providing general information about NDA submissions, we will walk you through the 
application, explaining what you should put in each section of your application.  Incorporate 
these sections into the module (1 through 5) components of the CTD format. 
 
When an NDA is submitted to FDA as a paper submission, three copies are required:  (1) an 
archival copy for the official record, (2) a review copy to be used to evaluate your application, 
and (3) a field copy, which will be used as part of your preapproval inspection by the FDA.  We 
will describe the specific requirements for the field copy later in this guidance.  
  
You should send your completed paper application to: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Medical Imaging Products (DMIP) 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
 
If you choose to supply your application electronically, submit via the electronic submission 
gateway, as described in section V.A.34   
 
An NDA submission generally consists of an application form and a series of individual 
sections. 
 
A.  Application Form  
 
The application form is Form FDA 356h.  This form must be completed and signed by the 
applicant or responsible official.   
                                                 
34CDERs specifications for submitting applications on physical and electronic media, including CDs are available 
at 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163567.pdf.    
  16 
    Contains Nonbinding Recommendations 
 
The form contains seven major sections:  (1) applicant information, (2) product description, 
(3) application information, (4) establishment information, (5) the individual items based on the 
regulations, (6) certification, and (7) signature of responsible official.  Each of these sections is 
discussed in detail in the following paragraphs.  
 
1.  Applicant information 
 
This section requests general information about the applicant:  name, address, telephone number, 
and fax number.  If you wish to use an agent or consultant to act on your behalf, you should also 
provide the name and address of the person authorized on your behalf in the application.  If a 
particular section does not apply, please write NA (not applicable). 
 
2.  Product description 
 
Below is a template that can be adapted for use in the Product Description section of Form FDA 
356h: 
 
Template for product descriptions  
 
 
  Established Name:  Fludeoxyglucose F 18 injection (or ammonia N 13 injection or 
  sodium fluoride F 18 injection) 
   
  Proprietary Name*:    Indicate proprietary name (or write none) 
   
  Dosage Form:     Injection 
   
  Strengths:  Indicate amount of drug substance range in mCi/mL at end of 
  synthesis (EOS) calibration time 
   
  Route of Administration:  Intravenous 
   
 
 
*We do not anticipate the need for proprietary names.  If you wish to propose a proprietary name, 
information on the proposal submission process is available in FDA guidance.35
 
Supply a previously assigned application number within the designated space on the form. 
 
3.  Application description 
 
This section asks for information about the type of application you are submitting. 
  You should check the appropriate application type in the first box (NDA). 
                                                 
35 See Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names available 
at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075068.pdf. 
  17 
    Contains Nonbinding Recommendations 
 
 
  In the next box, you should identify that you are submitting a 505(b)(2) type of NDA. 
 
  In the box for ANDAs, you should write NA. 
 
  Under Type of Submission, you should check the appropriate type.  For the three drugs 
addressed in this guidance, you will most likely check Original Application.  
 
  Under Reason for Submission, you should write Complete new application that has never 
before been submitted. 
 
  Under Proposed Marketing Status, you should check Prescription Product (Rx).  
 
  You should check the appropriate boxes to identify the number of volumes submitted and the 
application format. 
 
4.  Establishment information 
 
You should supply the requested information; if you need more space, attach an additional sheet.  
 
In the next part, on Cross References, you may want to reference other applications in your 
application.  For example, you may refer to an investigational new drug application (IND), an 
NDA or ANDA, or a drug master file (DMF).  If you reference another application or a DMF, 
you should list the number(s) of the referenced documents in this Cross References section.  
 
5.  The individual items based on the regulations  
 
This is the longest, most detailed part of Form FDA 356h.  The individual items in this section 
are discussed in detail in section B below.  
  
6.  Certification 
 
This section is at the end of Form FDA 356h following the individual items.  It provides your 
certification to FDA that the information you are providing is true to the best of your knowledge.  
You also agree to update specific parts of your application as needed and submit required safety 
reports.  Finally, the certification shows that you agree to comply with all applicable laws and 
regulations.   
 
  Current good manufacturing practices  
 
As directed by section 121 of FDAMA, FDA has developed CGMP requirements for PET drugs 
(74 FR 65409, December 10, 2009).  These requirements are set forth in 21 CFR part 212 and 
become effective December 12, 2011.  In the future, Form FDA 356h will be changed to reflect 
the PET drug industrys need to comply with the regulations in part 212.  Until then, you should 
provide the following statement in your application: 
  18 
    Contains Nonbinding Recommendations 
 
 
 
 
 
(Name of Applicant) certifies that the methods used in and the facilities and controls used 
 
for the compounding, manufacturing, processing, packaging, testing, and holding of (name 
 
of drug) conform and will continue to conform to the positron emission tomography 
 
compounding standards and the official monographs of the United States Pharmacopeia 
 
until December 12, 2011.  As of  December 12, 2011, the methods used in and the facilities 
 
and controls used for  the compounding, manufacturing, processing, packaging, testing, and 
 
holding of (name of drug) will conform to the requirements in 21 CFR 212.  
 
 
 
7.  Signature of responsible official 
 
After reading and understanding the information provided in the Certification section, the 
responsible official is asked to sign the application and provide some additional routine 
information.  
 
B.  Individual Items in the Application Form 
 
The following discussion addresses the individual items in an NDA as they appear on page 2 of 
Form FDA 356h and is based on the specific requirements in the regulations (21 CFR 314.50).  
Each item is discussed, and recommendations are made as to what information should be 
included in the application.  These items may be submitted in the CTD format, with 
incorporation of each item into its applicable module.  Administrative information, the index, 
and labeling are included within module 1.  Other module contents are designated within each 
item. 
 
All applicants should follow the list of items on page 2 of Form FDA 356h as they complete 
their applications.  This list, which corresponds to the following discussion, identifies what 
should be included and should be used as a road map for organizing and locating information in 
the application.  See also the suggested formats for Form FDA 356h in the separate attachments.   
 
1.  Index 
 
You should provide an index for your submission.  If you submit in a paper format, the 
individual sections of the application (i.e., the items in this list) and each section of each volume, 
if applicable, should be separated by dividers and tabbed.  Pages should be numbered 
sequentially from the first page in volume one to the last page in the last volume (i.e., each 
volume should not start with page one).   
  19 
    Contains Nonbinding Recommendations 
 
2.  Labeling 
 
The draft package insert must be submitted electronically, regardless of whether your NDA is 
paper-based or entirely electronic.  Other aspects of electronic labeling submission are described 
in section V.B. 
 
Within a paper-based submission, the application must also contain four (4) copies of a draft 
product label and all labeling for the drug product.  See section V.B. for information about 
submitting labeling electronically. 
 
