What protections are appropriate for research involving greater than minimal risk but presenting the prospect of direct benefit to the indi-vidual subjects?. What protections should be re
Trang 1and frequency of each emission of the radionuclide are known If we
designate E i as the energy of the i th emission, n iis the frequency of thatemission The amount of radiation energy emitted per unit of accu-mulated radioactivity can then be described as
tivity, Ã If a radionuclide deposited in the source organ has more than
one emission, the equilibrium absorbed dose constant should be culated for each emission and summated
cal-Total Energy Absorbed by Target Organ, D
Due to the distance and attenuation between the source organ andtarget oranges, only a fraction of the energy emitted by the source organ
is absorbed by the target organ This fraction factor needs to be quantified so that the total absorbed dose by the target organ can beestimated
Absorbed Fraction f
The absorbed fraction depends on the geometric relationship of thesource and target organ, the emission energy of the radionuclide, andthe composition of the source organs, the target organ, and those
organs in between Mathematically, the absorbed fraction of the i th
emission of the radionuclide can be expressed as fi (t k¨sj) The energy
absorbed by the target organ, t k , from the i th emission of the
radionu-clide in source organ, s j , is equal to à jfi (t k¨sj)Di So the total energy
absorbed by target organ, t k, from all emissions in the source organ,
sj, is
(7)
Because the absorbed dose is defined as energy absorbed in unit mass,
the dose delivered from the source organ, s j , to the target organ, t k, is
(8)
where à j is the cumulated activity in source organ, s j , and m kis the mass
of the target organ, t k The total dose to the target organ can be obtained
by summing the doses from all the source organ of the body:
The calculation of absorbed fraction, f, for each penetrating sion, for example, photons, is very complicated, as it is highly depen-dent on the energy of the radiation emission, the geometry between thetarget and source organs, and the characteristics of the tissue andorgan The range of f is between 0 and 1 from the source organ to target
Trang 2organ (target organ can be the source organ itself) for photons
with emitting energy >10 keV When the target organ is the same as the
source organ, and electron or photon energy is <10 keV, f = 1 If the
target organ is a different organ, then f = 0 This assumes that the source
organ will attenuate and absorb within itself the entire radiation
energy when the radiation emission is a low-energy photon or a
non-penetrating particle, such as an electron
Specific Absorbed Dose Fraction, F
A rearrangement of equation 8, gives us
(9)
The term , is defined as the specific absorbed fraction,
Fi (t k¨sj ) This is the fraction of the i th radiation emitter that is given
off by the radionuclide in the source organ, s j, and absorbed, per unit
mass, by target organ t k Equation 9 can then be written as
(10)
The specific absorbed fraction has been calculated using mathematical
phantom models based on different age groups with complex
mathe-matical simulations for source-target pairs The results are a set of
com-prehensive tables of specific absorbed fractions for each reference age
group Table 4.1 is an example that was formulated by Oak Ridge
National Lab (1) This example involves a 500 keV photon, the specific
absorbed fraction from the kidney (source organ) to what could be
con-sidered the average liver of a 10-year-old (2.35E-2/kg or 2.35E-5/g)
A simplified quantity, dose per cumulated activity, or S value, has been
calculated for the source-target organs for many radionuclides of
inter-est The S value of the source-target organs, pair j and k, is defined
as
.This is calculated in the conventional
units of rad/mCi-hr Medical Internal Radiation Dose (MIRD)
com-mittee pamphlet No 11 tabulated many of the most commonly used
radionuclides for the standard adult phantom (2) Now Equation 10
can be rewritten as
D(tk¨sj )(rad) = Ã jS(tk¨sj) (11)
The total dose D(t k ) to target organ k is then described as
(12)
If the accumulated radioactivity in each source organ is known, one
can calculate the total dose to the target organ by using the S-value
table and summing up the dose delivered to the target organ from each
Trang 4source organ In absence of the S-value tables for other age groups, the
S value can be calculated using tabulated F and D values, as discussed
earlier
Pediatric Dose Estimate
For pediatric patients, radiopharmaceutical dosages are based on
a pediatric dosing schedule There are many different dosing
sche-dules The most common ones are those using body weight or body
surface areas as guides to scale the dose Pediatric dose schedules
consider many factors to scale down the dosage from that
of adult to child, including organ doses, effective dose, and image
quality
However, absorbed radiation dose and effective dose to pediatric
patients are not as simple as the dosing schedule They are not just
simple linear scaled-down doses of those for adult patients As we
