Guidance 

 
Investigational New Drug Applications 

for Positron Emission Tomography 

(PET) Drugs 

 
 
 
GUIDANCE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
December 2012 

Clinical/Medical 

 
     
Guidance 

 
Investigational New Drug Applications 

for Positron Emission Tomography 

(PET) Drugs 

 
 
Additional copies are available from: 

 
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 20993-0002 
  
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) 

 
December 2012 

Clinical/Medical 

  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 

 
I.   INTRODUCTION..............................................................................................................................................1
  
II.   BACKGROUND ................................................................................................................................................1
  
A.   PET  DRUGS .....................................................................................................................................................1
  
B.   IND..................................................................................................................................................................2
  
III.   SUMMARY OF APPLICATION SUBMISSION REQUIREMENTS.....................................................3
  
IV.   WHEN AN IND IS NOT NEEDED FOR A PET DRUG ...........................................................................5
  
A.   CONDUCTING  RESEARCH USING PET  DRUGS UNDER RDRC  RATHER THAN UNDER AN IND.........................5
  
B.   EXEMPTION  FROM AN  IND ..............................................................................................................................6
  
V.   HOW TO SUBMIT A TRADITIONAL IND FOR INVESTIGATIONAL USE .........................................7
  
A.   WHAT INFORMATION  SHOULD  BE SUBMITTED IN A TRADITIONAL  IND?.........................................................7
  
B.   WHERE SHOULD THE IND  BE SUBMITTED? .....................................................................................................9
  
VI.   EXPANDED ACCESS  FOR CLINICAL  USE OF CERTAIN PET DRUGS..........................................9
  
A.   DEFINITION OF  EXPANDED ACCESS ...................................................................................................................9 
 
B. 	  GENERAL  CRITERIA FOR EXPANDED  ACCESS...................................................................................................9
  
C. 	  TYPES OF  EXPANDED ACCESS  APPROPRIATE FOR PET  DRUGS ......................................................................11
  
D. 	  USE OF EXPANDED ACCESS  INDS FOR PET  DRUGS IN SITUATIONS FOR WHICH NDAS OR ANDAS ARE NOT 

FEASIBLE .......................................................................................................................................................12
  
E.  	 CONTENT OF AN  EXPANDED  ACCESS SUBMISSION .........................................................................................14
  
F. 	  ADDITIONAL  INFORMATION FOR SPONSORS OF EXPANDED ACCESS INDS FOR PET  DRUGS..........................18
  
VII.   CHARGING  FOR AN INVESTIGATIONAL PET DRUG....................................................................18
  
A.   WHAT INFORMATION  SHOULD  BE INCLUDED IN A  REQUEST TO CHARGE  SUBMISSION?................................19
  
B.   HOW LONG  CAN  I  CHARGE FOR THE  COST OF  AN INVESTIGATIONAL  DRUG? ................................................19 
 
C.   ARE THERE ANY SPECIAL  CHARGING  CONSIDERATIONS FOR INVESTIGATIONAL PET  DRUGS? ....................20
  
APPENDIX  A: INFORMATION TO INCLUDE IN  AN  EXPANDED ACCESS SUBMISSION.....................21
  
APPENDIX B: CRITERIA  FOR EVALUATING  A REQUEST TO  CHARGE IND SUBMISSION ..............24
  
  i  Contains Nonbinding Recommendations 
1 
Guidance  
 
Investigational New Drug Applications for Positron Emission 

Tomography (PET) Drugs 

 
 
This guidance represents the Food and Drug Administration's (FDA's) 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 
 
This guidance summarizes the investigational new drug application (IND) process for 
unapproved positron emission tomography (PET) drugs, makes recommendations on how to 
submit an IND, provides advice on investigational PET drug access options, and describes the 
process for requesting permission to charge for an investigational PET drug.  This guidance does 
not describe all the considerations relevant to an Expanded Access submission or to an IND 
Request to Charge submission.   For details about these processes, we encourage sponsors to 
review the applicable regulations and advice available on the FDA Web site,2 and consult the 
review division, if necessary.      
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
II.   BACKGROUND 
 
A.   PET Drugs  
   
PET drugs are diagnostic radiopharmaceuticals that, following injection into humans, produce 
signals for medical images through the emission of a positron.  The dual photons that emerge 
from the positron annihilation are detected by PET scanning devices to form images that map the 
location of the radiopharmaceutical within the body.  Most PET drugs are produced using 
                                                 
1 This  guidance has been  prepared by the Division of Medical Imaging Products in the Center for Drug  Evaluation 

and Research  (CDER) at FDA.  

2 The regulations may be found by  placing the key  words expanded access into the search box at www.fda.gov or at 

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ 
 
ApprovalApplications/ InvestigationalNewDrugINDApplication/ucm172492.htm. 

  1
  Contains Nonbinding Recommendations 
radionuclides generated from cyclotrons at locations in close proximity to the facility that 
performs the PET scanning.   
 
Throughout this document, clinical use refers to administration of the PET drug to patients as a 
component of their clinical care with no intent to study the safety or effectiveness of the drug in 
any systematic way.  This is to be differentiated from  investigational use and research use of 
PET drugs.  Investigational use refers to the administration of PET drugs to subjects under an 
IND to establish the safety and/or effectiveness of a new use of the drug to support an 
application for approval of that use.  Research use refers to administration of PET drugs to 
human research subjects typically under a Radioactive Drug Research Committee (RDRC) 
application to obtain basic information regarding the metabolism, physiology, pathophysiology, 
or biochemistry of the PET drug.  Such administration is not intended for immediate therapeutic, 
diagnostic purposes, nor to determine the safety and effectiveness of the drug. 
 
The Food and Drug Administration Modernization Act of 19973 (the Modernization Act) 
provided that certain unapproved PET drugs would not be considered adulterated until the new 
current good manufacturing practice (CGMP) regulations for PET drugs (21 CFR part 212) took 
effect, if the production facility maintained compliance with United States Pharmacopeia (USP) 
monograph expectations for the specific drug, as well as compliance with the USP chapter 823 
standards.4  As of September 1, 2011, the following PET drugs had USP monographs:  
 
   ammonia N13 injection      methionine C11 injection 
   carbon monoxide C11     raclopride C11 injection 
   fludeoxyglucose F18 injection     rubidium chloride Rb82 injection 
   fluorodopa F18 injection     sodium acetate C11 injection 
   flumazenil C11 injection     sodium fluoride F18 injection 
   mespiperone C11 injection     water O15 injection 
 
B.   IND 
   
An IND is a request for authorization from the FDA (1) to administer an investigational drug or 
biological product to humans, (2) to obtain exemption from the premarketing approval 
requirements that are otherwise applicable, and (3) to lawfully ship the investigational drug or 
product for the purpose of conducting clinical investigations.5  FDA has developed several 
guidance documents to assist in the development of an IND.6  These documents describe 
                                                 
3 Public Law 105-115.
  
4 See section 501(a)(2)(C) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 351(a)(2)(C)), 

added by section 121(b) of the Modernization Act.   Section 121(b) also  provided that section 501(a)(2)(C) would 

sunset 2 years after the date on  which the Secretary of Health and Human Services established PET CGMP
  
regulations, which is December 12, 2011.  

5 See 21 CFR 312.1. 

6 The IND guidances are available on the Internet at 

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati 

ons/ InvestigationalNewDrugINDApplication/default.htm.
  
  2
  Contains Nonbinding Recommendations 
considerations for a traditional IND7 as well as those for special situations (e.g., emergency IND 
and treatment IND). 
 