Once FDA approves your NDA, you will need to submit the final content of labeling (package 
insert) electronically.   The final vial and lead container labels may be submitted electronically 
or as paper copies.  If you submit paper copies of the vial and container labels, supply 12 
copies.36  
 
3.  Summary  
 
You must provide a summary of your application (module 2 of the CTD).  The summary can be 
a simple statement naming the drug product, listing the indication(s), and stating your reliance on 
the PET Safety and Effectiveness Notice, which provides the basis for the determination of 
safety and effectiveness required for FDA approval.  Here is an example of an application 
summary for fludeoxyglucose F 18 injection for all three indications:  
 
 
  In accordance with FDAs PET Safety and Effectiveness Notice published in the Federal 
  Register of March 10, 2000 (65 FR 12999), (Name of applicant) is submitting this new 
  drug application, as described in section 505(b)(2) of the Federal Food, Drug and 
  Cosmetic Act, for fludeoxyglucose F 18 injection for the following indications: 
   
  1.  Fludeoxyglucose F 18 injection is indicated in positron emission tomography 
  (PET) imaging for assessment of abnormal glucose metabolism to assist in the 
  evaluation of malignancy in patients with known or suspected abnormalities 
  found by other testing modalities, or in patients with an existing diagnosis of 
  cancer. 
 
2.  Fludeoxyglucose F 18 injection is indicated in positron emission tomography 
(PET) imaging in patients with coronary artery disease and left ventricular 
dysfunction, when used together with myocardial perfusion imaging, for the 
identification of left ventricular myocardium with residual glucose metabolism 
and reversible loss of systolic function. 
 
3.  Fludeoxyglucose F 18 injection is indicated in positron emission tomography 
(PET) imaging in patients for the identification of regions of abnormal glucose 
metabolism associated with foci of epileptic seizures. 
 
                                                 
36 See 21 CFR 314.50(e)(2)(ii) 
  20 
    Contains Nonbinding Recommendations 
 
 
Here is an example of an application summary for ammonia N 13 injection: 
 
 
In accordance with FDAs PET Safety and Effectiveness Notice published in the 
 
Federal Register of March 10, 2000 (65 FR 12999), (Name of applicant) is submitting 
 
this new drug application, as described in section 505(b)(2) of the Federal Food, 
 
Drug, and Cosmetic Act, for ammonia N 13 injection.  Ammonia N 13 injection is 
 
indicated for positron emission tomographic (PET) imaging of the myocardium under 
 
rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients 
 
with suspected or existing coronary artery disease. 
 
 
 
Here is an example of an application summary for sodium fluoride F 18 injection: 
 
 
  In accordance with FDAs PET Safety and Effectiveness Notice published in the 
  Federal Register of March 10, 2000 (65 FR 12999), (Name of applicant) is submitting 
  this new drug application as described in section 505(b)(2) of the Federal Food, Drug 
  and Cosmetic Act, for sodium fluoride F 18 injection.  Sodium fluoride F 18 injection is 
  indicated for positron emission tomography (PET) imaging as a bone imaging agent to 
  define areas of altered osteogenic activity. 
 
 
 
4.  Chemistry section 
 
We have provided as separate attachments on our web site sample formats for chemistry sections 
(that can be submitted in CTD module 3) for each of the three PET drug products addressed in 
this guidance.37  You can use these sample formats to provide information and data in your 
application about your manufacture of these PET drugs.   
 
5.-12.  Sections 5 through 12 
 
You will not need to supply much information for these sections.  Within Module 4 (nonclinical 
study reports), you may designate the section as not applicable if you are relying on the PET 
Safety and Effectiveness Notice as the basis for the determination of safety and effectiveness 
required for FDA approval of your NDA for fludeoxyglucose F 18 injection, sodium fluoride F 
18 injection, or ammonia N 13 injection.  You should provide a statement referencing the notice 
(CTD Module 5).  In addition, you must provide a pediatric assessment indicating the 
requirement has been satisfied, waived, or deferred, as appropriate, as required by the Pediatric 
Research Equity Act (PREA) Public Law 108-155 (2003) (codified at 21 U.S.C. 355B).  These 
are discussed below, and sample statements are provided.  
                                                 
37 Module 3 of the CTD includes both a drug substance and a drug product section.  If the drug substance and drug 
product in your application are the same, you need only provide the information once.  You may, however, provide 
information about the precursor in the drug substance section.  
  21 
    Contains Nonbinding Recommendations 
 
 
Here is an example of a statement referring to the PET Safety and Effectiveness Notice as the 
basis for your NDA.  Please fill in the name of the appropriate PET drug. 
 
 
 
For this NDA for (name of drug), information requirements for the following sections 
 
are satisfied by the PET Safety and Effectiveness Notice published in the Federal 
 
Register of March 10, 2000 (65 FR 12999):  
 
 
 
Clinical pharmacology and toxicology 
 
Human pharmacokinetics and bioavailability 
 
Clinical data 
 
Safety update report 
 
Statistical section 
 
Case report tabulations 
 
Case report forms 
 
 
 
The PET Safety and Effectiveness Notice states that FDA will consider the evidence for 
 
approval of this PET drug to include FDAs determination of safety and effectiveness 
 
for the indications stated above. 
 
 
  Pediatric Research Equity Act (PREA) 
 
PREA requires that all applications for a new active ingredient, new indication, new dosage 
form, new dosing regimen, or new route of administration contain an assessment of the safety 
and effectiveness of the drug for the claimed indication in relevant pediatric subpopulations 
unless the requirement is waived or deferred.  Among the three PET drugs and indications 
discussed in this guidance, safety and effectiveness have been established among pediatric 
patients in all relevant age groups for ammonia N 13 injection, for sodium fluoride F 18 
injection, as well as for the neurologic use (epilepsy) of fludeoxyglucose F 18 injection.   
 
The pediatric use of fludeoxyglucose F18 injection for the oncology and cardiac indications has 
not been established.   If you submit an NDA for all three fludeoxyglucose F 18 injection 
indications, include a statement that describes your plans to address the need for pediatric 
assessments in all relevant pediatric age groups.  We suggest that you include the following 
statements to address the pediatric assessment expectations within an NDA. 
 
Within an NDA for ammonia N 13 injection, sodium fluoride F 18 or fludeoxyglucose F 18 
injection (neurologic indication): 
 
  The PET Safety and Effectiveness Notice states that there is sufficient information for 
  pediatric assessment in the labeling of (name of PET drug) for the indications listed in the 
  notice in all relevant pediatric age groups. 
 
Within an NDA for fludeoxyglucose F18:    
  22 
    Contains Nonbinding Recommendations 
 
 
 
 
The PET Safety and Effectiveness Notice states that the pediatric assessment for sodium 
 
fluoride F 18 injection is deferred for five years until the agency adopted approval 
 
procedures and CGMP requirements.  A five year deferral is also requested for the 
 
oncologic and cardiac indications for fludeoxyglucose F 18 injection. 
 
 
 
13.-14. Patent Certification and Exclusivity Statement 
 
Applicants submitting 505(b)(2) NDAs must submit information regarding the patent  
protections covering and exclusivity sought for the PET product for which approval is sought 
and patent certifications and exclusivity statements regarding patents or exclusivity covering the 
listed drug they reference.  More information on these two topics and examples of the statements 
you will need to provide in your application are provided here.  This information is provided 
within CTD module 1.   
 