dis-cussed before, radiation doses to patients depend on geometric and
anatomic relationships of source to target organs Differences in
pedi-atric organ size, density, and composition significantly change the
geo-metric and anatomic relationships that were established for adult
patient (or phantom) Differences of biokinetics, due to age-related
dif-ferences in uptakes (e.g., thyroid uptake of iodine), and excretion (e.g.,
bladder voiding interval), must be considered when estimate radiation
doses for pediatric patients
Mathematical phantoms for age groups considering the geometric
and anatomic variables have been well developed They are typically
for infants, and 1-, 5-, 10-, and 15-year-olds Specific absorbed fraction
has been calculated and tabulated (e.g., Table 4.1) for each age-specific
phantom group Combined with dose schedule, age-adjusted uptake
and excretion parameters, pediatric radiation doses can then be
estimated according to Equation 10
Practical Approach to Internal Dose Estimate
The estimation of internal dose from a radionuclide in a human is
rather a complicated process Studies of biokinetic models of a
partic-ular radiopharmaceutical normally begin through investigations of the
model in animals Modeling data are collected starting with the initial
amount of the radiopharmaceutical of interest that is injected into
the animal The percentage of the radionuclide that is taken up by
the source organ is determined through imaging Other pertinent data
are collected through assays of blood and urine These data points
are then carefully plotted or fitted to an established mathematical
model that describes the biokinetics of the radionuclides in each source
organ Complex regulatory requirements regarding human research
subjects dictate that dose estimates in human subjects should
con-ducted after successful animal studies Many radiopharmaceuticals are
not directly studied for pediatric applications because of complicated
social and ethical issues related to conducting radiation research in
children
Trang 5A wealth of information concerning internal dosimetry for the mostcommonly used radionuclides in nuclear medicine has been estab-lished and published, including dosimetry data for radionuclides used
in positron emission tomography (PET) scanning (3–6) Pediatric doseestimates have also been calculated for different age groups based onadult biokinetics of radiopharmaceuticals and anatomic phantommodels Researchers have observed the differences between pediatricbiokinetic models and those of an adult, especially in regard to infants,and so improvements in dosimetry data for pediatric patients continue
The Annals of International Commission on Radiological Protection
(ICRP) Publication 53 provides biokinetic models and lists radiationdoses to patients from the most commonly used radiopharmaceuticals
in nuclear medicine (7) ICRP Publication 80 recalculated 19 of the mostfrequently used radiopharmaceuticals from ICRP 53 and added 10more new radiopharmaceuticals (8) Tables 4.2 to 4.4 are absorbed-dosetables of several radiopharmaceuticals used for PET imaging, adaptedfrom ICRP 80
Table 4.2 Absorbed dose of 18 F-FDG (2-fluoro-2-deoxy-D-glucose)
Absorbed dose per unit activity administered
18 F 109.77 min (mGy/MBq) Organ Adult 15 years 10 years 5 years 1 year Adrenals 1.2E - 02 1.5E - 02 2.4E - 02 3.8E - 02 7.2E - 02 Bladder 1.6E - 01 2.1E - 01 2.8E - 01 3.2E - 01 5.9E - 01 Bone surfaces 1.1E - 02 1.4E - 02 2.2E - 02 3.5E - 02 6.6E - 02 Brain 2.8E - 02 2.8E - 02 3.0E - 02 3.4E - 02 4.8E - 02 Breast 8.6E - 03 1.1E - 02 1.8E - 02 2.9E - 02 5.6E - 02 Gall bladder 1.2E - 02 1.5E - 02 2.3E - 02 3.5E - 02 6.6E - 02 GI-tract
Stomach 1.1E - 02 1.4E - 02 2.2E - 02 3.6E - 02 6.8E - 02
SI 1.3E - 02 1.7E - 02 2.7E - 02 4.1E - 02 7.7E - 02 Colon 1.3E - 02 1.7E - 02 2.7E - 02 4.0E - 02 7.4E - 02 (ULI 1.2E - 02 1.6E - 02 2.5E - 02 3.9E - 02 7.2E - 02) (LLI 1.5E - 02 1.9E - 02 2.9E - 02 4.2E - 02 7.6E - 02) Heart 6.2E - 02 8.1E - 02 1.2E - 01 2.0E - 01 3.5E - 01 Kidneys 2.1E - 02 2.5E - 02 3.6E - 02 5.4E - 02 9.6E - 02 Liver 1.1E - 02 1.4E - 02 2.2E - 02 3.7E - 02 7.0E - 02 Lungs 1.0E - 02 1.4E - 02 2.1E - 02 3.4E - 02 6.5E - 02 Muscles 1.1E - 02 1.4E - 02 2.1E - 02 3.4E - 02 6.5E - 02 Oesophagus 1.1E - 02 1.5E - 02 2.2E - 02 3.5E - 02 6.8E - 02 Ovaries 1.5E - 02 2.0E - 02 3.0E - 02 4.4E - 02 8.2E - 02 Pancreas 1.2E - 02 1.6E - 02 2.5E - 02 4.0E - 02 7.6E - 02 Red marrow 1.1E - 02 1.4E - 02 2.2E - 02 3.2E - 02 6.1E - 02 Skin 8.0E - 03 1.0E - 02 1.6E - 02 2.7E - 02 5.2E - 02 Spleen 1.1E - 02 1.4E - 02 2.2E - 02 3.6E - 02 6.9E - 02 Testes 1.2E - 02 1.6E - 02 2.6E - 02 3.8E - 02 7.3E - 02 Thymus 1.1E - 02 1.5E - 02 2.2E - 02 3.5E - 02 6.8E - 02 Thyroid 1.0E - 02 1.3E - 02 2.1E - 02 3.5E - 02 6.8E - 02 Uterus 2.1E - 02 2.6E - 02 3.9E - 02 5.5E - 02 1.0E - 01 Remaining organs 1.1E - 02 1.4E - 02 2.2E - 02 3.4E - 02 6.3E - 02 Effective dose 1.9E - 02 2.5E - 02 3.6E - 02 5.0E - 02 9.5E - 02 (mSv/MBq)
Source: ICRP Publication 80 Radiation Dose to Patients from Radiopharmaceutical.
Annals of ICRP 1998;28(3):10–49, with permission from the ICRP.