An IND is submitted by a sponsor.   The sponsor is the person or entity who takes responsibility 
for and initiates a clinical investigation.  The sponsor can be a company, a private or academic 
organization, or an individual. A sponsor-investigator is an individual who both initiates and 
conducts a clinical investigation and under whose immediate direction the investigational drug is 
being administered or dispensed.  For administrative reasons, only one individual or entity 
should be designated as an IND sponsor. 
 
Upon receipt of the IND by the FDA, an IND number is assigned.  The FDA reviewing division  
sends a letter to the sponsor providing notification of the IND number assigned, date of receipt of 
the original application, address where future submissions to the IND should be sent, and the 
name and telephone number of a contact person at FDA to whom questions about the application 
should be directed. Clinical investigations cannot be initiated until 30 days after the date of 
receipt of the IND by FDA unless FDA provides earlier notification that the studies can begin.8   
If FDA identifies deficiencies during the 30-day review period, the deficiencies will be 
communicated to the sponsor. Certain deficiencies may warrant FDA placing a clinical hold 
upon the investigations until the deficiencies are addressed.9  
 
III.   SUMMARY OF APPLICATION SUBMISSION REQUIREMENTS  
 
Section 121(c)(1)(A) of the Modernization Act directed FDA to establish appropriate approval 
procedures and CGMP requirements for PET drugs.  Section 121(c)(2)(A) of the Modernization 
Act specified that PET drug manufacturers and compounders would be required to submit 
applications for approval within 24 months of the establishment of  such procedures and 
requirements.  The publication of the final rule on CGMP for PET drugs on December 10, 
2009,10 triggered the requirement that all producers of PET drugs submit applications by 
December 12, 2011.  Until June 12, 2012, FDA does not intend to take enforcement action 
against a PET facility currently producing PET drugs for clinical use for a failure to submit a 
new drug application (NDA) by December 12, 2011, provided that the facility complies with all 
other FDA requirements, including CGMPs.  FDA will not exercise enforcement discretion after 
June 12, 2012. If producers of certain PET drugs submit an NDA or abbreviated new drug 
application (ANDA), FDA will not object if clinical use of these drugs continues during the 
application review period. However, all PET producers must be operating under an approved 
NDA or ANDA, or effective IND, by December 12, 2015.11    
 
FDA recognizes that it may be very difficult to develop NDAs for certain PET drugs that are 
currently in clinical use.  This guidance specifies that expanded access is available for these 
                                                 
7 IND  for an investigational use of a drug  under circumstances that do not satisfy criteria for special types of INDs, 

such as expanded access, exploratory, emergency, or treatment INDs. 

8 21 CFR 312.40(b).   

9 See 21 CFR 312.42.   

10 See the final rule, Current  Good Manufacturing  Practice for Positron Emission Tomography Drugs (74 FR 
 
65409). 

11 Section 121(c)(2)(A) of the Modernization  Act. 

  3
  Contains Nonbinding Recommendations 
types of drugs. See section VI.D for a description of when FDA would consider it difficult to 
develop an NDA for certain PET drugs. 
 
Section 121(c)(2)(B) of the Modernization Act states that nothing in the Modernization Act 
exempts PET producers from the requirement to have an IND.  FDA has not been enforcing the 
IND requirements pending completion of the CGMP regulations and approval procedures.  Now 
that the CGMP regulations and approval procedures have been completed, our expectations 
regarding INDs for PET drugs under investigational use are as follows:   
 
 	  If the PET drug used in the clinical trial is being made at a facility for which 
manufacturing data have been submitted in an NDA or ANDA for the PET drug, then  
FDA does not intend to object to use of the PET drug in a clinical trial without an 
IND until December 12, 2015, if this and the requirements in 21 CFR 312.2 (other 
than being lawfully marketed) are met (see 21 CFR 312.2(b))  However, if significant 
manufacturing deficiencies are found during the NDA or ANDA review, or during 
inspection of the facility the PET drug is sourced from, FDA may notify the sponsor 
that the PET drug may no longer be used in clinical trials. 
   
 	  After December 12, 2015, investigational use of a PET drug must be covered by an 
IND unless it is exempt from all of the IND requirements.      
 
FDA has prepared two tables that summarize the application and IND submission requirements 
for PET drugs.  These tables are contained in the guidance on FDA Oversight of PET Drug 
Products  Questions and Answers.12  
 
In the discussion that follows, we provide guidance on the different uses of PET drugs; which, if 
any, IND is appropriate; and what to submit to FDA. 
 
 	  Investigational use: Submit traditional IND (see section V) 
 
 	  Clinical use when an NDA or ANDA cannot be submitted (see section VI.B): Submit 
expanded access IND   
 
 	  Research use: No IND required if reviewed by RDRC (see section IV) 
 
Section IV.A describes when certain research on a PET drug can be performed subject to 
approval of an RDRC. In such a case, an IND is unnecessary.  In some  cases, performing certain 
studies or trials of a PET drug may be exempt from IND and RDRC requirements.  Criteria for 
IND exemption are described in section IV.B.  
 
                                                 
12 The guidances referenced in this document are available on the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update 
guidances  periodically.  To make sure you  have the most recent version of a guidance, check the FDA Drugs 
guidance Web page. 
 
  4
  Contains Nonbinding Recommendations 
Sections V.A and V.B describe the logistics of submitting a traditional IND for investigational 
use of a PET drug. In some cases, described in section VI, an expanded access IND can be used 
for continued clinical use of a drug for which an NDA or ANDA is not feasible.13  Finally, 
section VII contains information about when a sponsor can charge for a PET drug under an IND.  
 
IV. 	  WHEN AN IND IS NOT NEEDED FOR A PET DRUG 
 
A. 	  Conducting Research Using PET Drugs Under RDRC Rather Than Under 
an IND 
   
FDA regulations at 21 CFR 361.1 describe conditions under which radioactive drugs (including 
PET drugs) can be used for certain research without an IND because they are generally 
recognized as safe and effective for those uses, subject to approval by an RDRC. 14  RDRC 
approval to conduct research is based upon a determination that the research is basic science 
research, and not research that is intended for immediate therapeutic, diagnostic, or similar 
purposes, or to determine the safety and effectiveness of the radioactive drug or biological 
product for such purposes (i.e., the research cannot constitute a clinical trial for the product).  
The regulations list three additional requirements for human subject research that may be 
conducted under an RDRC: 
 
1.	   The research must be approved by an RDRC that is approved by FDA (21 CFR 
361.1(b)(1) and (c)(4)). 
 
2.	   The dose to be administered must be known not to cause any clinically detectable 
pharmacological effect in humans (21 CFR 361.1(b)(2)). 
 
3.	   The total amount of radiation to be administered as part of the study must be the 
smallest radiation dose practical to perform the study without jeopardizing the 
benefits of the study, and must be within specified limits (21 CFR 361.1(b)(3)). 
 
Only RDRCs approved by the FDA are authorized to review and approve the proposed basic 
research studies. If the basic science research study is approved by an RDRC, the research can 
be conducted without the submission of an IND.  An IND is necessary if the proposed research 
project does not meet the criteria for review and approval by an RDRC15 or criteria for IND 
exemption (see section IV.B).16   
 
FDA anticipates that most investigational uses of PET drugs will be conducted under an IND 
because these studies will likely involve assessments of the drugs safety and/or efficacy and not 
meet all the criteria for RDRC approval.  An IND is often the preferred route, because the goal of 
research conducted under RDRC oversight is very limited, whereas clinical research performed 
                                                 
13 FDA regulations pertaining to expanded access and charging are found  on the Internet at  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati 

ons/ InvestigationalNewDrugINDApplication/ucm172492.htm. 

14 See also the guidance for industry and researchers on  The Radioactive Drug Research Committee:  Human 

Research  Without an Investigational New Drug  Application.
  