Protections covering the PET product for which approval is sought: 
 
  Patent information 
 
Any applicant who submits an NDA must provide the Agency with the patent number and 
expiration date for patents, held by the applicant or anyone else, for certain patents (21 CFR 
314.53). Specifically, information must be submitted for patents covering the drug product 
  
(formulation, composition), the drug substance (active ingredient), or a method of use for which 
the applicant seeks approval, such as a drug products indication for use.38   
 
Prior to approval, applicants must use FDA form 3542a to submit information on these patent(s) 
to the Agency.  After an NDA is approved, the applicant must confirm the patent(s) to be listed 
by submitting FDA form 3542 within 30 days of approval.  These forms must be used even when 
the applicant has no patents to list.39 
 
 
After approval, the applicant will be required to submit relevant patent information for patents 
that claim the approved drug substance, drug product, or method of use on form 3542. 
 
  Claimed exclusivity 
 
FDA can grant 3- or 5-year marketing exclusivity for certain drug products approved through the 
NDA process.40 For example, 5 years of marketing exclusivity are granted by FDA for new 
   
chemical entities that have never been previously approved by FDA alone or in combination. 
                                                 
38 Process patent information must not be submitted to FDA (21 CFR 314.53(b)).  When the application is 
approved, patent information will be published in the Orange Book. 
39 This form is available on the Internet at http://www.fda.gov/opacom/morechoices/fdaforms/default.html. 
40 See 21 CFR 314.108. 
  23 
    Contains Nonbinding Recommendations 
 
Three-year exclusivity may be granted if new clinical studies are conducted by or for the 
applicant and are essential to the approval of an NDA or a supplement to an NDA, such as for 
approval or a new indication.  Because we anticipate no need for you to submit clinical study 
data, an exclusivity claim is not likely to be appropriate for NDAs and ANDAs submitted in 
accordance with this guidance.  NDA applicants who believe they are eligible for either 3- or 5-
year exclusivity must include in the NDA information describing the basis for the claimed 
exclusivity.41   
 
Protections covering other approved NDAs for the same PET drug: 
 
  Patent certifications 
 
Applicants submitting 505(b)(2) NDAs are required to submit patent certifications for the patents 
listed for the listed drug their application references.42 If you seek to reference fludeoxyglucose 
   
F 18 injection, sodium fluoride F 18 injection, or ammonia N 13 injection and no patents are 
listed for the drug in the Orange Book at the time of your submission, you need only provide a 
no relevant patents certification.43 
 
Here is an example of a no relevant patents certification statement that you can use for 
fludeoxyglucose F 18 injection, sodium fluoride F 18 injection, or ammonia N 13 injection:    
 
 
 
In the opinion and to the best knowledge of (name of applicant), there are no patents that 
 
claim the listed drug or that claim a use of the listed drugs.   
 
 
 
In the future, when additional applications for these PET drug products are approved, the patent 
status of these PET drugs could change.  Patent information should be verified with the latest 
version of the Orange Book (published and updated electronically) and its supplements. 
 
  Exclusivity statement 
 
The submission and approval of 505(b)(2) NDAs may be affected by exclusivity granted to an 
approved product.  Fludeoxyglucose F 18 injection, and sodium fluoride F 18 injection are 
approved PET drug products and currently are not covered by any market exclusivity.  Because 
they are not covered by any market exclusivity, you should provide a no exclusivity statement in 
your NDA.44 Here is an example of a no exclusivity statement you can use in your NDA for 
   
fludeoxyglucose F 18 injection or sodium fluoride F 18 injection. 
 
 
                                                 
41 See 21 CFR 314.50(j). 
42 Additional information about patent certifications can be found in 21 CFR 314.50(i). 
43 See 21 CFR 314.50(i)(1)(ii). 
44 See 21 CFR 314.107(d).  
  24 
    Contains Nonbinding Recommendations 
 
 
According to the Approved Drug Products with Therapeutic Equivalence Evaluations 
 
(Orange Book), the reference listed drug is not subject to a period of marketing 
 
exclusivity under section 505(c)(3)(E) of the Act (21 U.S.C. 355(c)(3)(E)). 
 
 
 
Ammonia N 13 injection is covered by NCE exclusivity.  However, the NDA holder has waived 
the exclusivity.45  Here is an example of a statement you can use for Ammonia N 13 in your 
NDA until August 23, 2012, when the exclusivity for Ammonia N 13 injection expires. After 
that time, the no exclusivity statement may be used in your NDA for Ammonia N 13. 
 
 
 
[Name of applicant] acknowledges the New Chemical Entity (NCE) exclusivity attached to 
 
NDA 022119.  This exclusivity expires on August 23, 2012.  However, as indicated in the 
 
Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), the 
 
holder of NDA 022119, Feinstein Institute Medical Research, has waived this exclusivity.  
 
Because NCE exclusivity for NDA 022119 has been waived, [Name of applicant] may 
 
submit an NDA for Ammonia N 13 prior to the expiration of NCE exclusivity.  
 
 
 
 
In the future, when additional applications for these PET drug products are approved, the 
exclusivity status of these PET drugs could change.  Exclusivity information should be verified 
with the latest information in the Orange Book and its supplements. 
 
15.  Establishment description 
 
This item on Form 356h does not apply to drug applications submitted to the Center for Drug 
Evaluation and Research. 
 
16.  Debarment certification 
 
You must provide a debarment certification and a conviction statement.  Explanations and 
examples are provided below.  
 
  Debarment certification 
 
As of June 1, 1992, an NDA must include certification that the applicant did not and will not use 
the services (in any capacity) of any person debarred under section 306(a) or (b) of the Act 
(21 U.S.C. 355a(a) or (b)) in connection with the submission of their application.46  
                                                 
45 See Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) available at 
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.  
 
46 Use of a debarred individual or firm may preclude the approval of the application. 
 
  25 
    Contains Nonbinding Recommendations 
 
Debarment is an administrative procedure used by the Agency to bar individuals and/or 
companies who have been convicted of a felony or a misdemeanor related to the development or 
approval of any drug from providing certain services to an applicant or manufacturer.  Typically, 
a debarred person is an individual or company convicted of fraud related to the submission of a 
drug application. 
 
Debarment certification is a self-attestation by the applicant.  Applicants must include a 
certification addressing debarment and a statement about conviction of crimes that could lead to 
debarment.  Here is an example of a debarment certification that you can use in your NDA.  
 
 
 
I, (name of applicant), certify that I, or we, did not and will not use the services, in any 
 
capacity, of any person debarred under section 306 of the Federal Food, Drug, and 
 
Cosmetic Act in connection with this application. 
 
 
 
  Convictions 
 
No information or statement with respect to convictions is needed if your application is an NDA. 
 
17.  Field copy certification 
 
The field copy of your NDA will be used by FDA field investigator(s) during your PET drug 
production facilitys preapproval inspection.  The field copy must contain the NDAs technical 
section, the application form, and the summary.  You must certify that it is a true copy of the 
technical section described in the regulations and contained in the archival and review copies of 
the application.  
 
Here is an example of a field copy certification you can use. 
 