Trang 6Table 4.3 Absorbed dose [methyl- 11 C]thymidine
Absorbed dose per unit activity administered
11 C 20.38 min (mGy/MBq)
Organ Adult 15 years 10 years 5 years 1 year
Adrenals 2.9E - 03 3.7E - 03 5.8E - 03 9.3E - 03 1.7E - 02
Bladder 2.3E - 03 2.7E - 03 4.3E - 03 7.1E - 03 1.3E - 02
Bone surfaces 2.4E - 03 3.0E - 03 4.7E - 03 7.6E - 03 1.5E - 02
Brain 1.9E - 03 2.4E - 03 4.0E - 03 6.7E - 03 1.3E - 02
Breast 1.8E - 03 2.3E - 03 3.6E - 03 5.9E - 03 1.1E - 02
Gall bladder 2.8E - 03 3.4E - 03 5.2E - 03 7.9E - 03 1.5E - 02
GI-tract
Stomach 2.4E - 03 2.9E - 03 4.6E - 03 7.3E - 03 1.4E - 02
SI 2.4E - 03 3.1E - 03 4.9E - 03 7.8E - 03 1.5E - 02
Colon 2.4E - 03 2.9E - 03 4.7E - 03 7.4E - 03 1.4E - 02
(ULI 2.4E - 03 3.0E - 03 4.8E - 03 7.7E - 03 1.4E - 02)
(LLI 2.3E - 03 2.7E - 03 4.5E - 03 7.1E - 03 1.3E - 02)
Heart 3.4E - 03 4.3E - 03 6.8E - 03 1.1E - 02 2.0E - 02
Kidneys 1.1E - 02 1.3E - 02 1.9E - 02 2.8E - 02 5.1E - 02
Liver 5.2E - 03 6.8E - 03 1.0E - 02 1.6E - 02 2.9E - 02
Lungs 3.0E - 03 3.9E - 03 6.2E - 03 9.9E - 02 1.9E - 02
Muscles 2.1E - 03 2.6E - 03 4.1E - 03 6.6E - 03 1.3E - 02
Oesophagus 2.2E - 03 2.8E - 03 4.3E - 03 6.9E - 03 1.3E - 02
Ovaries 2.4E - 03 3.0E - 03 4.8E - 03 7.6E - 03 1.4E - 02
Pancreas 2.7E - 03 3.4E - 03 5.3E - 03 8.3E - 03 1.6E - 02
Red marrow 2.5E - 03 3.1E - 03 4.8E - 03 7.6E - 03 1.4E - 02
Skin 1.7E - 03 2.1E - 03 3.4E - 03 5.6E - 03 1.1E - 02
Spleen 3.0E - 03 3.7E - 03 5.9E - 03 9.6E - 03 1.8E - 02
Testes 2.0E - 03 2.5E - 03 3.9E - 03 6.2E - 03 1.2E - 02
Thymus 2.2E - 03 2.8E - 03 4.3E - 03 6.9E - 03 1.3E - 02
Thyroid 2.3E - 03 2.9E - 03 4.7E - 03 7.8E - 03 1.5E - 02
Uterus 2.4E - 03 3.0E - 03 4.8E - 03 7.6E - 03 1.4E - 02
Remaining organs 2.1E - 03 2.6E - 03 4.2E - 03 6.8E - 03 1.3E - 02
Effective dose 2.7E - 03 3.4E - 03 5.3E - 03 8.4E - 03 1.6E - 02
(mSv/MBq)
Source: ICRP Publication 80 Radiation Dose to Patients from Radiopharmaceutical.
Annals of ICRP 1998;28(3):10–49, with permission from the ICRP.
Table 4.4 Absorbed dose 15 O-abeled water
Absorbed dose per unit activity administered
15 O 2.04 min (mGy/MBq)
Organ Adult 15 years 10 years 5 years 1 year
Adrenals 1.4E - 03 2.2E - 03 3.1E - 03 4.3E - 03 6.6E - 03
Bladder 2.6E - 04 3.1E - 04 5.0E - 04 8.4E - 04 1.5E - 03
Bone surfaces 6.2E - 04 8.0E - 04 1.3E - 03 2.3E - 03 5.5E - 03
Brain 1.3E - 03 1.3E - 03 1.4E - 03 1.6E - 03 2.2E - 03
Breast 2.8E - 04 3.5E - 04 6.0E - 04 9.9E - 04 2.0E - 03
Gall bladder 4.5E - 04 5.5E - 04 8.6E - 04 1.4E - 03 2.7E - 03
GI-tract
Stomach 7.8E - 04 2.2E - 03 3.1E - 03 5.3E - 03 1.2E - 02
SI 1.3E - 03 1.7E - 03 3.0E - 03 5.0E - 03 9.9E - 03
Colon 1.0E - 03 2.1E - 03 3.7E - 03 6.2E - 03 1.2E - 02
(ULI 1.0E - 03 2.1E - 03 3.7E - 03 6.2E - 03 1.2E - 02)
(LLI 1.1E - 03 2.1E - 03 3.7E - 03 6.2E - 03 1.2E - 02)
Heart 1.9E - 03 2.4E - 03 3.8E - 03 6.0E - 03 1.1E - 02
Kidneys 1.7E - 03 2.1E - 03 3.0E - 03 4.5E - 03 8.1E - 03
Trang 71 Cristy M, Eckerman KF Specific absorbed fraction of energy at various ages from internal photon source IV Ten-year-old Oak Ridge National Labora- tory Report ORNL/TM-8381, vol 4, 1987.
2 Snyder WS, Ford MR, Warner GG, et al “S” absorbed dose per unit lated activity Nm/MIRD Pamphlet No 11 New York: Society of Nuclear Medicine, 1975.
cumu-3 Ruotsalainen U, Suhonen-Polvi H, Eronen E, et al Estimated radiation dose
to the newborn in FDG-PET studies J Nucl Med 1996;37:387–393.
4 Hays MT, Watson EE, Stabin M, et al MIRD dose estimate report No 19: radiation absorbed dose estimates from 18F-FDG J Nucl Med 2002;43:210– 214.
5 Sorenson JA, Phelps ME Physics in Nuclear Medicine New York: Harcourt Brace Jovanovich, 1987.
6 Stabin MG, Stabbs JB, Toohey RE, et al Radiation Dose for ceuticals, NEREG/CR Radiation Internal Dose Center, Oak Ridge Institute
Radiopharma-of Science and Education, 1996.
7 ICRP Publication 53, Radiation Dose to Patient from Radiopharmaceutucal, Annals of ICRP, vol 18, pp 1–4 New York: Elsevier, 1988.
8 ICRP Publication 80, Radiation Dose to Patients from Radiopharmaceutical, Annals of ICRP, vol 28, p 3 New York: Elsevier, 1998.