15 See 21 CFR 361.1. 

16 See also  21 CFR 312.2(b). 

  5
  Contains Nonbinding Recommendations 
under an IND may have many goals, including a goal of providing patient access to the 
investigational PET drug. 
 
B.   Exemption From an IND 
 
In considering the need for an IND, sponsors should recognize that some  studies or trials are 
exempt from an IND if the investigational drug is approved for a clinical indication.  A clinical 
investigation of a drug is exempt from the IND requirements if all of the criteria for an 
exemption in 21 CFR 312.2(b) are met: 
 
	   The drug product is lawfully marketed in the United States.   
 
	   There is no intent to report the investigation to FDA as a well-controlled study in support 
of a new indication and no intent to use it to support any other significant change in the 
labeling of the drug. 
 
	   In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug. 
 
	   The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases  the acceptability of the risk) 
associated with the use of the drug product.17   
 
 	  The investigation is conducted in compliance with the requirements for review by an 
Institutional Review Board (IRB)18 and with the requirements for informed consent.19  
 
	   The investigation is conducted in compliance with the requirements of 21 CFR 312.7 
(i.e., the sponsor or investigator does not intend to promote or commercialize the drug 
product). 
 
When considering the possible exemption of an investigation from the IND submission 
requirement based on the fact that the drug is approved, investigators should be aware that FDA 
approval of a PET drug or submission of an NDA or ANDA for a PET drug allows 
manufacturing of the drug only at the approved manufacturing facility.  For example, by 
December 2010, FDA had approved three NDAs for fludeoxyglucose F18 injection with 
manufacturing performed at the specific facilities cited within the NDA.  Fludeoxyglucose F18 
drugs produced at other facilities are unapproved drugs that generally may only be used under an 
IND, except as described below. 
 
Because sponsors need only submit NDAs or ANDAs by June 12, 2012, as stated previously: 
 
 	  If the PET drug used in the clinical trial is being made at a facility for which 
manufacturing data have been submitted in an NDA or ANDA for the PET drug, then  
                                                 
17 See 21 CFR 312.2(b)(1)(iii). 
18 See 21 CFR part 56. 
19 See 21 CFR part 50. 
  6
  Contains Nonbinding Recommendations 
FDA does not intend to object to use of the PET drug in a clinical trial without an IND 
until December 12, 2015, if this and the requirements in 21 CFR 312.2 (other than being 
legally marketed) are met (see 21 CFR 312.2(b)).  However, if significant manufacturing 
deficiencies are found during the NDA/ANDA review, or during inspection of the facility 
the PET drug is sourced from, FDA may notify the sponsor that the PET drug may no 
longer be used in clinical trials. 
   
	   After December 12, 2015, investigational use of a PET drug must be covered by an IND 
unless it is exempt from all of the IND requirements.      
 
For example, if PET producer A submits an ANDA to make fludeoxyglucose F18 at PET centers 
B, C, and D, FDA does not intend to object to investigational use of fludeoxyglucose F18 
sourced from PET producer A and made at PET centers B, C, and D without an IND.  However, 
an IND would be required for investigational use of fludeoxyglucose F18 sourced from PET 
producer A and made at PET center E, which is not proposed as a facility in the ANDA, or from  
PET producer X, if X has not submitted an ANDA or NDA for fludeoxyglucose F18.  
 
V.    HOW TO SUBMIT A TRADITIONAL IND FOR INVESTIGATIONAL USE 
 
A.   What Information Should Be Submitted in a Traditional IND? 
 
The minimum contents for a clinical trial IND submission are described in 21 CFR 312.23 and 
summarized below (for Expanded Access submission, see Appendix A).  We also request that 
you include a Certification of Compliance (Form FDA 3674) to address the requirements of the 
ClinicalTrials.gov Data Bank. At a minimum, an IND should contain: 
 
 	  A cover sheet (Form FDA-1571) with the requisite contact information and other form-
specified commitments. 
 
 	  A table of contents. 
 
 	  An introductory statement and description of the general investigational plan.20  
 
 	  A copy of the Investigators Brochure to be provided to each site investigator.  An 
Investigators Brochure is not required for sponsor-investigators.21  
 
 	  A copy of the clinical protocol (including a description of objectives, eligibility criteria, 
total enrollment size, time and nature of evaluations, major endpoints and analyses, 
identification of the study safety monitor, supportive safety information, any stopping 
rules for toxicity,22 description of mass/radiation dose and administration route, 
screening for pregnancy, and plan for development of final report).23  
                                                 
20 See 21 CFR 312.23(a)(3). 
 
21 See 21 CFR 312.23(a)(5). 
 
22 See the guidance for industry on Content  and Format  of  Investigational New Drug Applications (INDs) for Phase 

1 Studies of  Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived  Products. 

23 See 21 CFR 312.23(a)(10)(ii) and 21 CFR  312.23(a)(11).  

  7
  Contains Nonbinding Recommendations 
 
	   Chemistry, manufacturing, and control information for the investigational PET drug (for 
details see section VI.E). 
 
 	  Pharmacology and toxicology information that support the sponsors conclusion that it is 
reasonably safe to conduct the proposed clinical investigation. 
 
	   A summary of any previous clinical experience with the investigational PET drug. 
 
	   Sufficient data and information to allow a reasonable calculation of radiation-absorbed 
dose to the whole body and critical organs.24  
 
An IND can be submitted in a paper or electronic format.25  If submitted in a paper format, at 
least three copies of the application should be supplied.   
 
Copies of Form FDA 1572 (Statement of Investigator) with its attachments can be sent by a 
sponsor-investigator to satisfy Form 1571, box 12, item 6 b-d.  Information can be supplied in 
the form of attachments (such as curriculum vitae) rather than entering that information directly 
onto the form, but this information should be so noted under the relevant section numbers.  The 
Form 1572 is not required for submission with an IND. 
 
If an IND is submitted to study any PET drug in a clinical trial, including any one of the 12 drugs 
listed with bullets in section II, the clinical trial use of the drug may not begin until the IND goes 
into effect. However, FDA does not intend to object to the use of a PET drug in a clinical trial 
before an IND takes effect under the circumstances described in sections III and IV.B above 
when an NDA or ANDA has been submitted for the drug and the manufacturing facility at which 
it is made, or takes effect under expanded access as described in section VI.E.  As noted in 
section II.B, an IND goes into effect 30 days after FDA receives the IND, unless FDA notifies 
the sponsor that the proposed clinical trial is subject to a clinical hold.  In some situations, FDA 
may permit an IND to go into effect and the clinical trial to begin fewer than 30 days following 
the date FDA receives the IND submission.  In these situations, FDA will notify the sponsor 
when the IND is in effect. Sponsors should describe within the IND submission any special 
considerations for the desired trial initiation timeline.   
 
For phase 1 clinical trial submissions, sponsors should refer to the guidance for industry on 
Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of 
Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products.  
 
For phase 2 and phase 3 clinical trial submissions, sponsors should refer to guidance for industry 
on INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls 
Information.  
                                                 
24 Additional information is available in the FDA guidance for industry on  Developing Medical Imaging Drug and 
Biologic Products, Part 1: Conducting Safety Assessments. 
25Information regarding the electronic submission process is  available at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ 
default.htm. 
  8
  Contains Nonbinding Recommendations 
 
B.   Where Should the IND Be Submitted? 
 
For clinical investigations of PET drugs in diagnostic imaging, the IND should be submitted to: 
 
Food and Drug Administration 
Central Document Room 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
 
Telephone inquiries regarding the submission of INDs for PET drugs can be directed to the 
Division of Medical Imaging Products, project management staff, at 301-796-2050. 
 