 
 
(Name of applicant) certifies that the field copy is a true copy of the technical section of the 
 
application described in 21 CFR 314.50(d)(1) and contained in the archival and review 
 
copies of the application. 
 
 
 
If questions arise regarding the field copy, please contact CDERs Office of Compliance at 301-
796-3100 
 
18.  User fee cover sheet (Form FDA 3397) 
 
For NDAs: 
 
  26 
    Contains Nonbinding Recommendations 
 
  Complete the PDUFA user fee cover sheet online at 
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119184.htm.  
Detailed instructions are provided on the Web page. 
  In response to the question asking if you have a waiver, answer Yes if your 
505(b)(1) or (b)(2) application was submitted in accordance with the PET Safety 
and Effectiveness Notice. 
 
  When you have answered all questions, review the form for accuracy. 
 
  Submit the form electronically for assignment of a user fee ID number.  Print the 
final cover sheet with the assigned user fee ID number. 
 
  Include a signed copy of the cover sheet with the assigned user fee ID number 
with Form FDA 356h in the NDA. 
 
19.  Financial Disclosure Information 
 
Because the determination of safety and effectiveness for these PET drugs is based on the 
Agencys review of the literature or on previous Agency findings regarding approved 
applications, rather than on clinical trials to support the submission of an application, it is not 
necessary to include a financial disclosure form (Form FDA 3455) with these applications.  For 
this same reason, financial certifications and disclosure statements by clinical investigators (21 
CFR part 54) are not required as part of the applications for fludeoxyglucose F 18 injection, 
ammonia N 13 injection, and sodium fluoride F 18 injection.   
  27 
    Contains Nonbinding Recommendations 
 
APPENDIX B:  ANDAS  WHAT SHOULD YOU INCLUDE IN YOUR ANDA? 
 
This section of the guidance is based largely on section 505(j) of the Act and regulations in 21 
CFR part 314, subpart C.  As a result, this section contains extensive mandatory language.  This 
mandatory language is used whenever the Act and/or FDA regulations require the submission of 
certain information.  Unlike other guidance documents in which mandatory language is typically 
accompanied by the related cite, to make the guidance more user friendly and less cumbersome, 
we do not cite each regulation each time we discuss a requirement.  
 
This section of the guidance discusses the content and format of an ANDA.  If your drug is the 
same as a listed drug (e.g., fludeoxyglucose F 18 injection, sodium fluoride F 18 injection, or 
ammonia N 13 injection), you should submit an ANDA.  After providing general information, 
we will present a step-by-step description of what you should put in each section of the ANDA.  
Sample formats for the content and format of the chemistry sections for each PET drug are 
provided as separate attachments.  
 
Before beginning to fulfill the submission requirements of the ANDA, you should determine 
whether your product is the same as the listed drug you reference (RLD).  As noted in section 
IV.B., some minor differences are permitted. 
 
Once you have decided to submit an ANDA, you must fill out Form FDA 356h and provide the 
FDA with a variety of information on your product.  An ANDA contains a completed and signed 
application form (Form FDA 356h) and a number of individual items based on the regulations.     
 
When an ANDA is submitted to the FDA, three copies are required if the application is paper-
based:  (1) an archival copy for the official record, (2) a review copy to be used to evaluate your 
application, and (3) a field copy, which will be used as part of your preapproval inspection by 
the FDA.  The archival copies are to be submitted in blue jackets, the review copies are to be 
submitted in red jackets, and the field copies are to be submitted in burgundy jackets.  We will 
describe the specific requirements for the field copy later in this guidance.   
 
If submitting a paper application, your completed application should be sent to: 
 
       Director, Office of Generic Drugs 
Center for Drug Evaluation and Research 
Food and Drug Administration 
Metro Park North VII 
7620 Standish Place 
Rockville, MD  20855 
 
If you choose to submit your application electronically, you may submit it via the electronic 
submission gateway, or you may submit it electronically on physical media.  See 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire
ments/ElectronicSubmissions/UCM163567.pdf.  If you are submitting through the gateway, 
organize the submission in the CTD format, in a manner similar to that for an NDA. 
 
  28 
    Contains Nonbinding Recommendations 
 
A.  Application Form  
 
The application form is Form FDA 356h.47  This form should be completed and signed by the 
applicant, or the responsible official.  
 
The form contains seven major sections:  (1) applicant information, (2) product description, 
(3) application description, (4) establishment information, (5) the individual items based on the 
regulations, (6) certification, and (7) signature of responsible official.  These sections are 
discussed in detail in the following paragraphs.  
 
1.  Applicant information 
 
This section requests general information about the applicant:  name, address, telephone number, 
and fax number.  If you wish to use an agent or consultant to act on your behalf, you should also 
provide the name and address of the person authorized on your behalf in the application.  If a 
particular section does not apply, please write NA (not applicable). 
 
2.  Product description 
 
The descriptions below should be used in completing this section for these three PET drugs: 
 
Product description template for use in PET drug application 
 
 
  Established Name:  Fludeoxyglucose F 18 injection (or sodium fluoride F 18 injection) 
   
  Proprietary Name:     Write none or identify the proposed proprietary name* 
   
  Dosage Form:     Injection 
   
  Strengths:  Indicate amount of drug substance range in mCi/mL at end of 
  synthesis (EOS) reference time 
   
  Route of Administration:  Intravenous 
   
  Indication(s) for use:   As in Section III (above) 
                                                 
47 This form contains the information required under 21 CFR 314.94(a)(1) for an ANDA. 
 
  29 
    Contains Nonbinding Recommendations 
 
 
 
*We do not anticipate the need for proprietary names.  If you wish to propose a proprietary name, 
information on the proposal submission process is available in FDA guidance.48
 
3.  Application description 
 
This section asks for information about the type of application you are submitting.  
 
  You should check the appropriate application type in the first box (ANDA). 
 
  You should write NA in next box and go to the third box. 
 
In this box, you are asked to provide general information on the RLD.  An ANDA must state the 
name of the RLD including its dosage form and strength as identified by the symbol (+) in the 
Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book).   
 
For fludeoxyglucose F 18 injection, the RLD should be listed as one of the 
following: 
 
 
NDA 20-306, Fludeoxyglucose F 18 Injection, held by Downstate 
 
Clinical PET Center 
 
 
 
 
  NDA 21-768, Fludeoxyglucose F 18 Injection, held by Weill Medical 
  College of Cornell University  
   
 
 
  NDA 21-870, Fludeoxyglucose F 18 Injection, held by Feinstein Institute 
  for Medical Research 
 
 
 
NDA 21-768, Fludeoxyglucose F 18 Injection, held by Weill Medical 
 
College of Cornell University  
 
 
 
 
NDA 21-870, Fludeoxyglucose F 18 Injection, held by Feinstein Institute 
 
for Medical Research 
 
 
                                                 
48 See Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names.  This 
guidance is located at the internet address of: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075068.pdf. 
  30 
    Contains Nonbinding Recommendations 
 
 
Note:  If FDA approves other applications for fludeoxyglucose F 18 injection 
submitted in accordance with the PET Safety and Effectiveness Notice, it is 
possible that these products could become alternative RLDs. 
 