Table 4.4 Absorbed dose 15O-abeled water (Continued)
Absorbed dose per unit activity administered
15 O 2.04 min (mGy/MBq) Organ Adult 15 years 10 years 5 years 1 year Liver 1.6E - 03 2.1E - 03 3.2E - 03 4.8E - 03 9.3E - 03 Lungs 1.6E - 03 2.4E - 03 3.4E - 03 5.2E - 03 1.0E - 02 Muscles 2.9E - 04 3.7E - 04 6.1E - 04 1.0E - 03 2.0E - 03 Oesophagus 3.3E - 04 4.2E - 04 6.7E - 04 1.1E - 03 2.1E - 03 Ovaries 8.5E - 04 1.1E - 03 1.8E - 03 2.8E - 03 5.8E - 03 Pancreas 1.4E - 03 2.0E - 03 4.2E - 03 5.4E - 03 1.2E - 02 Red marrow 8.5E - 04 9.7E - 04 1.6E - 03 3.0E - 03 6.1E - 03 Skin 2.5E - 04 3.1E - 04 5.2E - 04 8.8E - 04 1.8E - 03 Spleen 1.6E - 03 2.3E - 03 3.7E - 03 5.8E - 03 1.1E - 02 Testes 7.4E - 04 9.3E - 04 1.5E - 03 2.6E - 03 5.1E - 03 Thymus 3.3E - 04 4.2E - 04 6.7E - 04 1.1E - 03 2.1E - 03 Thyroid 1.5E - 03 2.5E - 03 3.8E - 03 8.5E - 03 1.6E - 02 Uterus 3.5E - 04 4.4E - 04 7.2E - 04 1.2E - 03 2.3E - 03 Remaining organs 4.0E - 04 5.6E - 04 9.4E - 04 1.7E - 03 2.9E - 03 Effective dose 9.3E - 04 1.4E - 03 2.3E - 03 3.8E - 03 7.7E - 03 (mSv/MBq)
Source: ICRP Publication 80 Radiation Dose to Patients from Radiopharmaceutical.
Annals of ICRP 1998;28(3):10–49, with permission from the ICRP.
Trang 8Pediatric PET Research Regulations
Geoffrey Levine
Good intentions are necessary, but not sufficient, to conduct pediatric
positron emission tomography (PET) research This chapter provides
direction to guide the process of conducting PET research in children
Code of Federal Regulations (CFR)
When the executive rule-making voice of the government speaks, it
does so officially through the Code of Federal Regulations (1) These
are not the laws, per se, but rather the nitty gritty rules necessary to
carry out the laws that are made by Congress For example, Congress
may pass a law to provide for a safe drug supply; the executive branch
(e.g., the Food and Drug Administration, FDA) carries out the intent of
the law and writes the rules (e.g., “Intravenous products shall be sterile
and pyrogen-free”)
Reading 21 CFR (Title 21 of the CFR, where the FDA rules are
located) is about as exciting as reading the telephone book or the
Inter-nal Revenue Service regulations for preparing tax returns (until you
come to that one paragraph that appears to justify your objective), but
it is necessary The judicial system interprets the regulations and may
enforce compliance Each agency of the executive branch of the
gov-ernment or each specific purpose for a set of regulations has a
partic-ular location Title 10, for example, is where one finds radiation safety
and safe use of radiopharmaceutical use in humans Table 5.1 provides
an example of several other locations within the CFR that may be of
interest to the reader (3) In addition to the CFR, the various agencies
issue letters, guidelines, interpretations, descriptions of courses,
com-ments, request for comcom-ments, etc., in an effort to communicate with the
public and research investigators, among others And, like cement, the
rules become more solidified with time Occasionally, the book is
opened for a rewrite, providing a glimpse into the “mind” of the
gov-ernment One such opportunity appeared on November 16, 2004, in an
open meeting at the FDA headquarters in which an update of the
Radioactive Drug Research Committee (RDRC) regulations was being
47
Trang 9Table 5.1 Some additional examples of codified federal policy
07 CFR Part 1C Department of Agriculture
10 CFR Part 35 Human Use of Radiopharmaceuticals
10 CFR Part 745 Department of Energy
15 CFR Part 27 Department of Commerce
16 CFR Part 1028 Consumer Product Safety Commission
21 CFR Part 361.1 Radiopharmaceutical Use in Humans
40 CFR Part 26 Environmental Protection Agency
45 CFR Part 46 Public Welfare, Protection of Human Subjects
45 CFR Part 690 National Science Foundation
Note: There are source documents, regulations, amendments to regulations, Web sites, parts, subparts, preliminary documents for review, rewrites, updates, clarifications, and numerous other forms of communication.
Source: Data from ref 2.