In some situations, investigational PET drugs can be used in diagnostic imaging agent 
assessments for investigational therapeutic drugs.  In these situations, when both investigational 
drugs are submitted under one IND, the IND generally will be routed to and managed by the 
FDA review division responsible for the investigational therapeutic drug.  
 
VI.   EXPANDED ACCESS FOR CLINICAL USE OF CERTAIN PET DRUGS 
 
A.   Definition of Expanded Access  
 
Expanded access refers to a range of IND mechanisms intended to provide access to 
investigational drugs outside of traditional clinical investigations.26  In this context, 
investigational drugs consist of all unapproved PET drugs.  See sections VI.B and VI.D for 
appropriate use of expanded access as a mechanism for continuing clinical use of a PET drug.  
 
When an investigational drug is made available under an expanded access IND, the primary 
purpose is to diagnose, monitor, or treat a patients disease or condition, rather than characterize 
the safety and/or effectiveness of the investigational drug.27  There are situations in which 
expanded access can be used as an alternative to traditional clinical investigations (as described 
in section VI.C) to make investigational PET drugs available to certain patients.     
 
An Expanded  Access Submission refers to a type of IND submission (either an original IND or a 
protocol submitted to an existing IND) that contains all the information for FDA to assess the 
appropriateness of the proposed treatment use.  In the context of PET drugs, treatment refers to 
clinical use for diagnostic purposes. 
  
B.   General Criteria for Expanded Access 
 
                                                 
26 See 21 CFR part 312, subpart I. 
27 See 21 CFR 312.300. 
  9
  Contains Nonbinding Recommendations 
To permit expanded access to an investigational drug, FDA must determine that the following 
general criteria are met in accordance with 21 CFR 312.305, as well as additional criteria that are 
specific to each of the IND categories:28  
 
1. 	 The Patient or Patients To Be Treated Have a Serious or Immediately Life-
Threatening Disease or Condition. 
 
An immediately life-threatening disease or condition means a stage of disease in which there is 
reasonable likelihood that death will occur within a matter of months or in which premature 
death is likely without early treatment.29  A serious disease or condition means a disease or 
condition associated with morbidity that has substantial impact on day-to-day functioning.30   
FDA recognizes that a serious health risk may represent a serious condition, including when a 
patient does not have a clinically evident active serious condition or disease.  Therefore, even in 
the absence of an active, clinically evident serious condition, a disease or condition may be 
considered serious if it is likely that the disease would progress to a serious condition if left 
untreated. So use of an investigational PET drug to help detect a serious disease or condition in 
the situation where the patient does not actively manifest the disease or condition would still be 
considered use for a serious disease or condition. 
 
2. 	 There Is No Comparable or Satisfactory Alternative Therapy to Diagnose,  
Monitor, or Treat the Disease or Condition. 
 
FDA has generally recognized the term  alternative therapy to refer to any therapy that is 
specified in the approved labeling of regulated products, with only rare exceptions.31  In making 
an expanded access submission for an investigational PET drug, the sponsor should explain why 
the PET imaging diagnostic information cannot be attained with comparable or satisfactory 
alternatives that use approved drugs.  FDA recognizes that the diagnostic evaluation of patients 
could involve multiple test methods that use approved drugs and that these tests commonly 
provide incremental information without any single test establishing a clinical diagnosis.  In this 
context, the unique capabilities from the use of a PET drug (e.g., the ability to assess metabolic 
activity or identify specific receptors within organs) might support the finding that there is no 
comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or 
condition.32  For example, magnetic resonance imaging (MRI) or Computerized Tomography 
(CT) with an approved contrast agent might provide considerable central nervous system (CNS) 
structural information, but a PET drug might provide important CNS blood flow or receptor-
binding site information that cannot be obtained with MRI or CT.  In that setting, MRI or CT 
would not represent a comparable or satisfactory alternative diagnostic test to PET imaging 
because of the different nature of the information provided by PET imaging.   
 
                                                 
28 For additional criteria applicable to each category of an expanded access IND, see 21 CFR 312.310 for an 

individual  patient IND, 21 CFR 312.315 for an intermediate-size population use, and 21  CFR 312.320  for a 

treatment IND.  

29 See 21 CFR 312.300. 

30 See 21 CFR 312.300. 

31Additional information is available in the FDA guidance for industry  on  Available Therapy. 

32 See 21 CFR 312.305(a)(1). 

  10
  Contains Nonbinding Recommendations 
3. 	 The Potential Patient Benefit Justifies the Potential Risks of the Treatment Use, 
and Those Potential Risks Are Not Unreasonable in the Context of the Disease or 
Condition to Be Treated. 
 
FDA makes this determination based on the available evidence to support the treatment use, the 
size and nature of the population that will be exposed, and the relative seriousness of the disease 
or condition.  PET drugs can be used to assist in the diagnosis of multiple serious conditions, 
such as coronary artery disease or malignancies.  In these situations, we anticipate that the 
potential risks of the diagnostic use will not prove unreasonable in most patient populations.  The 
administered mass doses of PET drugs are generally low enough to lack pharmacologic activity 
and to produce relatively large safety margins (i.e., the doses are often several fold lower than 
the no observed adverse effect level (NOAEL) doses tested in preclinical studies).  The 
radiation-absorbed dose from the radionuclide (e.g., F18, N13) is also generally low.33  In some  
patient populations, such as children and pregnant women,34 the risks of exposure to 
radioactivity raise special concerns and applicants should specifically justify the unique risks to 
these more vulnerable populations. 
 
4. 	 Providing the Investigational Drug for the Requested Use Will Not Interfere With 
the Initiation, Conduct, or Completion of Clinical Investigations That Could 
Support Marketing Approval of the Expanded Access Use or Otherwise 
Compromise the Potential Development of the Expanded Access Use. 
  
For the types of expanded access INDs that will be used for PET drugs, FDA does not expect 
that interference with development of the drug for marketing approval will usually be an issue.  
As discussed in more detail in section VI.D, FDA anticipates that expanded access INDs for PET 
drugs will generally be used in situations in which it is not feasible to develop the PET drug for 
marketing approval. 
 
C. 	  Types of Expanded Access Appropriate for PET Drugs 
 
The regulations provide for three categories of expanded access INDs based on the size of the 
population in which the drug will be used: 
 
 	  individual patients (including emergency use), where each submission is limited to a 
single patient (21 CFR 312.310) 
 
 	  an intermediate-size patient population, where the submission supports administration of 
the drug to more than one patient but not the widespread use of the drug (21 CFR 
312.315) 
 
 	  widespread use under a treatment IND or treatment protocol (21 CFR 312.320) 
 
                                                 
33 See Einstein,  AJ, Moser, KW, Thompson, RC, Cerqueira, MD, Henzlova, MJ. Radiation Dose to Patients from 
 
Cardiac Diagnostic Imaging. Circulation 2007;  116:1290-1305. 

34 See 21 CFR  361.1 and also the guidance for industry  on  The Radioactive Drug Research Committee: Human 

Research  Without an Investigational New Drug  Application. 