For sodium fluoride F 18 injection, the RLD should be listed as one of the 
following: 
 
 
NDA 17-042, (18 F) as Fluoride Ion in Saline Solution, held by GE 
 
Healthcare. 
 
 
 
NDA 22-494, Sodium Fluoride F-18 Injection, held by the National 
 
Cancer Institute. 
 
 
 
  NDA 22-494, Sodium Fluoride F-18 Injection, held by the National 
  Cancer Institute. 
 
 
For ammonia N 13 injection, the RLD should be listed as follows: 
 
 
NDA 22-119, Ammonia N 13 injection, held by Feinstein Institute for 
 
Medical Research  
 
 
As with fludeoxyglucose F 18 injection, if FDA approves other applications for sodium fluoride 
F 18 injection or ammonia N 13 injection submitted in accordance with the PET Safety and 
Effectiveness Notice, it is possible that these products could become alternative RLDs.  
 
  Under Type of Submission, you should check the appropriate type.  For the drugs 
addressed here, you will most likely check Original Application.  
 
  Under Reason for Submission, you should write Submission of an ANDA. 
 
  Under Proposed Marketing Status, you should check Prescription Product (Rx).  
 
4.  Establishment information 
 
Supply the requested information; if you need more space, attach an additional sheet. 
  
5.  Cross References 
 
You may want to reference other applications in your ANDA which contain information upon 
which you want to rely.  For example, you may refer to an investigational new drug (IND), 
  31 
    Contains Nonbinding Recommendations 
 
NDA, or other ANDA, or a drug master file (DMF).  If you are going to reference another 
application or DMF, you should list the number(s) of the referenced documents in this section.   
 
6.  The individual items based on the regulations 
 
This is the longest, most detailed part of Form FDA 356h.  The individual items in this section 
are discussed in detail in section B, below.  The items required for an ANDA differ from those 
on page 2 of Form FDA 356h.  Please use the list presented in section B as the proper list of 
individual items to be submitted (see also 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064995.htm). 
  
7.  Certification 
 
This section is at the end of Form FDA 356h following the individual items.  It provides your 
certification to the FDA that the information you are providing is true to the best of your 
knowledge.  You also agree to update specific parts of your application as needed and submit 
required safety reports.  Finally, the certification states that you agree to comply with all 
applicable laws and regulations.   
 
  Current good manufacturing practices  
 
As directed by section 121 of the Modernization Act, the FDA has developed current good 
manufacturing practice (CGMP) requirements for PET drugs (74 FR 65409, December 10, 
2009).  These requirements are set forth in 21 CFR part 212 and become effective on December 
12, 2011.  In the future, Form FDA 356h will be changed to reflect the PET drug industrys need 
to comply with the regulations in part 212.  Until then, you should provide the following 
statement in your application: 
 
 
(Name of Applicant) certifies that the methods used in and the facilities and controls used 
 
for the compounding, manufacturing, processing, packaging, testing, and holding of (name 
 
of drug) conform and will continue to conform to the positron emission tomography 
 
compounding standards and the official monographs of the United States Pharmacopeia, 
 
until December 12, 2011.  As of December 12, 2011, the methods used in and the facilities 
 
and controls used for the compounding, manufacturing, processing, packaging, testing and 
 
holding of (name of drug) will conform to the requirements in 21 CFR 212.  
 
 
 
8.  Signature of responsible official  
 
After reading and understanding the information provided in the Certification section, the 
responsible official is asked to sign the application and provide some additional routine 
information.  
 
B.  Individual Items in the Application 
 
  32 
    Contains Nonbinding Recommendations 
 
The following discussion addresses the individual items in an ANDA.  Rather than providing the 
items listed on page 2 of Form FDA 356h, some of which apply only to NDAs, you should 
provide information to FDA according to the list that follows here.  Each of the following items 
is discussed and recommendations are made as to what information should be included.  The 
following discussion is based on the specific requirements in the regulations (21 CFR 314.94) 
and section 306(k) of the Act.    
 
An ANDA contains the following individual items or sections:  
 
1.  Table of contents 
2.  Basis for ANDA submission (reference to listed drug or approved suitability petition) 
3.  Patent certification and exclusivity statement  
4.  Comparison of RLD and generic drug 
  Conditions of use 
  Active and inactive ingredients 
  Route of administration, dosage form, and strength 
5.  Bioequivalence information 
6.  Labeling 
7.  Chemistry, manufacturing, and controls information  
8.  Financial disclosure 
9.  Debarment certification 
10. Field copy certification 
11. Other  
  
This list, which corresponds to the following discussion, identifies what should be included and 
can be used as a road map for organizing the application.  In addition, we have prepared sample 
formats for the chemistry sections for the PET drug products addressed in this guidance, 
available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078740.pdf  
 
1.  Table of contents 
 
All ANDAs should include a table of contents following Form FDA 356h. The current 
recommended format for submitting an ANDA is the CTD.  Applications in CTD format may be 
submitted to the Agency in either paper CTD or electronic CTD format.  For information 
regarding the organization of an ANDA in CTD format, see the ANDA checklist for CTD or 
eCTD format, which is available at the Office of Generic Drugs Web page at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approva
lApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm142112.htm.  The eleven items 
listed in this section should be organized in a manner that corresponds to the modules of the 
CTD, as indicated in the ANDA checklist. 
 
The table of contents provides a road map to locate information in the application.  Each section 
of the application should be delineated by dividers and tabbed when submitted in paper, and the 
pages should be numbered sequentially from the first page in volume one to the last page in the 
last volume (i.e., each volume should not start with page 1). 
  33 
    Contains Nonbinding Recommendations 
 
 
2.  Basis for ANDA submission (RLD) 
 
You should cite the RLD you will be using in the application as described above under 
Application Description. 
 
3.  Patent Certification and exclusivity statements 
 
You will need to submit both a patent certification and an exclusivity statement.  Examples are 
provided here.  
 
  Patent certification 
 
ANDA applicants are required to submit patent certifications.  The need for patent certifications 
depends on the patents listed for the RLD in the Orange Book.49   
 
Currently, there are no patents listed in the Orange Book for the approved PET drugs, 
fludeoxyglucose F 18 injection, sodium fluoride F 18 injection, or ammonia N 13 injection.  If at 
the time of ANDA submission there are no listed patents for your RLD, you must provide a no 
relevant patents certification in your ANDA. 
 
Here is an example of a no relevant patents certification that you can use for fludeoxyglucose F 
18 injection, sodium fluoride F 18 injection, and ammonia N 13 injection, as long as no patents 
are listed. 
 
 
In the opinion and to the best knowledge of (name of applicant), there are no patents that claim 
 
the listed drug referred to in this application or that claim a use of the listed drug.  
 