considered (4) The regulations will be examined shortly, particularly
as they relate to PET research in children Table 5.2 provides a resourcelist to facilitate communication (4,5,14)
Pathways Allowed by the Federal Regulatory System
There are three major routes to conduct research that are allowed bythe federal regulatory system: (1) an investigational new drug (IND)application, (2) a physician-sponsored IND, and (3) the RDRC mecha-nism (6–8,15–21)
The full IND approach is the one taken by drug manufacturers whointend to obtain FDA approval to market a pharmaceutical to thegeneral public, usually for commercial purposes The manufacturerconducts physical, chemical, and biologic studies in vitro and then inanimals prior to studies in humans (clinical trials, phases I, II, IIIdescribed below), followed by postmarketing studies (phase IV),post–new drug approval The pharmaceutical house has sufficienttalent, expertise, and staff in its regulatory and medical departments toknow how to proceed on its own
A second pathway is the physician-sponsored IND, which usuallyinvolves studies with more than 30 subjects, can be conducted at one
or multiple sites, and can involve agents that are new entities, newroutes of administration, new dosage forms for existing or new drugs,new populations (including children) or disease states, new indica-tions, etc The physician or other qualified investigator (with a physi-cian as co-investigator) is usually medical center or hospital based andwill be required to fill out FDA forms 1571, 1572, and 1573 among pos-sibly others This process of how to compile, assemble, complete andsubmit the physician-sponsored IND has been reviewed broadly and
in detail elsewhere (15)
A third pathway is the RDRC approach Using this mechanism, theFDA delegates authority to a local committee to approve researchstudies (usually up to 30 patients, although the number can be higherunder certain circumstances, for example, if FDA form 2915 is com-pleted) The composition of the membership of that committee hasFDA prior approval Authority is given by this committee to investi-gators to conduct only phase I and phase II clinical trials, meeting very
Trang 10strict and specific criteria (see below) Under no circumstances are the
results from such studies to be used to make clinical decisions for any
of the participants in the study until the study is completed and the
data are analyzed In theory, the findings are investigational and
remain unproven at this point It is possible that approved clinical
methods used to validate the research finding may be clinically helpful
or of benefit to a study participant For example, the findings from a
computed tomography (CT) scan used to study the metabolism and
distribution of a new diagnostic radiopharmaceutical such as a
radio-labeled monoclonal antibody that was designed to locate a tumor, may
find their way to the patient’s or subject’s medical record, but not
infor-mation provided by the radiolabeled monoclonal antibody This RDRC
Table 5.2 Selected reference sites and sources relative to pediatric
PET research
Food and Drug Administration (December, 2004)
Main telephone number 1-888-INFO-FDA
E-mail http://www.FDA.gov
Drug information telephone number 1-301-827-4570
Pediatric Drug Development (PDD) 1-301-594-PEDS (7337)
Radioactive Drug Research Program
Address Food and Drug Administration
Center for Drug Evaluation and Research
Division of Medical Imaging and Radiopharmaceutical Drug Products HFD-160 Parklawn Building, Room 18R-45 5600 Fishers Lane Rockville, MD 20852 Attention: RDRC Team Director George Mills, MD
Senior manager Capt Richard Fejka, USPHS,
Kowalsky RJ, Falen SW Radiopharmaceuticals in Nuclear Pharmacy, 2nd
ed Available from the American Pharmaceutical and Nuclear Medicine
Association, Washington, D.C http://www.pharmacist.com/store/cfm
Clinical evidence by the evidence-based update on more than 1000 medical
conditions including clinical trials British Medical Journal Free of
charge to healthcare professionals.
http://www.unitedhealthcarefoundation.org/Emb.html
Legislative Information Gateway to the Congressional Record and
Congressional Committee Information http://thomas.loc.gov
Source: Data from refs 4–13.
Trang 11approach to conduct PET research in children is the one on which weconcentrate in this chapter (6–8,16–18,21).
The Clinical Trial Process
The clinical trial is a biomedical or behavioral research study of humansubjects that is designed to answer specific questions about biomedical
or behavioral interventions (drugs, treatments, devices, or new ways
of using known drugs, treatments, or devices) Clinical trials are used
to determine whether new biomedical or behavioral interventions aresafe, efficacious, and effective (17,18) Trials of an experimental drug,device, treatment, or intervention may proceed through four distinctphases Sometimes more than one phase can be conducted at the sametime The actual number of subjects studied in each phase may depend
in part on the incidence or prevalence of the disease state or conditionbeing investigated
Phase I
This phase entails testing in a small group of people (e.g., 20 to 80 jects) to determine efficacy and evaluate safety (e.g., determine a safedosage range) and identify side effects A typical phase I trial of a newdrug agent frequently involves relatively high risk to a small number
sub-of participants The investigator and occasionally others have the onlyrelevant knowledge regarding the treatment because these are the firsthuman uses The study investigator may be required to perform con-tinuous monitoring on participant safety with frequent reporting toinstitute and center staff with oversight responsibility
Phase II
This phase entails a study of a larger group of people (several hundred)
to determine the efficacy and further evaluate safety A typical phase IIstudy follows phase I studies, and there is more information regardingrisks, benefits, and monitoring procedures However, more participantsare involved, and the disease process confounds the toxicity and out-comes An institute or center may require monitoring similar to that of
a phase I trial or may supplement that level of monitoring with viduals with expertise relevant to the study who might assist in inter-preting the data to ensure patient safety (17,18)
indi-Phase III
This phase entails a study to determine the efficacy in large groups ofpeople (from several hundred to several thousand) by comparing theintervention to other standard or experimental interventions, tomonitor adverse effects, and to collect information to allow safe use.The definition includes pharmacologic, nonpharmacologic, and behav-ioral interventions given for disease prevention, prophylaxis, diagno-sis, or therapy Community-based trials and other population-basedtrials are also included A phase III trial frequently compares a new
Trang 12treatment to a standard treatment or to no treatment, and treatment
allocation may be randomly assigned and the data masked These
studies frequently involve a large number of participants followed
for longer periods of treatment exposure Although short-term risk is
usually slight, one must consider the long-term effects of a study agent
or achievement of significant safety or efficacy differences between
the control and the study groups for the masked study An institute
or center may require a data safety monitoring board (DSMB) to
perform monitoring functions This DSMB would be composed of
experts relevant to the study and would regularly assess the trial
and offer recommendations to the institute or center concerning its
continuation
Phase IV
This phase entails studies done after the intervention has been
mar-keted These studies are designed to monitor the effectiveness of the
approved intervention in the general population and to collect
infor-mation about any adverse effects associated with widespread use The
controversy that appeared in the lay media in December 2004 as well
as in medical publications (22) concerning adverse events associated
with Vioxx and Celebrex is an example of a postmarketing discovery
following new drug approval
Radioactive Drug Research Committee Update
Meeting and Transition
After more than a quarter of a century, it became obvious that
techno-logic progress and events had surpassed the intent of the original 1975
FDA, RDRC regulations (6–8,16) During the current transition period
(June 2005) and until the updated RDRC regulations are finalized, the
1997 FDA Modernization Act (FDAMA) provides a mechanism for the
uninterrupted production of PET radiopharmaceutical by specifying
that they should meet United States Pharmacopoeia (USP) monograph
standards (23,24) An example of a PET radiopharmaceutical coming
through that process was 18F-fluorodeoxyglucose (FDG) injection,
which received a new drug approval in less than 6 months after
sub-mission on August 5, 2004 (25)
RDRC Update Issues
Six issues or areas of concern, proposed by the FDA/RDRC, were
placed on the agenda for discussion (4,5):
1 Pharmacologic issues
2 Radiation dose limits for adult subjects
3 Assurance of safety for pediatric subjects
4 Quality and purity
5 Exclusion of pregnant women
6 RDRC membership
Trang 13As this chapter is being written, participants at the open meeting andother interested parties and organizations are submitting written com-ments for the record and for consideration regarding the updated reg-ulations Who could have predicted in 1975 how to best conductresearch or manufacture pharmaceuticals (including radiopharmaceu-ticals), given the advent of monoclonal antibodies, cloning, stem cells,gene therapy, biologic response modifiers, and the growth of PET andother imaging modalities?