  11
  Contains Nonbinding Recommendations 
An individual patient IND or protocol can be used if the PET drug is only used very infrequently.  
As with all categories of expanded access, an individual patient IND or protocol typically must 
be submitted before use of the drug.35  But, in the case of an emergency that requires the patient 
to be treated before a written submission can be made, FDA may authorize the use to begin 
without a written submission and use of the drug may begin upon verbal authorization from FDA 
before use.36    
 
If a sponsor anticipates that there will be more than sporadic, isolated use of an investigational 
PET drug, FDA recommends use of an intermediate-size population IND.  Under this type of 
IND, FDA typically authorizes use prospectively in a prespecified number of patients.  If that 
number is reached, the sponsor can then ask FDA to authorize use in additional patients.  There 
are three possible intermediate-size population INDs for an investigational drug  (1) for a drug 
being actively developed, (2) for a drug that cannot be developed (see section VI.D below), and 
(3) for an approved or related drug that is not available through marketing channels.37    
 
To be able to provide access under a treatment IND or treatment protocol, a sponsor must be 
actively pursuing marketing approval of the drug, and clinical trials adequate to support the 
marketing application must have been completed or must be ongoing.38  Although not excluding 
the option of PET drug treatment INDs or treatment protocols, FDA anticipates that the 
treatment IND or treatment protocol category of expanded access will have limited utility as a 
pathway to make investigational PET drugs available to patients.  FDA anticipates that expanded 
access INDs for PET drugs will generally be individual patient or intermediate-size patient  
population INDs. 
 
D. 	  Use of Expanded Access INDs for PET Drugs in Situations for Which NDAs 
or ANDAs Are Not Feasible 
 
When the CGMP regulations take effect in December 2011, FDA expects that an NDA or 
ANDA will have been submitted for the clinical use of PET drugs.  However, FDA recognizes 
that for certain PET drugs in clinical use, NDA or ANDA submissions will not be feasible at this 
time because of difficulties associated with commercial development of these products.  FDA 
also recognizes that there will still be clinical situations in which these PET drugs will continue 
to be needed.  In these situations, if there is no satisfactory alternative diagnostic imaging drug 
for the clinical setting in which the PET drug is used (see discussion in section VI.B.2) and the 
other applicable criteria are met, an individual patient expanded access submission or an 
intermediate-size population access submission for a drug that is not being developed may be 
used to provide access to the PET drug.   
 
FDA generally prefers use of an intermediate-size access IND, where appropriate, because it 
permits FDA to prospectively authorize multiple uses of the PET drug.  If the drug is not being 
                                                 
35 See 21 CFR 312.305(d).   
36 See 21 CFR 312.310(d). 
37 See 21 CFR 312.315(a).  
38 See 21 CFR 312.320. 
  12
  Contains Nonbinding Recommendations 
developed, this type of access submission must explain, among other things, why the drug cannot 
be developed and under what circumstances, if any, the drug could be developed.39    
 
In general, a PET drug will be considered difficult to develop if all of the following conditions 
exist: 
 
 	  Use of the PET drug by the institution producing the PET drug is limited to use within 
that institution. 
  
	   The isotope properties (e.g., very short half-life) and nature of use (e.g., use is limited to a 
small niche population) of the PET drug preclude commercialization. 
 
 	  There is no commercially available formulation of the PET drug. 
 
Expanded access is generally not the appropriate mechanism to make a PET drug available to 
patients if there is an approved NDA for the same formulation and the NDA holder does not 
have marketing exclusivity, even if the drug cannot be made commercially available outside the 
NDA holders institution. In this situation, FDA expects submission of ANDAs for the drug, 
using the approved NDA product as the reference product. 
 
Four of the 12 drugs with a USP monograph listed in section II (ammonia N13, fludeoxyglucose 
F18, sodium fluoride F18, and rubidium chloride Rb82) have been approved by the FDA for 
production at certain facilities. FDA believes that expanded access is generally not an  
appropriate mechanism to make these drugs available to patients for indications that are the same  
as the reference drug. Instead, FDA expects submission of an ANDA or NDA for those PET 
drugs. However, an intermediate-size expanded access IND may be appropriate to continue 
clinical use of a PET drug for an indication that differs from the reference drug.   
 
FDA recognizes that the clinical use of the remaining eight drugs with a USP monograph may 
prove so uncommon that the usage may not justify the submission of an NDA.  Accordingly, 
sponsors might choose to make these drugs available to patients under an expanded access 
submission as outlined above or under an IND submission that contains a clinical trial protocol.    
 
In addition to the 12 drugs with a USP monograph, other PET drugs might be eligible for 
expanded access. For these other PET drugs, sponsors should be particularly aware of the 
requirement that an expanded access submission include chemistry, manufacturing, and controls 
information adequate to ensure the proper identification, quality, purity, and strength of the drug 
(i.e., justification for adequate production quality).40   
 
Once an expanded access IND or treatment protocol is submitted, FDA does not intend to object 
to the continued clinical use during the 30-day IND review period (given IRB approval) because 
FDA understands that the prior clinical use will have been supported by compliance with USP 
standards, which continue as standards for INDs.  If FDA detects important safety concerns 
during the 30-day review period, the sponsor will be notified.  If the treatment protocol or 
                                                 
39 See 21 CFR 312.315. 
40 See 21 CFR 312.305. 
  13
  Contains Nonbinding Recommendations 
expanded access IND is for a new clinical use (no prior clinical  use of the drug manufactured at a 
particular facility for a particular indication), then clinical use of the drug may not begin until 30 
days after FDA receives the treatment protocol or expanded access IND, or on earlier 
notification by FDA.41    
 
E.  	 Content of an Expanded Access Submission 
 
Appendix A lists the requirements for the content of an Expanded Access IND submission.42  In 
this section, we discuss how to meet the submission requirements for some of the required 
content in an Expanded Access IND submission for a PET drug.   
 
In some situations, a sponsor may not have direct access to all the information called for in a 
complete expanded access submission.  For example, the investigational PET drugs 
manufacturing information might be contained within an existing IND.  In this situation, the 
expanded access IND submission could contain a right of reference letter. The right of reference 
letter comes from the sponsor of the existing IND and is addressed to the sponsor of the 
expanded access submission.  This letter should provide permission for the FDA to access the 
existing IND manufacturing information to support the expanded access IND submission.  This 
letter should then be included within the expanded access IND submission. 
 
1. 	  Is the Chemistry, Manufacturing, and Controls (CMC) Information Adequate to 
Ensure Identity, Strength, Purity, and Quality of the Investigational PET Drug? 
 
FDAs regulations at 21 CFR 312.305(b)(2)(vi) require that an expanded access submission 
include sufficient CMC information to ensure the proper identification, strength, quality, and 
purity of the drug. The amount and depth of CMC information in an Expanded Access IND 
should be similar to the information necessary to support a phase 3 clinical trial. 
 
Sponsors can reference an official compendium to provide certain CMC information (e.g., 
general methods, monograph standard) for an investigational drug substance or drug product, 
when applicable. Reference to drug master files (DMFs) or other existing INDs or NDAs, with 
  
an authorization letter from the holder, sponsor, or applicant, can also be used to provide CMC 
information in support of the IND submission.43   
 
For an IND submission for a traditional clinical trial, the amount of information submitted can 
vary with the phase of the investigation, the proposed duration of the investigation, and the 
amount of information otherwise available from referenced sources.   Similarly, for an expanded 
access IND submission, the amount of CMC information required depends on the size of the 
population to be treated. 
 