 
  Exclusivity statement 
 
The submission and approval of ANDAs may be affected by exclusivity granted to the RLD.50  
Fludeoxyglucose F 18 injection and sodium fluoride F 18 injection are approved PET drugs and 
currently are not covered by any market exclusivity.  If at the time of ANDA submission they are 
not covered by any market exclusivity, you should provide an exclusivity statement in your 
ANDA acknowledging that there is no unexpired exclusivity for the RLD.51  
 
                                                 
49 Additional information about patent certifications can be found in 21 CFR 314.94(a)(12). 
50 See 21 CFR 314.108(b). 
51 See 21 CFR  314.94(a)(3)(ii). 
  34 
    Contains Nonbinding Recommendations 
 
Here is an example of an exclusivity statement you can use for fludeoxyglucose F 18 injection 
and sodium fluoride injection in your ANDA. 
 
 
 
According to the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange 
 
Book), the reference listed drug is not entitled to a period of marketing exclusivity under Section 
 
505(j)(5)(F) of the Act (21 U.S.C. 355(j)(5)(F)). 
 
 
 
Ammonia N 13 injection is covered by exclusivity, however, the NDA holder has waived the 
exclusivity.52  Here is an example of a statement you can use for Ammonia N 13 in your ANDA. 
 
 
  [Name of applicant] acknowledges the New Chemical Entity (NCE) exclusivity attached to NDA 
  022119.  This exclusivity expires on August 23, 2012.  However, as indicated in the Approved 
  Drug Products with Therapeutic Equivalence Evaluations (Orange Book), the holder of NDA 
  022119, Feinstein Institute for Medical Research, has waived this exclusivity.  Because NCE 
  exclusivity for NDA 022119 has been waived, [Name of applicant] may submit an ANDA for 
  Ammonia N 13 prior to the expiration of NCE exclusivity.  
 
 
 
In the future, when additional applications for these PET drug products are approved, the patent 
or exclusivity status could change and other patent and/or exclusivity statements could be 
required.  Patent and exclusivity information always should be verified with the latest 
information in the "Patent and Exclusivity Addendum" of the Orange Book and its supplements.  
 
4.  Comparison of RLD to generic drug 
 
This is the section in which you should provide information comparing your drug (the generic 
drug) to the RLD you are referencing.  You will be asked to provide information on the 
conditions of use, active and inactive ingredients, route of administration, dosage form, and 
strength. 
 
Following a brief discussion of each, an example statement is provided in the box at the end of 
this section along with tables showing comparisons of the proposed generic with the RLD for 
fludeoxyglucose F 18 injection, sodium fluoride F 18 injection, and ammonia N 13 injection. 
 
  Conditions of use 
 
                                                 
52 See Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) available at 
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.  
 
  35 
    Contains Nonbinding Recommendations 
 
You should provide a statement that the conditions of use prescribed, recommended, or 
suggested in the labeling proposed for the drug product have been previously approved for the 
RLD.  In the statement, indicate that you have provided the necessary information in the labeling 
section of the application (see example statements below).   
 
  Active and inactive ingredients 
 
ANDA submission requires that the proposed generic drug be the same as the RLD, with certain 
exceptions discussed below.  Same means that the proposed drug has identical active 
ingredient(s), dosage form, strength, route of administration, and conditions of use as the RLD, 
and is bioequivalent to the RLD.  Generic injectable drug products can differ from the RLD in 
preservative, buffer, and/or antioxidant (exception excipients).  These differences must not affect 
the safety or effectiveness of the generic drug. 
 
You should provide a statement that the active ingredient in the proposed drug product is the 
same as the active ingredient in the RLD.  In the statement, indicate that you have provided the 
necessary information in the labeling section of the application (see example statements below). 
Examples of ways in which the generic product may differ from the RLD include: 
 
  The generic product may include a permissible exception excipient that does not 
appear in the RLD provided the difference does not affect the safety or effectiveness 
of the product. 
  The generic product may omit an exception excipient that is present in the RLD 
provided the difference does not affect the safety or effectiveness of the product. 
  The concentration of the exception excipient in the generic product may be different 
from that in the RLD, but has been previously approved in another drug product 
given by the same route of administration (e.g., intravenous). The difference must not 
affect the safety or effectiveness of the product. 
 
If the inactive ingredients in a generic PET injectable drug product differ from the RLD in ways 
other than those described in the bulleted list above, an ANDA may not be appropriate.  In such 
cases, a 505(b)(2) NDA might be appropriate. 
 
  Route of administration, dosage form, and strength 
 
You must provide a statement that the route of administration, dosage form, and strength of the 
proposed drug product are the same as those of the RLD (see example statements below).53  
Here is a statement you can use if your product is the same as the RLD in active ingredient, 
conditions of use, route of administration, dosage form, and strength. 
 
 
 
 
 
                                                 
53 Any differences require an approved suitability petition. 
  36 
    Contains Nonbinding Recommendations 
 
 
 
The conditions of use prescribed, recommended, or suggested in the labeling proposed 
 
for the generic drug have been previously approved for the RLD. 
 
 
 
The active ingredient, route of administration, dosage form, and strength are the same 
 
as that of the RLD. 
 
 
If differences exist between your proposed drug and the RLD and you have obtained approval of 
an ANDA suitability petition (see section IV.B.3.), these differences should be explained and a 
copy of the suitability petition approval letter should be included. 
 
The tables below compare a proposed drug with the RLD for fludeoxyglucose F 18 injection, 
sodium fluoride F 18 injection, and ammonia N 13 injection, respectively.  You can adapt these 
tables and insert the appropriate table into your application under Comparison of RLD and 
generic drug.  
  37 
    Contains Nonbinding Recommendations 
 
Comparison of proposed generic fludeoxyglucose F 18 injection with the RLD 
 
  Generic Drug  RLD 
Conditions of use:  1.     Fludeoxyglucose F 18  1.     Fludeoxyglucose F 18 
  injection is indicated in  injection is indicated in 
  positron emission  positron emission 
  tomography (PET) imaging  tomography (PET) imaging 
  for assessment of abnormal  for assessment of abnormal 
  glucose metabolism to assist  glucose metabolism to assist 
in the evaluation of  in the evaluation of 
malignancy in patients with  malignancy in patients with 
known or suspected  known or suspected 
abnormalities found by other  abnormalities found by other 
testing modalities, or in  testing modalities, or in 
patients with an existing  patients with an existing 
diagnosis of cancer.  diagnosis of cancer. 
   
2.  Fludeoxyglucose F 18  2.  Fludeoxyglucose F 18 
injection is indicated in  injection is indicated in 
positron emission  positron emission 
tomography (PET) imaging  tomography (PET) imaging 
in patients with coronary  in patients with coronary 
artery disease and left  artery disease and left 
ventricular dysfunction,  ventricular dysfunction, 
when used together with  when used together with 
myocardial perfusion  myocardial perfusion 
imaging, for the  imaging, for the 
identification of left  identification of left 
ventricular myocardium with  ventricular myocardium with 
residual glucose metabolism  residual glucose metabolism 
and reversible loss of  and reversible loss of 
systolic function.  systolic function. 
   