Vulnerable Populations
There are four populations addressed specifically in Title 45 part 46 ofthe Code of Federal Regulations, which deals with public welfare pro-tection of human subjects (2,19–21):
Subpart A: Human subjects, research subjects, and volunteers as trols or normals
con-Subpart B: Additional protections for pregnant women, human fetuses,and neonates
Subpart C: Additional protections pertaining to biomedical and ioral research in prisoners
behav-Subpart D: Additional protections for children as subjects in research(21)
Assurance of Safety for Pediatric Subjects
Currently 21 CFR 361.1 (that FDA section of the code that deals withradiopharmaceutical research in humans) allows the study of radioac-tive drugs in subjects less than 18 years of age without an IND appli-cation, if the following conditions are met:
1 The study presents a unique opportunity to gain information notcurrently available, requires the use of research subjects less than 18years of age, is without significant risk, and is supported withreview by qualified consultants to the RDRC
2 The radiation dose does not exceed 10% of the adult radiation dose
as specified in 21 CFR 361.1 (b)(i) and, as with adult subjects, the lowing additional requirements are met:
fol-3 The study is approved by an institutional review board (IRB) thatconforms to the requirements of 21 CFR part 56
4 Informed consent of the subject’s legal representative is obtained inaccordance with 21 CFR part 50
5 The study is approved by the RDRC, which assures all other ments of 21 CFR 361.1 are met (5,16)
require-Alternatively, when a study is conducted under an IND (as pared to a RDRC) in accordance with part 312 (21 CFR part 312), thesponsor must submit to the FDA the study protocol, protocol changesand information amendments, pharmacology/toxicology and chem-istry information, and information regarding prior human experiencewith the same or similar drugs (see 21 CFR 312.22, 312.33, 312.30 and312.31) Additionally, 21 CFR 32 requires that sponsors (of the IND)promptly review all information relevant to the safety of the drugobtained or otherwise received by the sponsor by any source, foreign
Trang 14com-or domestic This includes infcom-ormation derived from any clinical com-or
epi-demiologic experience, reports in the scientific literature and
unpub-lished scientific papers, as well as reports from foreign regulatory
authorities 21 CFR part 32 also requires that sponsors submit IND
safety reports to the FDA (4,5)
Pediatric Concerns Considered for Update
Does 21 CFR 361.1 provide adequate safeguards for pediatric subjects
during the course of a research project intended to obtain basic
infor-mation about a radioactive drug, or should these studies be conducted
only under an IND?
If we assume that 21 CFR 361.1 provides adequate safeguards for
pediatric studies during such studies, given our present knowledge
about radiation and its effects, can we conclude that the current dose
limits would be appropriate to ensure no significant risk for pediatric
participants? Should there be different dose limits for different
pedi-atric groups (5)? At present, it is estimated that only about half of
the RDRCs in conjunction with their IRBs consider approval of
radioac-tive drug research in children The operaradioac-tive phrase appears to be
minimal risk
Protections for Children Involved as Subjects of PET Research
There are three basic areas of concern in using children as PET research
subjects: (1) conformity with IRB requirements, (2) radiation
dosime-try of not more than 10% of the adult dose and in conformity with
ALARA (as low as reasonably achievable) considerations, and (3)
special considerations relevant to vulnerable populations (2,5,16,21)
Under certain circumstances, the secretary of the Department of Health
and Human Services (HHS) may waive some or all of the requirements
of these regulations for research of this type (2,21)
Some Additional Protections Addressed in 45 CFR
Part 46, Subpart D
To whom do the requirements to carry out the regulations apply?
To whom do the requirements apply as subjects, and who may give
assent and grant permission for the children?
What are the IRB responsibilities related to children?
What protections are appropriate for research not involving greater
than minimal risk?
What protections are appropriate for research involving greater than
minimal risk but presenting the prospect of direct benefit to the
indi-vidual subjects?
What protections should be required for research involving greater
than minimal risk and no prospect of direct benefit to individual
sub-jects but likely to yield generalizable knowledge about the disorder
or condition?
What protections should be required for research not otherwise
approvable that presents an opportunity to understand, prevent, or
alleviate a serious problem affecting the health or welfare of children?
What is the requirement for permission by parents or guardians and
for assent by children?
Trang 15What protections should be required and who grants permission forchildren who are wards of the State? (21).