FDA recommends that the following information, which is considered CMC safety information 
(information needed to assess safe use of a drug product), be submitted in the original IND 
submission.  If during the course of investigation any CMC changes are made that could affect 
                                                 
41 See 21 CFR 312.305(d).   
42 See 21 CFR 312.305(b). 
43 See 21 CFR 312.23(b). 
  14
  Contains Nonbinding Recommendations 
safety, those changes should be submitted in an IND amendment.  The CMC information 
submitted can be formatted in Common Technical Document (CTD) format.44  
 
 	  Radioactive Drug Substance (entire radioactive molecule including the 
radionuclide), Reference Standard and Intermediate (Precursor)  
(Note: Radioactive drug substance manufacturing and control information, 
highlighted in italics, may be provided in the drug product section if the drug 
substance is not isolated). 
 
a. 	 General Information  include name; structure; and relevant physical, 
chemical, and biological properties. 
 
b.  Manufacture 
i. 	 Manufacturers  include name, address, and responsibility of each facility  
involved in the manufacturing or testing of radionuclide, nonradioactive 
intermediate (precursor),  and radioactive drug substance.  
ii.  Description of Manufacturing Process and Process Controls  include flow  
diagram(s) and description of the synthesis and production processes for 
the radionuclide, nonradioactive intermediate (precursor) from starting 
material, and the radioactive drug substance. Include the batch formula 
and the equipment used for the synthesis of radioactive drug substance.  
iii.  Control of Materials  include controls for starting material(s), reagents, 
solvents, and other auxiliary materials used in the synthesis of 
radionuclide, nonradioactive intermediate, and the radioactive drug 
substance. 
iv. Controls of Critical Steps and Intermediates  include suitable controls for 
intermediates isolated during the synthesis of nonradioactive intermediate 
(precursor) and controls employed during the radioactive drug substance 
synthesis. 
 
c. Characterization 
i. 	 Include structure characterization data on nonradioactive drug substance 
and analysis for the radioactive drug substance using a well-characterized  
single lot of nonradioactive reference standard; provide a comparison of 
chromatographic mobility of the radioactive drug substance and the 
nonradioactive reference standard. 
ii. 	 Nonradioactive intermediate (precursor)  include structure 
characterization data and analysis, method of synthesis of the reference 
standard lot, and information on stereoisomeric purity and potential for 
isomerism.  
iii. Reference Standards or Materials  
-	 Nonradioactive drug substance reference standard  include 
information on manufacturer, manufacturing process used, structure 
                                                 
44  See Module 3  Quality in the International Conference on  Harmonization guidance for industry, M2 eCTD:  
Electronic Common Technical Document  Specification, available at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  15
  Contains Nonbinding Recommendations 
characterization data on the lot with interpretation, information on 
purity of the lot, batch analysis data on primary and working reference 
standard lot, container closure, storage and stability information on 
reference standard. 
-	 Information on nonradioactive intermediate (precursor) reference 
standard (if applicable).  
iv. 	Information on Container Closure System Used for the Nonradioactive 
Intermediate (Precursor).  
v. Information on Stability and Storage of the Nonradioactive Intermediate. 
 
 	  Drug Product 
  
a. 	 Description and Composition of the PET Drug Product  include list of all the 
components, their quality grade (e.g., USP, National Formulary (NF)), and 
their amounts on a per unit basis.  Indicate the function of each component. 
Provide a description of any diluent used and the container closure used. 
 
b.  Manufacture 
i. 	 Manufacturers  include name, address, and responsibility of each facility  
involved in the manufacturing or testing of the PET drug product. 
ii.  Description of Manufacturing Process and Process Controls  include flow  
diagram(s) and description of the drug product manufacturing process, 
including the batch formula used. 
iii.  Controls  include description of any controls used during the drug 
product manufacture. 
 
	   Control of Excipients  include information on specification, quality grade, and 
acceptance procedures for excipients. 
 
 	  Control of Drug Product - include a listing of all the tests performed (e.g., 
appearance, radiochemical identity and purity, assay, radionuclidic identity and 
purity, pH, specific activity, impurities, residual solvents, membrane filter integrity, 
bacterial endotoxin testing, and sterility testing) and the tentative acceptance criteria.  
Test results and analytical data (e.g., spectra, chromatograms) from three batches, 
made similarly to the clinical batches, should also be provided.  Information on the 
analytical procedures should be provided and impurities and their control should be 
discussed. 
 
 	  Reference Standards or Materials  include information on any unique reference 
materials used in the drug product analyses. 
 
 	  Container Closure System  include specifications for the container closure system  
used for the PET drug product. If a reference is made to a drug master file (DMF), 
include an authorization letter from the DMF holder.  For packaging components 
(e.g., glass, elastomeric stopper), compliance with appropriate compendial standards 
should be stated. 
  16
  Contains Nonbinding Recommendations 
 
	   Stability  include stability data to support the expiration dating period.  Stability 
should be performed at the upper range of the radioactive concentration produced. 
 
 	  Labeling  include a copy of the labels that are affixed to the drug product (e.g., vial, 
lead shielding). In addition to the relevant identifying and other information, the 
label for the investigational product should contain the statement Caution: New 
Drug  Limited by Federal (or United States) law to investigational use in  
accordance with 21 CFR 312.6(a).  
 
	   Environmental Assessments  FDA  believes that the PET drug products use small 
quantity of materials and will qualify for a categorical exclusion.  Sponsors may 
request categorical exclusion from performance of an environmental assessment in 
accordance with 21 CFR 25.31(e). 
 
FDA recommends that the sponsor carefully assess any changes in the drug substance and the 
drug product manufacturing process (or drug product formulation) that are used while the IND is 
in effect to determine whether the changes can directly or indirectly affect the safety or efficacy 
of the PET drug product. For changes with significant potential to affect the safety of the 
product, an information amendment must be submitted that describes the changes and contains  
relevant information at a level of detail sufficient for an adequate review and assessment.45   
When appropriate, this amendment should include data from tests on the drug substance and/or 
drug product produced from the previous manufacturing process and the changed manufacturing 
process to evaluate product equivalency, quality, and safety.  In addition, when analytical data 
from tests on the drug substance and/or drug product demonstrate that the materials 
manufactured before and after are not comparable, sponsors should perform additional 
qualification and/or bridging studies to support the safety of the material to be used in the 
investigational studies. 
 
2. 	  Is Pharmacology and Toxicology Information Adequate to Conclude That the 
Investigational PET Drug Is Reasonably Safe at the Dose and Duration Proposed 
for Expanded Access Use?46  
 
Because PET drugs are usually administered at microdose levels, an expanded access IND 
submission for these drugs will generally call for limited pharmacology and toxicology  
information.  The submission should contain a description of the drugs  receptor binding 
characteristics and the mechanism of action, and should provide evidence of an adequate safety  
margin (i.e., the proposed clinical doses are several fold lower than the NOAEL doses tested in 
preclinical studies).  These data could be obtained from the sponsors own work, from publicly 
available clinical and nonclinical data, or by right of reference to proprietary data.  In some  
situations, a sponsor may not have direct access to all the information called for in a complete 
expanded access IND submission.  For example, the investigational PET drugs pharmacology 
and toxicology information might be contained within an existing IND.  In this situation, the 
                                                 
45 See 21 CFR 312.31.   
46  21  CFR 312.305(b)(2)(vii).   
  17
  Contains Nonbinding Recommendations 
expanded access IND submission could contain a right of reference letter (See introduction to 
section VI.E). 
 
3. 	  Is There Clinical Evidence Available to Support Use of an Investigational PET 
Drug (Preliminary Clinical Evidence of Effectiveness or Plausible Pharmacologic 
Effect)?  
 
The expanded access submission should contain clinical data and information that provides at 
least preliminary evidence that the PET drug is effective for the expanded access use and does 
not present an unreasonable risk of harm in the type of population in which it is anticipated to be 
used. A range of clinical data and information might be relied on, including data from clinical 
trials, clinical pharmacology data (pharmacodynamic and pharmacokinetic findings), clinical 
experience (e.g., case series), and other evidence from scientific literature.    
 