3.  Fludeoxyglucose F 18  3.  Fludeoxyglucose F 18 
injection is indicated in  injection is indicated in 
positron emission  positron emission 
tomography (PET) imaging  tomography (PET) imaging 
in patients for the  in patients for the 
identification of regions of  identification of regions of 
abnormal glucose  abnormal glucose 
metabolism associated with  metabolism associated with 
foci of epileptic seizures.  foci of epileptic seizures. 
   
Active ingredient:  2-Deoxy-2[18F]fluoro-D-glucose  2-Deoxy-2[18F]fluoro-D-glucose 
Route of  Intravenous  Intravenous 
administration: 
  38 
    Contains Nonbinding Recommendations 
 
Dosage form:  Injection  Injection 
Strength:  4  90  mCi/mL (EOS*)  4  90  mCi/mL (EOS*) 
                 or                   or 
10  100 mCi/mL (EOS*)  10  100 mCi/mL (EOS*) 
                 or                    or  
20  200 mCi/mL (EOS*)  20  300 mCi/mL (EOS*) 
   
*End of synthesis calibration time 
 
 
Comparison of proposed generic sodium fluoride F 18 injection with the RLD 
 
 
  Generic Product  RLD
 
Conditions of use: Sodium fluoride F 18 Injection is  Sodium fluoride F 18 Injection is 
indicated for diagnostic positron  indicated for diagnostic positron 
emission tomography (PET)  emission tomography (PET) 
imaging of bone to define areas of  imaging of bone to define areas of 
 
altered osteogenic activity. altered osteogenic activity 
Active ingredient:  Sodium fluoride F 18  Sodium fluoride F 18 
Route of  Intravenous   Intravenous  
administration: 
Dosage form:  Injection  Injection 
Strength:  10  200 mCi/mL at EOS (end of  10  200 mCi/mL at EOS (end of 
synthesis)  synthesis) 
 
  39 
    Contains Nonbinding Recommendations 
 
Comparison of proposed generic ammonia N 13 injection with the RLD 
 
 
  Generic Product  RLD
 
Conditions of use: Ammonia N 13 injection is  Ammonia N 13 injection is 
indicated for diagnostic  indicated for diagnostic positron 
positron emission tomography  emission tomography imaging of 
imaging of the myocardium  the myocardium under rest or 
under rest or pharmacologic  pharmacologic stress conditions 
stress conditions to evaluate  to evaluate myocardial perfusion 
myocardial perfusion in  in patients with suspected or 
patients with suspected or  existing coronary artery disease. 
existing coronary artery 
 
disease.
Active ingredient:  Ammonia N 13  Ammonia N 13 
Route of  Intravenous  Intravenous 
administration: 
Dosage form:  Injection  Injection 
Strength:  3.75-37.5 mCi/mL (EOS)  3.75-37.5 mCi/mL (EOS) 
 
 
5.  Labeling 
 
The term product labeling is a collective term that includes the package insert, vial labels, and 
lead container labels.  The contents of labeling must be submitted electronically, regardless of 
whether you submit a completely electronic or paper-based application.  See section V.B. for 
information about submitting labeling electronically.  If your application is paper-based, you 
must also submit four (4) copies of a draft product label and all proposed labeling for the drug 
product.  
    
You must submit a statement that your proposed labeling is the same as the labeling for the RLD 
except for any differences annotated and explained.  If you reference the labeling templates on 
FDAs web site, you will incorporate by reference the appropriate information and you will not 
need to provide a side-by-side comparison. 
 
If you do not reference the labeling templates on FDAs web site, you also need to include a 
side-by-side comparison of your package insert and container labels with the RLD with all 
differences annotated and explained.  The labeling for approved drugs is available online at 
Drugs@FDA and the National Library of Medicine (see http://dailymed.nlm.nih.gov/dailymed). 
 
Once FDA approves your ANDA, you will need to electronically submit the final content of 
labeling (package insert).  The final vial and lead container labels may be submitted 
electronically or as paper copies.  If you submit paper copies of the carton and container 
labeling, supply 12 copies.  
 
  40 
    Contains Nonbinding Recommendations 
 
 
6.  Bioequivalence 
 
This section of the application should include a side-by-side comparison of the formulation of 
the proposed generic drug and the RLD.  Below are examples of side-by-side comparisons for 
each drug that you can adapt to your application.54
 
If your injectable product is identical to the RLD, containing the same active and inactive 
ingredients in the same concentrations (inactive ingredient variability of +/-5% is allowed), you 
can request a waiver under 21 CFR 320.22 of any requirement for evidence of in vivo 
bioequivalence.  In this case, bioequivalence will be established based on other data in the 
application.  You should request a waiver using the following language: 
 
 
  (Applicant name) requests that the FDA waive the requirement for the submission of 
evid ence demonstrating in vivo bioequivalence for (the proposed drug product).  (Drug 
pro duct) meets the provisions of 21 CFR 320.22(b)(1)(i) and (ii). 
 
 
 
If the proposed product is not Q1 and Q2 the same (as discussed above), the products 
bioequivalence must be demonstrated in accordance with 21 CFR 320.24.  For intravenously 
administered PET drug products, in accordance with 21 CFR 320.24(b)(6), FDA has determined 
that bioequivalence has been demonstrated in cases where differences in the inactive ingredients 
are sufficiently small that they will not significantly affect the physical and chemical properties 
of the drug product and where such ingredients have been previously used in the same or greater 
quantities in an approved drug product for the same route of administration.  
 
Examples of situations where FDA has determined that a bioequivalence study is not necessary 
to demonstrate bioequivalence include: 
 
  Presence of or absence of a preservative, buffer or an antioxidant (see 21 CFR 314.94(a) 
(9)(iii)) in the proposed PET drug product, where such ingredients and their amounts 
have been previously approved in a drug product and their amounts do not affect physical 
or chemical properties (e.g., specific gravity, viscosity, pH) in relation to the RLD.  
   Presence of or absence of a preservative, buffer or an antioxidant (see 21 CFR 314.94(a) 
(9)(iii)) in the proposed PET drug product, where such a change does not affect tonicity 
(osmolality) of the solution in relation to the RLD or an applicant has established  that the 
change in tonicity will not affect safety or effectiveness of the product. 
 
