Clin Eval 43（1）2015

Translation

The trend of U.S. regulations
concerning PET examination ＊Chieko Kurihara
Molecular Imaging Center, National Institute of Radiological Sciences

Abstract
United States (U.S.) Food and Drug Administration (FDA) issued the report on the Clitical Path
Initiative in 2004 in which they mentioned imaging technology as one of the tools for assessment ofbiomarkers of drug efficacy, which should facilitate clinical development. Additionally the FDA issued
several guidances to facilitate development of imaging diagnostic drugs and regulations for PET (Positron
Emission Tomography) drug specific Good Manufacturing Practice (PET drug GMP). Actually in the U.S.,
medical/research institutions and companies have been developing various PET drugs aiming at regulatory
approval and public health reimbursement coverage. This article reports such situations in the U.S.,
considering related situations in Japan.
Key words
PET (Positron Emission Tomography), RDRC (Radioactive Drug Research Committee), IND (Investigational New Drug application), GMP (Good Manufacturing Practice), FDA (Food and Drug Administration)［Epub ahead of the issue publication］
Rinsho Hyoka（Clinical Evaluation）．2015；43：W37−W45．

＊ This article is an English translation of the article originally written in Japanese and published in. 2011;9(11): 76-9, under the permission of the publisher, Medical Eye. The information included is not completely identicalwith the original one and has not been updated since the time of original publication except for some of the important
information subsequently added.
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臨床評価43 巻 1 号

2015

may be submitted for IND aiming at diagnostic

1．Regulatory frameworkof PET drugs

drug development or may be used as a measurement
tool of a biomarker of the effect of therapeutic
drug.

RDRC program (Fig. 1, right)

In the U.S. (United States) there are two tracks
of clinical research or clinical trials using radiop-

The RDRC program was established by the Codeharmaceuticals including PET (Positron Emissionof Federal Regulations (CFR) in 1975. In 2010 the

1）

Tomography) imaging agents (Fig. 1) : (1) RDRC

FDA issued a guidance 2） to explain this program.

(Radioactive Drug Research Committee) program

If you use radioactive drugs which are defined “safe(Fig. 1, right) for basic research using radioactive

and effective” in this CFR, and you do not have any

drugs in humans without an IND (Investigational

intention of therapeutic/diagnostic drug develop-

New Drug application) when the drug is adminis-

ment or intention of clinical therapeutic/diagnostic

tered under the defined conditions where the drug

assessment, but just have an intention of “basic”

is safe and effective; (2) IND framework (Fig. 1,

research involving human to explore pathophysiology

left) where application documents have to be sub-of human or mechanism of actions of the agent, youmitted to the FDA (Food and Drug Administration)

can conduct such studies without submitting an IND

for conduct of clinical trials of therapeutic or diag-

to FDA. Instead, you have to submit your protocol

nostic drug. This IND requirement is a general rule

to an FDA-approved RDRC. You also have to sub-not specific to radiopharmaceuticals. PET drugs

mit to an IRB (Institutional Review Board), which

Fig. 1

Constructions of guidance documents by FDA concerning medical
imaging drug development and radioactive drug clinical research

Drug development

IND
FDA authorization
IRB authorization
FDA guidance imaging/PET drug
Part 1: Safety assessment
Non-clinical and clinicalPart 2: Clinical indications
A: Structure delineation
B: Disease/pathology
detection/assessment
C: Functional, Physiological, orBiochemical Assessment
D: Patient Management
Part 3: Clinical studies design

Basic, exploratory clinical research
Collaboration
betweenindustry andacademia

RDRC
RDRC authorization
IRB authorization
FDA guidance on RDRC
- Basic clinical research to determine themetabolism of drug or humanphysiology, the pathology, and thebiochemistry, without immediate
therapeutic or diagnostic intention or
intention of efficacy/safety assessmentof a therapeutic/diagnostic drug
- Mass Balance study- Molecular imaging studies toinvestigate biochemical processes