RDRC Specific Responsibilities Abstracted from the CFR
This section is taken directly from the minutes of the University of Pittsburgh Medical Center (UPMC) RDRC and Human Use Subcommit-tee (HUSC), Radiation Safety Committee, Dennis Swanson, M.S., Chair-man (26)
In taking this action, the RDRC considered and assured that each ofthe following criteria were met:
1 The research study is intended to obtain basic information ing the metabolism (including kinetics, distribution, and localization)
regard-of a radioactively labeled drug or regarding human physiology, physiology or biochemistry The research study is not intended forimmediate therapeutic, diagnostic, or similar purposes or to determinethe safety and effectiveness of the drug in humans for such purposes
patho-2 The research study involves the use of a radioactive drug(s), whichwill be prepared in accordance with a RDRC-approved drug master file
or HUSC/RDRC Form 1002 The drug master file of HUSC/RDRCForm 1002 documents:
a that the amount of active ingredient or combination of active ingredient shall not cause any clinically detectable phar-macologic effect in humans as known based on pharmacologicdose calculations derived from data available published orother valid human studies;
b absorbed dose calculations based on the MIRD formalism andbiologic distribution data available from the published litera-ture or from other valid studies;
c that an acceptable method will be used to radioassay the drugprior to its use;
d that adequate and appropriate instrumentation will be utilizedfor the detection and measurement of the specific radionuclide;
e that the radioactive drug meets appropriate chemical, maceutical, and radionuclidic standards of identity, strength,quality, and purity as determined by suitable testing proce-dures;
phar-f that, for parenteral use, the radioactive drug is prepared in asterile and pyrogen free form; and
g that the package and labeling of the radioactive drug is in pliance with the requirements of 21 CFR 361.1 and NRC (ifapplicable) and Commonwealth of Pennsylvania regulationsregarding radioactive drugs
com-3 For this specific research protocol:
a Scientific knowledge and benefit is likely to result from thisstudy;
— The proposed research is based on sound rationale derivedfrom the published literature or other valid studies
— The proposed research is of sound design
Trang 16b The radiation dose is sufficient and no greater than necessary
to obtain valid data
— In consideration of available radioactive drugs, the
radioac-tive drug used in the study has the combination of half-life,
type of radiation, radiation energy, metabolism, and
chem-ical properties that results in the lowest radiation
dosime-try as needed to obtain the necessary information
— For adult subjects: the projected radiation dose to the
whole body effective dose equivalent (EDE), active
blood-forming organs, lens of eye, and gonads does not exceed 3
rem (single study) or 5 rem (annual and total dose), and
the projected radiation dose to any other organ does not
exceed 5 rem (single study) or 15 rem (annual and total
dose)
— For subjects under the age of 18 (if applicable), the projected
radiation dose does not exceed 10% of the adult limits
— The projected radiation dose commitments address
expected radionuclidic contaminants and x-ray and other
radiation-emitting procedures performed as part of the
research study
c The projected number of subjects is sufficient and no greater
than necessary for the purpose of the study as supported by a
statistical or other valid justification;
d The proposed population is appropriate to the purpose of the
study; and
— The involvement of subjects less than 18 years of age, if
applicable, is justified as (1) presenting a unique
opportu-nity to gain information not currently available; and (2)
necessitating the use of such subjects The scientific review
of research involving subjects less than 18 years of age is
supported by qualified pediatric consultants to the RDRC
— Pregnancy testing, to confirm absence of pregnancy prior to
administration of the radioactive drug(s), is performed on
female subjects of childbearing potential
e The investigators are qualified by training and experience to
conduct the proposed research study
— The research study involves, as a listed co-investigator, a
physician “authorized user” recognized by the Radiation
Safety Committee, University of Pittsburgh, as qualified to
oversee the preparation, handling and use of the
radioac-tive drug (26)
Illustrative Examples that Have Come to
the UPMC-RDRC Requiring Directed Change,
Correction, or Reconsideration
1 Not including the gallium-68 rod transmission scan to calibrate
the PET scanner as part of the radiation dosimetry
2 Submitting a phase III clinical trial to the RDRC
Trang 173 Submitting an appropriate research protocol and informedconsent for a study using 18F-FDG to the IRB, but not the RDRC.
4 Inappropriate expression of radiation dose and risk to the patient
in the informed consent The UPMC has adopted a uniform radiationrisk statement model which it recommends be used in both the consentand protocol, although other statements are also acceptable, forexample, “Participation in this research study involves exposure toradiation from the two PET transmission scans, the one 12 mCi (a unit
of radioactivity dosage) injection of [15-O] water, one 15-mCi dose of[11-C]WAY, and one 10-mCi injection of [11-C]raclopride The amount
of radiation exposure you will receive from these procedures isequivalent to a whole-body radiation dose of 0.47 rem (a unit ofradiation exposure) This is less than 10% of the annual whole-bodyradiation exposure (5 rem) permitted to radiation workers by federalregulations There is no minimum level of radiation exposure that isrecognized as being totally free of the risk of causing genetic defects(cell abnormalities) or cancer However, the risk associated with theamount of radiation exposure that you will receive from this study isconsidered to be low and similar to other everyday risks” (26)
5 While using magnetic resonance imaging (MRI) for co-registrationwith PET, performing the PET scan before MRI A certain number ofMRI subjects will be eliminated or withdrawn due to claustrophobia
If this is the case, then they have been exposed to the radiation doseunnecessarily
6 A patient has a pregnancy test at a screening session 1 month prior
to a research PET scan The pregnancy test is due to the research nature
of the PET scan The pregnancy test should be conducted as close as sible to the time that the PET scan is scheduled; within 48 hours of PET
pos-7 A patient has a pacemaker and is going to have an MRI prior to
a PET study If there is a question of metal or metal fragment beingattracted by the magnets, then an x-ray may be required The x-ray isrequired as part of the research and thus should be included as part ofthe dosimetry table and consent
8 A new drug that has been tested in thousands of mice to treatmemory loss is to be trace radiolabeled and administered to humans
as part of a multicenter trial of 50 patients at each site Because the drughas never been given to a human (lack of a pharmacologic effect cannot
be substantiated), and is a multicenter study with over 30 patients, it
is best conducted under an IND Even for a radiopharmaceutical, themass of the administered radiolabeled compound currently must bequantified
9 A physician wants to test a brachytherapy unit on his patientswho have a tumor different from the one for which the FDA gave initialapproval There are 10 patients and he is comparing two types of seeds
in two different cell types This should not be submitted to the RDRC,but should be reviewed by the Human Use Subcommittee The holder
of the IND is a manufacturer of a radiation device
10 A study comes before the RDRC that is so complicated that themembers of the committee don’t believe it can be carried out withoutlosing data The project is sent back for reconsideration because if the
Trang 18data cannot be analyzed in a meaningful way, then subjects will have
been exposed unnecessarily
References
1 Fostering a culture of compliance National Institutes of Health education
and outreach seminar Pittsburgh, July 15, 2004.