F.  	 Additional Information for Sponsors of Expanded Access INDs for PET 
Drugs 
 
Sponsors of expanded access programs must comply with the applicable responsibilities for 
sponsors set forth in 21 CFR part 312, subpart D.47  Among other things, sponsors are 
responsible for providing licensed physicians with the information they need to safely administer 
the PET drug so as to minimize the drugs risk and maximize its potential benefits, maintaining 
an effective IND for the expanded access use, maintaining adequate drug disposition records, 
and submitting to FDA IND safety reports as described in 21 CFR 312.32(c) and IND annual 
reports as described in 21 CFR 312.33 (when the IND or protocol continues for 1 year or longer).  
FDA recognizes that expanded access use of the PET drug may continue for several years.  
Review of the submitted annual report will help  to verify the appropriateness of this continued 
use, particularly with respect to evolving clinical considerations.  
 
VII. 	  CHARGING FOR AN INVESTIGATIONAL PET DRUG 
 
FDAs regulations on charging for an investigational drug describe criteria for charging for (1) a 
drug used in a clinical trial and (2) a drug used under an Expanded Access IND (21 CFR 312.8).   
 
FDA authorizes cost recovery only for the drug.  Seeking cost recovery for monitoring or 
supportive aspects is beyond FDAs purview. 
 
   Charging in a clinical trial 
 
FDA believes that in most cases the cost of an investigational drug in a clinical trial intended to 
support a marketing application is an ordinary cost of doing business that should be borne by the 
trial sponsor.  The purpose of permitting charging for an investigational drug in a clinical trial is 
to permit a sponsor to recover the costs of making certain drugs available to study subjects when 
clinical trials, which would be essential for establishing that a drug is safe or effective or would 
support a significant change in labeling for an approved drug, could not be conducted without 
                                                 
47 21 CFR 312.305(c)(5).    
  18
  Contains Nonbinding Recommendations 
charging because the cost of the drug is an extraordinary cost for the sponsor.48 A sponsor 
authorized to charge for its drug in a clinical trial can only recover its direct costs (i.e., the costs 
that can be specifically and exclusively attributed to providing the drug for the investigational 
use). 49  For the definition of direct costs, see 21 CFR 312.8(d)(1). 
 
   Charging in an expanded access program  
 
The purpose of permitting cost recovery for expanded access use is to facilitate access to 
investigational drugs for treatment (diagnostic) use in situations in which a sponsor might not be 
able to provide such drug absent charging, or to facilitate broader access than would be possible 
absent charging. In light of this purpose, and because sponsors of intermediate-size patient 
population expanded access programs and treatment INDs or protocols incur costs in addition to 
the anticipated and ordinary costs of drug development, such sponsors may recover direct costs 
as well as certain administrative costs associated with the expanded access program, including 
costs associated with monitoring the IND or protocol and complying with IND reporting 
requirements.50  However, a sponsor of an individual patient IND or protocol can only recover its 
direct costs because the administrative costs associated with an IND or protocol for a single 
patient use are generally negligible. 
 
A.   What Information Should Be Included in a Request to Charge Submission? 
 
A Request to Charge submission should address all the relevant criteria for the type of IND for 
which charging is requested (see Appendix B).51  To facilitate review of the request, we 
encourage sponsors to prominently highlight that the IND submission is a Request to Charge 
on the cover letter of the submission.  A Request to Charge is specific to a protocol and can be 
submitted as a component of an original IND or as an amendment to an existing IND.  A 
charging request should be mailed to the address cited above (see section V.B).  A sponsor may 
not charge for an investigational drug without prior written authorization from FDA.52  If the 
investigational agent is acquired from a PET drug producer, the sponsor of the IND that 
implements a protocol to administer the drug should submit the request to charge. 
 
B.   How Long Can I Charge for the Cost of an Investigational Drug? 
 
For a clinical trial, charging can continue for the length of the clinical trial unless FDA specifies 
a shorter period.53  To provide expanded access to an investigational PET drug for treatment use, 
charging can continue only for 1 year from the time of FDA authorization, unless FDA specifies 
a shorter period.  A sponsor can request that FDA reauthorize charging for additional periods.54  
 
                                                 
48 See CFR 21  312.8(b)(1)(iii). 
49 See 21 CFR 312.8(d)(1).  
50 See 21 CFR 312.8(d)(2).  
51 See also  21 CFR 312.8. 
52 See 21 CFR 312.8 (a)(3). 
53 See 21 CFR 312.8(b)(2).  
54 See 21 CFR 312.8(c)(4).  
  19
  Contains Nonbinding Recommendations 
Sponsors should be aware that FDA can withdraw authorization to charge at any time if it 
determines that charging is interfering with the development of a drug for marketing approval or 
that the criteria for the authorization are no longer being met.55  
 
C. 	  Are There Any Special Charging Considerations for Investigational PET 
Drugs? 
 
Sponsors can submit a Request to Charge coincident with or following an expanded access IND 
submission or the submission of an IND intended to support a clinical trial.  Following review of 
the Request to Charge, FDA will provide a written authorization or denial of the request.   
 
	   Sponsors can charge for an approved drug to be used in a clinical trial (e.g., trial of a new 
use of an approved drug or for use of an approved drug as an active control) without 
permission from FDA if the approved drug is obtained from an entity not affiliated with 
the sponsor. 
  
	   Some clinical trials can use an investigational PET drug that has an approved reference 
drug (ammonia N13, fludeoxyglucose F18, sodium fluoride F18, and rubidium chloride 
Rb82 reference drugs) to evaluate an indication that differs from the reference drug.  If 
the investigational PET drug production site is not listed in the approved application for 
the reference drug, a Request to Charge can be submitted, but FDA believes that 
demonstrating extraordinary cost (Appendix B) will be difficult to fulfill because an 
approved production alternative exists. 
                                                 
55 See 21 CFR 312.8(a)(4).  
  20
  Contains Nonbinding Recommendations 
APPENDIX A:  INFORMATION TO INCLUDE IN AN EXPANDED ACCESS 

SUBMISSION 

 
FDA regulations at 21 CFR 312.305(b)(1) states that an expanded access submission is required 
for each category of expanded access, and that submission may be a new IND or a protocol 
amendment to an existing IND.  The items listed below must be included in the expanded access 
submission for a PET drug, and its mailing cover must be plainly marked EXPANDED 
ACCESS SUBMISSION ( 312.305(b)). Expanded access submission for PET drugs should be  
mailed to the IND mailing address previously identified in section V.B.  FDAs review is greatly 
facilitated by sponsors providing a title and number for reference purposes.  The submission 
must contain: 
 
	   A cover sheet (completed Form FDA 1571). 
 
	   The following information, which typically may be contained in a protocol: 
 
o	   The rationale for the intended use of the drug, including a list of available 
diagnostic options that would ordinarily be tried before resorting to the 
investigational drug or an explanation of why the use of the investigational drug is 
preferable to the use of available diagnostic options.56  
 
o 	  The criteria for patient selection or, for an individual patient, a description of the 
patients disease or condition, including recent medical history and previous 
treatments of the disease or condition.57  
 
o 	  The method of administration of the drug, dose, radiation-absorbed dose, and any 
plan for repeat administration.58  
 
o 	  Clinical procedures, laboratory tests, or other monitoring necessary to evaluate the 
effects of the drug and minimize its risks.59  
 
o 	  The facility where the drug will be produced.60  
 
 	  Chemistry, manufacturing, and controls information adequate to ensure the proper 

identification, quality, purity, and strength of the investigational drug.61
  
 
 	  Pharmacology and toxicology information adequate to conclude that the drug is 

reasonably safe at the dose and duration proposed for expanded access use.62
  
 
                                                 