GMP
21CFR212
FDA guidance on CGMP for PET products
USP823− W38 −

Clin Eval 43（1）2015

is the same process as for ordinary clinicalPath 4）in which they mentioned about imaging tech-research. The definition of “safe” in this regulation

nology as one of the tools for assessment of bio-means that the administered agent does not havemarkers of drug efficacy for facilitating clinicalany clinically detectable effect and the radiation

development. At the same time, the FDA issued adose does not exceed the following limit, which has

set of three guidances for the development of med-

to be confirmed by the RDRCs:

ical imaging drugs (including the agents of PET− In whole body; active blood-forming organs;and SPECT imaging, etc.) for (1) safety assess-lens of the eye; and gonads: 3 rem (30 mSv)

ments 5）, (2) clinical indications 6）; and (3) design,for single dose; 5 rem (50 mSv) for a cumu-

analysis and interpretation of clinical studies 7）.

lative annual dose

The FDA also issued and finalized in 2009 the− In other organs: 5 rem (50 mSv) for single
dose; 15 rem (150 mSv) for a cumulative

PET drug specific regulations of GMP (PET drug
GMP) and issued its guidance 8）.
Also in 2006, the FDA issued the Exploratory-

annual dose
According to the presentation by the FDA per-IND guidance 9）which allowed the conducting of thesonnel of this program in 2010 3）, 76 RCRCs sub-first-in-human study of specific design with admin-

mitted their reports to the FDA as they are

istration of smaller doses to human, and based on

working in 2010 and 628 research protocols wereless preclinical data, compared to traditional phaseconducted in 2009 within this RDRC program.

1 studies, which typically include a dose escalation

This framework of the RDRC program is similar

design for safety assessment in human. Thisto “clinical research” in Japan which does not require

Exploratory-IND guidance facilitated research

an IND submission to the regulatory authority con-using PET not only for biomarker assessment ofducted under the governmental guidelines. However

therapeutic drug trial but also for diagnostic drugin the U.S., FDA oversees the research within thisdevelopment, because the required preclinical data

RDRC program under the legally-defined rules andfor PET agents were clarified in this guidance.

also the number of protocols and research subjects

Manufacturing standard

with summarized characteristics of these studies(GMP and USP823) (Fig. 1)

are annually reported to the FDA from the RDRCs.

As for the manufacturing standard, the above

This point is different from the regulatory frame-mentioned PET drug GMP regulation was intended

work of Japanese clinical research.

at first to cover manufacturing of the investiga-

IND framework (Fig. 1, left)

tional drug in the IND framework; however, in

If you conduct a clinical trial of PET drug for

response to public consultation, this regulation

new diagnostic drug development or use a PET

came to cover only manufacturing for clinical use in

drug as a tool of measurement of a biomarker in a

general practice, after the approval of each PET

clinical trial of a therapeutic drug, you have to sub-drug (Actually in later phases of clinical trials

mit an IND to the FDA for conducting a clinical

NDA applicants will follow PET drug GMP). In

trial. You also need to get authorization of an IRB.

the framework of RDRC and IND, the manufactur-(In case you do not have an intention of develop-

ing standard is not the above PET drug GMP but

ment of this PET drug for an approved biomarker,“USP (United States Pharmacopeia) 823”. Thisit may be applicable for an IND exemption.)

USP 823 was amended to make it compatible with

In 2004, FDA issued the report on the Critical

the PET drug GMP. Comparing with PET drug

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臨床評価43 巻 1 号

2015

GMP, USP 823 is a short document and its imple-

institutions did not get approval, they have to use

mentation is rather flexible. In the U.S., mono-

the drug in a research status within the frame-graphs and related standards in pharmacopeia areworks of RDRC or IND. In this case, the medical

developed by a non-governmental institution named

institution should not provide a diagnostic exami-

the “United States Pharmacopeial Convention” col-nation as a part of clinical practice and should notlaborating with specialists from academic institutes

ask patients for payment.