To demonstrate bioequivalence under 21 CFR 320.24(b)(6), the application should include a 
discussion with supportive evidence, usually from the FDA list of inactive ingredients for 
                                                 
54 As noted in section IV.B. this refers to a comparison between the end products. 
  41 
    Contains Nonbinding Recommendations 
 
previously approved products to support that the proposed product differences from the RLD are 
not likely to affect the safety or efficacy of the product.55
Fludeoxyglucose F 18 injection: side-by-side comparison (applicant to fill in missing 
information) 
 
Description  RLD  Applicant's Proposed 
Drug Product 
Active Ingredient:  4 mCi to  90 mCi/mL @ EOS*    ?   mCi to   ?  mCi/mL @ 
2-Deoxy-2-[18F]fluoro-D-glucose                   or  EOS* 
10 mCi to 100 mCi/mL @ 
EOS* 
                 or  
20 mCi to  300 mCi/mL @ 
EOS* 
Inactive Ingredients:     
Sodium chloride injection, USP  9 mg/mL    ?  mg/mL 
(Sodium chloride in WFI)   
                      or    
Sodium chloride ,  4.5 mg/mL 
Citrate   7.2 mg/mL 
(in water for injection (WFI) 
Osmolality  List from package insert of RLD ______  
Specific Activity   No carrier added  ? 
Dosage form  Injection  Injection 
Route of Administration  Intravenous  Intravenous 
 
Sodium fluoride F 18 injection:  side-by-side comparison (applicant to fill in missing 
information)  
 
Description  RLD  Applicants Proposed 
NDA 22-492  Drug Product 
  10  200 mCi/mL at EOS    ?   mCi/ mL to   ?   
(end of synthesis)  mCi/mL @ EOS 
Inactive Ingredients:     
0.9% Sodium chloride solution  9 mg/mL    ?  mg/mL 
Specific Activity   No carrier added  ? 
Dosage form  Injection  Injection 
Route of Administration  Intravenous  Intravenous 
 
                                                 
55 See http://www.fda.gov/Drugs/InformationOnDrugs/ucm113978.htm  
  42 
    Contains Nonbinding Recommendations 
 
Description  RLD  Applicants Proposed 
NDA 17-042  Drug Product 
Active Ingredient:  2 mCi / mL @ calibration      ?   mCi/mL @ calibration 
Sodium Fluoride F18  (4.22  0.22 mCi / mL)  (  ?  -  ?   mCi/mL) 
Inactive Ingredients:     
Sodium chloride injection, USP  9 mg/mL    ?  mg/mL 
(Sodium chloride in WFI) 
Specific Activity   No carrier added  ? 
Dosage form  Injection  Injection 
Route of Administration  Intravenous  Intravenous 
 
Ammonia N 13 injection:  side-by-side comparison (applicant to fill in missing information) 
 
Description  RLD  Applicants Proposed 
Drug Product 
Active Ingredient:     
Ammonia N 13   3.75 mCi to 37.5 mCi/mL   ?  mCi to ?  mCi/mL @ 
@ (EOS)*  (EOS)* 
Inactive Ingredient:     
0.9% aqueous sodium chloride  9 mg/mL    ?  mg/mL 
Specific Activity   No carrier added  ? 
Dosage form  Injection  Injection 
Route of Administration  Intravenous  Intravenous 
*  End of synthesis 
 
7.  Chemistry section 
 
Sample formats for chemistry sections for each of these PET drugs are available on FDAs web 
site at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078740.pdf
You may use these sample formats to provide information and data regarding your manufacture 
of these PET drugs.  
 
8.  Financial disclosure 
 
It is not necessary to include a financial disclosure form (Form FDA 3455) with an ANDA 
unless the application contains an in vivo bioequivalence study.  
 
9.  Debarment certification 
 
The regulations require submission of a debarment certification and a conviction statement. 
Explanations and examples are provided below.  
 
  Debarment certification 
  43 
    Contains Nonbinding Recommendations 
 
As of June 1, 1992, any ANDA must include certification that the applicant did not and will not 
use the services (in any capacity) of any person debarred under section 306(a) or (b) of the Act in 
connection with the submission of their application.56  
 
Debarment is an administrative procedure used by the FDA to bar an individual and/or company 
convicted of a felony or a misdemeanor related to the development or approval of any drug from 
providing certain services to an applicant or manufacturer.  Typically, a debarred person is an 
individual or company convicted of fraud related to the submission of a drug application.   
 
Debarment certification is a self-attestation by the applicant.  You simply need to include a 
certification addressing debarment and conviction of any crimes that could lead to debarment.   
 
Here is an example of a debarment certification that you can use in your NDA.  
 
 
 
I, (name of applicant), certify that I, or we, did not and will not use the services, in any 
 
capacity, of any person debarred under section 306 of the Federal Food, Drug, and 
 
Cosmetic Act in connection with this application. 
 
 
 
  Convictions 
 
All ANDAs should include a nonconviction statement or, if necessary, they must include 
information about any convictions (of the company or affiliated persons) of relevant offenses, 
i.e., felonies or misdemeanors related to the development or approval of any drug that could have 
led to debarment.57   
   
If you or anyone else who is responsible for the development or submission of the ANDA has 
not been convicted of a relevant offense within the last 5 years, a simple statement to that effect 
should be submitted.   
 
Here is an example of a nonconviction statement that you can use. 
 
 
 
(Name of applicant) did not and will not use the services, in any capacity, of anyone convicted 
  of a relevant offense within the last 5 years in connection with this application.   
 
 
 
If you or an affiliated person responsible for the development or submission of your application 
has a conviction(s) of a relevant offense that could lead to debarment and that conviction 
                                                 
56 Use of a debarred individual/firm may preclude the approval of the application. 
57 See 21 U.S.C. 335a.   
  44 
    Contains Nonbinding Recommendations 
 
occurred within 5 years before the date of the application, you must include a list of these 
convictions.  The list of convictions should include the following information:  
  
  The name(s) of the person and/or firm convicted 
  The title of the section of the Federal or State statute involved  
  The date of the conviction  
  The sentencing date  
  The court entering judgment  
  The case number, if known  
  A brief description of the offense  
 
In addition, the applicant should explain the role of each convicted person in the development of 
the application.  The debarment certification and conviction information should be signed by a 
responsible officer of the applicant or by an individual responsible for signing the application. 
 
10.  Field copy certification  
 
The field copy of your ANDA will be used by FDA field investigator(s) during your PET 
centers preapproval inspection.  The field copy should contain the technical section, the 
application form, and the summary.  You must certify that it is an exact copy of the information 
contained in the review copy of the application.  
 
Here is an example of a field copy certification you can use. 
 
 
  (Name of applicant) certifies that the field copy is a true copy of the technical section of the 
  application described in 21CFR 314.50(l)(3) and contained in the archival and review 
  copies of the application. 
 
 
If questions arise regarding the field copy, please contact the Pre-Approval Manager in your 
home FDA district office.  
 
11.  Other 
 
  User Fees 
 
Currently, fees do not apply to 505(j) applications.  You do not need to fill out the user fee cover 
sheet. 
  45 
    Contains Nonbinding Recommendations 
 
APPENDIX C:  FORMS 
 
The following sample formats are available as separate documents on FDAs Web site.   
 
I.    Sample formats for chemistry, manufacturing, and controls sections 
 
Fludeoxyglucose F 18 Injection  
Ammonia N 13 Injection  
Sodium Fluoride F 18 Injection 
 
Are available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm078740.pdf
 
II.  Sample formats for Form FDA 356h:  
 
Fludeoxyglucose F 18 Injection  
Ammonia N 13 Injection  
Sodium Fluoride F 18 Injection 
   
Are available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm078743.pdf
 
 
Sample formats for labeling of Fludeoxyglucose F 18 Injection, Ammonia N 13 Injection and 
Sodium Fluoride F 18 Injection are available on FDAs SPL web site at 
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm241316.htm.   
  46