56  See 21  CFR 312.305(b)(2)(ii).   
57 See 21 CFR 312.305(b)(2)(iii).   
58 See 21 CFR 312.305(b)(2)(iv).    
59 See 21 CFR 312.305(b)(2)(viii).   
60  See 21  CFR 312.305(b)(2)(v).   
61 See 21 CFR 312.305(b)(2)(vi).    
62 See 21 CFR 312.305(b)(2)(vii).   
  21
  Contains Nonbinding Recommendations 
	   Information to support a finding that: 
 
o 	  The patient or patients to be treated have a serious or immediately life-threatening 
disease or condition, and there is no comparable or satisfactory alternative therapy 
to diagnose or monitor the disease or condition.63  
 
o 	  The potential patient benefit justifies the potential risks of the diagnostic use and 
those potential risks are not unreasonable in the context of the disease or 
condition to be evaluated.64  
 
o 	  Provision of the investigational drug for the requested use will not interfere with 
the initiation, conduct, or completion of clinical investigations that could support 
marketing approval of the expanded access use or otherwise compromise the 
potential development of the expanded access use.65    
 
If the Expanded Access Submission is for an individual patient, the following additional 
information must be supplied: 
 
 	  Information demonstrating that the physician determined that the probable risk to the 
person from the investigational drug is not greater than the probable risk from the disease 
or condition.66  
 
	   Information to support a finding that the patient cannot obtain the drug under another 
IND or protocol.67  
 
If the Expanded Access Submission is for an intermediate-size population (i.e., for more than 
one patient, but for a smaller population than the large populations typical of treatment INDs or 
protocols), the following additional information must be supplied: 
 
	   State whether or not the investigational drug is under development for marketing 
approval. If the drug is not being developed, describe the reasons for lack of 
development, and the circumstances under which the drug could be developed.  If the 
drug is under development, describe why the proposed access patients are unable to 
participate in a clinical trial of the drug, and circumstances under which the sponsor 
would conduct a clinical trial in those patients.  For example, identify whether the trials 
are closed to enrollment or the trial sites are geographically inaccessible.68  
 
                                                 
63 See 21 CFR 312.305(a).  
64 See 21 CFR 312.305(a)(2).   
65 See 21 CFR 312.305(a)(3).   
66 See 21 CFR 312.310(a)(1). 
67 See 21 CFR 312.310(a)(2). 
68 See 21 CFR 312.315(c).  
  22
  Contains Nonbinding Recommendations 
	   Provide at least preliminary clinical evidence of the effectiveness of the drug or of a 
plausible pharmacologic effect of the drug to make expanded access use a reasonable 
diagnostic option in the anticipated patient population.69  
 
 	  Describe the patient population to be treated, including the planned size of the patient 
population.70    
                                                 
69 See 21 CFR 312.315(b)(2).  
70  See 21  CFR 312.315(c).    
  23
  Contains Nonbinding Recommendations 
APPENDIX B:  CRITERIA FOR EVALUATING A REQUEST TO CHARGE IND 

SUBMISSION 

 
When considering submission of a Request to Charge IND submission, the sponsor should first 
determine whether the request involves charging within a clinical trial or charging for expanded 
access to the investigational drug for treatment use.  If the charging is for expanded access, then 
the sponsor should identify which of the three categories is applicable to the access program, as 
follows: 
 
	   Individual patient 
	   Intermediate-size population 
	   Treatment IND or Treatment Protocol 
 
For requests to charge for all types of expanded access, a sponsor must provide reasonable 
assurance that charging will not interfere with developing the drug for marketing.71  To obtain 
authorization to charge under a Treatment IND or Treatment Protocol access program, that 
assurance must include specific information.72  For example, the sponsor must provide evidence 
of sufficient enrollment in any ongoing clinical trial(s) needed for marketing approval to 
reasonably assure FDA that the trial(s) will be successfully completed as planned (21 CFR 
312.8). In general, we anticipate that few, if any, sponsors will submit a Request to Charge 
under a Treatment IND or Treatment Protocol for an investigational PET drug, and we do not 
address this topic further in this guidance.  Please refer to  312.8 for additional information. 
 
Listed below is the information that must be submitted in a request to charge for a PET drug in a  
clinical trial or in an intermediate-size expanded access program. 
 
A. 	 Charging in a clinical trial: 
 
1. 	  Provide evidence that the drug has a potential clinical benefit that, if demonstrated in the 
clinical investigations, would provide a significant advantage over available products in 
the diagnosis of a disease or condition.73  
 
2.	   Demonstrate that the data to be obtained from the clinical trial would be essential to 
establishing that the drug is effective or safe for the purpose of obtaining initial approval 
of a drug or would support a significant change in the labeling of an approved drug (e.g., 
new indication, inclusion of comparative safety information).74  
 
3.	   Demonstrate that the clinical trial could not be conducted without charging because the 
cost of the drug is extraordinary to the sponsor.  The cost may be extraordinary because 
of manufacturing complexity, scarcity of a natural resource, the large quantity of drug  
                                                 
71 21 CFR 312.8(c)(1).  
72 21 CFR 312.8(c)(2).  
73 21 CFR 312.8(b)(1)(i). 
74 21 CFR 312.8(b)(1)(ii). 
 
  24
  Contains Nonbinding Recommendations 
needed (e.g., because of the size or duration of the trial), or some combination of these or 
other extraordinary circumstances (e.g., resources available to a sponsor).75  
 
4. 	  Describe the proposed cost to be charged to a patient and include supporting 
documentation to show that the calculations represent only direct costs. Direct costs 
include the costs per unit to manufacture the drug (e.g., raw materials, labor, and non-
reusable supplies and equipment used to manufacture the quantity of drug needed for the 
use for which charging is authorized) or costs to acquire the drug from another 
manufacturing source, and direct costs to ship and handle (e.g., store) the drug.  Only 
direct costs may be considered for charging in a clinical trial.76  
 
5. 	  Include a statement that an independent certified public accountant has reviewed and 
approved the cost calculations.77    
 
B. 	 Charging for expanded access to investigational drug for treatment use (intermediate-size 
patient population access): 
 
Provide reasonable assurance that charging will not interfere with developing the drug for 
marketing approval.78  For example, for certain PET drugs, it might not be feasible to 
conduct trials of sufficient size to support an NDA because of (a) the limited use and (b) on-
site preparation or limited region of distribution because of the relatively short half-life of the 
radionuclide. If the expanded access program is limited to a defined number of patients, 
FDA asks that applicants verify that the charging is also limited to this number of patients.  
In addition, the charging request must: 
 
1. 	  Describe the proposed cost to be charged to a patient and include supporting 
documentation to show the calculation is consistent with the requirements of 21 CFR 
312.8(d)(1) and, for intermediate-size patient population expanded access, (d)(2).79   
Under  312.8(d)(2), sponsors of intermediate-size patient population expanded access 
may recover direct costs (as outlined in section A above), as well as the indirect costs 
associated with monitoring the expanded access IND or protocol, complying with IND 
reporting requirements,80 and certain administrative costs directly associated with the 
expanded access IND. 
 
2. 	  Include a statement that an independent certified public accountant has reviewed and 
approved the cost calculations.81    
 
As stated in section VII.B, permission to charge to provide expanded access can be requested 
yearly (or sooner, if the previous authorization was for a period shorter than 1 year).  Request for 
                                                 
75 21 CFR 312.8(b)(1)(iii). 
76 21 CFR 312.8(d). 
77 See 21 CFR 312.8(d)(3).  
78 See 21 CFR 312.8(c)(1).    
79  See 21  CFR 312.8(d)(3).    
80 See 21 CFR 312.8(d)(2).  
81 See 21 CFR 312.8(d)(3).  
  25
  Contains Nonbinding Recommendations 
reauthorization must satisfy the same requirements that the initial request for charging 
authorization did. 
  26