and companies. FDA makes use of the monographs

FDA especially encouraged the institutions toof drugs listed in USP (Aside this exceptional

get approvals of the three PET drugs, F-18 FDG,

cases of PET drugs in USP, monographs in USP

F-18-NaF, N-13 Ammonia and issued guidance toare those of approved ones, reviewed by FDA).

explain necessary information for getting approvals

RDRC and IND (Fig. 1)of these specific drugs 10）. Among these three, F-18

The framework of IND in U.S. is similar to clin-

FDG and F-18 NaF were previously approved

ical trials in Japan under the GCP (Good Clinical(supply of NaF had been terminated), so it is pos-

Practice) Ordinance covered by the Pharmaceuticalsible for an applicant to apply within the framework

Affairs Law but an interesting point is that someof an Abbreviated New Drug Application (ANDA),

strategic researchers in the U.S. make use of bothwhich is the same as a generic drug application, ifof these IND and RDRC frameworks for develop-

the applied indication is in the range of the previ-1）

ment of new PET drugs . This means that they

ously approved one. Even if the indication is differ-conduct clinical research for proof of concept in theent, the applicant can apply based on a retrospective

RDRC framework and then conduct clinical trials

review of the literature, without conducting new

for development aiming at regulatory approval withinclinical trials. Responding to these suggestions by

the IND framework. In Japan some researchers

the FDA, the National Cancer Institute (NCI)

also adopt such strategy to make use of both frame-received approval for an NDA of F-18 NaF inworks of clinical trials under GCP Ordinance andJanuary 2011 and PETNET Solutions also received

clinical research under guidelines, but it has not

approval for an ANDA for FDG in February 2011.

become so common in Japanese PET community.

It is notable that among the literature which supported the NCIʼs application, two academic reports

2．Aiming at FDA approvalof PET drugsof Japanese researchers were included 11, 12）.
In Japan, most of the NDA applicants are companies (including small venture companies and Contract

FDA has provided various opportunities to dis-Research Organizations), but in the U.S. medical

cuss with the PET community and they provide

institutions and research institutions are also NDA

educational lecture meetings or workshops, collab-

applicants. In 2011 August FDA issued the PET

orating with the Society of Nuclear Medicine (SNM)

drug GMP guidance for small businesses 13）. The(since June 2011 “Society of Nuclear Medicine andPET drug is characterized by its short half-life

Molecular Imaging: SNMMI”). They encouraged

and is not suitable for large-scale production for

medical institutions to get approvals of PET drugs

supplying large areas. Therefore, it is useful thatby the end of 2011 when the PET drug GMP waseach manufacturing site inside hospitals can get an

implemented, if the institutions wanted to use a

NDA for their clinical use so that the PET drug is

PET drug in their general clinical practice. If the

not only supplied by a company.

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Clin Eval 43（1）2015

amyloid imaging PET drugs and these three are

3．Promoting development of
diagnostic drugs and devices

now at the stage of limited public insurance coverage. See the other articles 15, 16） for details.)
In addition, the FDA issued a guidance on medi-

The PET community in the U.S. has also been

cal imaging devices and imaging drug/biologicalpromoting the development of new PET diagnostic

products 17）. This guidance provides instructions

drugs, not only the above mentioned well-known PET

necessary for an NDA submission when some part

diagnostic drugs. In October 2008, the FDA formedof the device or drug/biological product is alreadythe “Peripheral and Central Nervous System Drugs

approved and the applicant is applying for a new

Advisory Committee” to discuss about the conditions

indication for some of them. It provides a similar

for approval of beta amyloid imaging to estimate

approach as in the case of the co-development

β-amyloid neuritic plaque density in adult patients

strategy for therapeutic and diagnostic drugs focus-

with cognitive impairment who are being evaluateding on pharmacogenomics. In the case of imaging

14）. The regulators and three

diagnostics, we should promulgate the harmonizedapplicant companies: Avid Radiopharmaceuticals;

development strategy among diagnostic drugs, diag-

Bayernostic devices, and therapeutic drugs.

for Alzheimerʼs Disease
HealthCare

Pharmaceuticals;

and

GE

Healthcare, discussed about the necessary informa-

4．Public insurance coverage
and accreditation of imaging
facilities

tion and design of phase three pivotal studies forapproval, based on the presentation of each companyʼs scientific results of studies up until then. It
seems to be a good opportunity to make use of theabove mentioned guidance for clinical development

As for the public insurance coverage of imaging

of medical imaging agents toward approval. Then

diagnosis in the U.S., we should first discuss aboutaccording to the FDAʼs recommendation, the firstthe process of expanding coverage of the new indi-of these three companies, Avid Radiopharmaceuticals

cations for FDG as the result of the patient regis-

completed a study to compare brain imaging during

tration system. We also have to discuss about thethe life time of the research subjects and brainaccreditation program of imaging facilities forautopsy after their deaths and submitted theseordinary imaging practice.

research results to the FDA for an NDA. At the

Coverage expansion of new indications for FDG

end of 2010, Eli Lilly purchased Avid. Then in

was achieved as the result of the program named

January 2011, the FDA held an Advisory Committee

the National Oncologic PET Registry (NOPR)

and they made a recommendation for approval on

which was led by the Academy of Molecular Imaging

the condition that the applicant should develop an

and the American College of Radiology. This reg-educational program for the method of reading

istration program was reviewed by the Department

these images to improve the validity of the imageof Health and started in May 2006 and more thanresults among the physicians. Now the company is

30,000 cases were registered. This project suc-preparing such a program, collaborating with spe-

ceeded in showing how the FDG-PET examination

cialists in this area. (Later on they developed an

influenced physiciansʼ decision-making for patient

educational program and obtained approval. The

management 18）. This project was designed inother two companies also obtained approvals of

response to the policy of the Centers for Medicare− W41 −

臨床評価43 巻 1 号

2015& Medicaid Services (CMS), named “coverage withthe activity of the Clinical Trial Network (CTN).

evidence development (CED)”, which described their

The FDAʼs position is that if you use PET imaging

evidence-based reimbursement policy.

for the measurement of drug efficacy during theAnother discussion point is the accreditation

process of clinical development of therapeutic

program of the imaging facility, which is a part ofdrugs, you need standardization of the techniques

the Medicare improvement program. It came to beof manufacturing the PET drug and you also needrequired that imaging facilities (except hospitals,

scanner validation. Based on this position, thewhich provide clinical imaging diagnostic examina-

SNM-CTN (now the SNMMI-CTN) developed ation using advanced imaging technologies, such as

registration and accreditation program of manufac-

PET, SPECT, CT, MRI (but excluding X-ray,turing sites and imaging sites, collaborating withultrasound, as they are not “advanced” technology)),industries. The SNM submitted an IND for FLT tothat are reimbursed by the Medicare program havethe FDA and therapeutic drug companies using

to get accreditation for their imaging procedures

FLT to evaluate the efficacies of their cancer

by January 2012. It was specified by the Medicare

drug. The SNM is the IND holder of FLT and

Improvements for Patients and Providers Act

several companies are able to use this FLT under(MIPPA).

the cross reference agreement of this IND with the

The CMS authorized three accreditation organi-

SNM. The SNM is the IND holder of FLT andzations: the American College of Radiology (ACR);

several companies are able to use this FLT underthe Intersocietal Accreditation Commission (IAC);

the cross reference agreement of this IND with theand the Joint Commission (JC). Both the ACR andSNM (Fig. 2, Table 1).

IAC have a history of more than 20 years of accredi-

At the time of starting this program, the SNM-

tation activities since the time before this MIPPA

CTN provided accreditation free of charge, but

regulation started and the ACR has given accredi-

recently it has begun to charge for scanner valida-

tation to more than 20,000 facilities. This imaging

tion. Now the SNMMI-CTN supplies their phantom

facility accreditation program excludes hospitals

to imaging facilities and the facilities send their

because hospitals have to get general accreditation

imaging data to the CTN, and then specialists col-for all the hospital activities. The JC has beenlaborating with the CTN review it and write achiefly engaged in this type of accreditation, notreport. As of 2011, more than 200 manufacturing

specific to imaging. The international section ofand 200 imaging facilities had been registered.

this JC is the JCI (Joint Commission International),

Ninety-two imaging sites passed the scanner vali-

which is well known for their accreditation activi-

dation and 29 had completed the process and areties given to the hospitals around the world which

waiting for the accreditations. In Japan three imag-

welcome medical tourists.

ing sites completed scanner validation at the beginning of 2011 (Update information is included in

5．Clinical Trial Network

another report 19）).
In 2011 August FDA issued a guidance for use ofApart from the above mentioned imaging accred-imaging data for the endpoint of clinical trials 20）.

itation for clinical practice, the Society of Nuclear
Medicine (SNM), (Now the Society of Nuclear
Medicine and Molecular Imaging: SNMMI) started− W42 −

Clin Eval 43（1）2015

Fig. 2Central IND strategy by SNM (now SNMMI)

Food and Drug Administration
IND

IND

Drug Master File

Company A
Drug “a”

US-SNM
Biomarker “x”
CMC (Chemistry,
Manufacturing and Control)

Manufacturing
site

Company B
Drug “b”
Company C
Drug “c”“Central IND” by SNM•First, open protocol without detailed description of each therapeutic drug, andthen protocol amendment for detailed description of each protocol.

Table 1

SNM, Imaging CRO, therapeutic industry ─ Each role and collaboration

US-SNM

Scanner/manufacturing validation,
education, standardization
Policy, methodology, open information
Equality, credibility

Imaging CRO

Specific technology of imaging
Detailed job responding needs of company
Accumulation of knowledge andinformation inside the company

Therapeutic
drug company

Their interest is therapeutic drugs, notbiomarkers
Biomarker issue is committed to SNM
Annual fee to SNM + cost for each protocol

Committee was established by the Japanese Society

6．Conclusionof Nuclear Medicine in 2011 and developed standardization guidelines for manufacturing, safety

As described above, the new regulatory frame-evaluation, and clinical development, learning fromwork of PET examination in the U.S. had been

the U.S. framework. In the August of 2011, they

developed by the end of 2011 and we will be able tostarted public consultation concerning this guide-

see the outcomes of this newly developed frame-line and it will be finalized in October 2011 (Thiswork from the end of 2011 through the year of

was authorized and then they started manufactur-2012 (Please see the other reports to find the out-

ing audit and scanner validation programs). The

comes 15, 16, 19）).

Japanese PET community is now at the starting

In Japan, the Molecular Imaging Strategic

point of a new era to promote the use of PET− W43 −

臨床評価43 巻 1 号

2015

molecular imaging for diagnostic and therapeutic

products. Part 2: Clinical indications. June 2004.

drug development as well as general clinical prac-7）U.S. Department of Health and Human Services, Foodtice, and finally to contribute to the improvement

and Drug Administration: Guidance for Industry:
Developing medical imaging drug and biologicalof public health.

products. Part 3: Design, analysis, and interpretation of clinical studies. June 2004.

Acknowledgement8）U.S. Department of Health and Human Services, FoodWe deeply appreciate the specialists in the U.S., someand Drug Administration: Guidance: PET Drug‒of them appear in this article. This English translation

Current Good Manufacturing Practice (CGMP).

and publication is supported by the following task force.

December 2009.

Ministry of Health, Labor and Welfare, 2014 fiscal year:9）U.S. Department of Health and Human Services, Food

Regulatory science concerning clinical application ofand Drug Administration: Guidance for Industry,
Investigators and Reviewers: Exploratory IND Studies.

nuclear medicine diagnosis using PET drugs produced by

January 2006.

an in-house PET drug synthesizer.

10）U.S. Department of Health and Human Services, Foodand Drug Administration: Guidance: PET drug applications − Content and format for NDAs and ANDAs.

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