2 Administering and overseeing clinical research Title 45 Public welfare Part
46 Protection of human subjects Revised November 13, 2001
Effective December 13, 2001 Subpart A—Federal policy for the protection
of human subjects Basic DHHS policy for the protection of human
research subjects In: Fostering a Culture of Compliance National Institutes
of Health education and outreach seminar Pittsburgh, PA, July 15,
2004 http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.
htm.
3 Fostering a culture of compliance National Institutes of Health education
and outreach seminar Code of Federal Regulations The common rule
(Federal Regulations) Pittsburgh, PA, July 15, 2004 http://ohrp.osophs.
dhhs.gov/ human subjects/guidance/45cfr46.htm.
4 Notice of public meeting—radioactive drugs for certain research uses.
Radioactive Drug Research Committee (RDRC) program Rockville,
MD, November 16,2004 http://www.fda.gov/cder/regulatory/RDRC/
default.htm.
5 Agenda of public meeting—radioactive drugs for certain research uses.
Radioactive Drug Research Committee (RDRC) program minutes.
Rockville, MD, November 16, 2004 http://www.fda.gov/cder/meeting/
clinicalresearch/default.htm.
6 Positron emission tomography (PET) related documents http://www.
fda.gov/cder/regulatory/PET/default.htm.
7 What information does the RDRC review? Radioactive Drug Research
Com-mittee (RDRC) program http://www.fda.gov/cder/regulatory/RDRC/
review.htm.
8 What are the responsibilities of the RDRC? Radioactive drug research
com-mittee (RDRC) program http://www.fda.gov/cder/regulatory/RDRC/
Responsibilities.htm.
9 http://grants.nih.gov/grants/guide/notice-files/not98–084.html.
10 Having trouble keeping up with clinical trials? APhA-AAPM news you can
use 4(2), October 28, 2004 http://www.pharmacist.com Info-center@
apha.org.
11 Kowalsky RJ, Falen SW Radiopharmaceuticals in Nuclear Pharmacy and
Nuclear Medicine, 2nd ed Washington, DC: APhA, 2004 http://www.
Pharmacist.com/store.cfm.
12 Clinical evidence to help support the clinician’s skillful use of
scientifically valid and evidence based information http://Unitedhealth
carefoundation.org.ebm.html.
13 How do I find and track bills? Health Physics News 2005;33(1):3 http://
www.hps.org.
14 FDA meeting to focus on radioactive drugs for basic research
APhA-AAPM electronic newsletter http://www.apha.net.org.
15 Levine G, Abel N Considerations in the assembly and submission of the
physician sponsored investigational new drug application In: Hladik WB,
Saha GB, Study KT, eds Essentials of Nuclear Medicine Science Baltimore:
Williams & Wilkins, 1987:357–386.
Trang 1916 Pediatric drug development http://www.fda.gov/cder/pediatrics/index htm.
17 NIH grants-general information glossary (NIH-grants policy statement, revised 12/01/03 In: Fostering a Culture of Compliance National Insti- tutes of Health education and outreach seminar Pittsburgh, PA, July 15, 2004:6–15 http://www.grants.nih.gov/grants/terms_.htm.
18 NIH guide: NIH policy for data and safety monitoring, release date June
10, 1998 In: Fostering a Culture of Compliance National Institutes of Health education and outreach seminar Pittsburgh, PA, July 15, 2004 http://grants.nih.gov/grants/guide/notice-files/not98–084.html.
19 Administering and overseeing clinical research Title 45 Public welfare Part
46 Protection of human subjects Revised November 13,2001 Effective December 13, 2001 Subpart B—additional protections for pregnant women, human fetuses and neonates involved in research In: Fostering a Culture of Compliance National Institutes of Health education and out- reach seminar Pittsburgh, PA, July 15, 2004 http://ohrp.osophs.dhhs gov./humansubjects/guidance/45cfr46.htm.
20 Administering and overseeing clinical research Title 45 Public welfare Part
46 Protection of human subjects Revised November 13, 2001 Effective December 13, 2001 Subpart C—additional protections pertaining to bio- medical and behavioral research involving prisoners as subjects in research In: Fostering a Culture of Compliance National Institutes of Health education and outreach seminar Pittsburgh, PA July 15, 2004 http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm.
21 Administering and overseeing clinical research Title 45 Public welfare Part
46 Protection of human subjects Revised November 13, 2001 Effective December 13, 2001 Subpart D—additional DHHS protections for children involved as subjects in research In: Fostering a Culture of Compliance National Institutes of Health education and outreach seminar Pittsburgh,
24 Radiopharmaceuticals for positron emission tomography-compounding Chapter 823 US Pharmacopeia 20/National Formulary 25, 2002.
25 Update—new fludeoxyglucose F-18 injection PET drug approved in less than 6 months http://fda.gov/cder/regulatory/pet/Fludeoxyglucose htm.
26 Swanson DP Radioactive drug research committee/human use mittee meeting minutes University of Pittsburgh Pittsburgh, PA, Novem- ber 17, 2004.
Trang 20Issues in the Institutional Review Board Review of PET Scan Protocols
Robert M Nelson
The lack of reliable information on the use of medications for children
has been addressed in the United States through two legislative
initia-tives: the Best Pharmaceuticals for Children Act (BPCA) of 2002 (1) and
the Pediatric Research Equity Act (PREA) of 2003 (2) These two
ini-tiatives have stimulated pediatric pharmaceutical research, resulting in
valuable information to guide the appropriate use of many medications
(3) In addition, the National Institutes of Health now requires (as of
1998) that children be included in research unless there are scientific
and ethical reasons not to include them (4) The resulting increase in
pediatric research has led to concerns that the regulations governing
pediatric research provide insufficient protection This chapter refers to
only the Food and Drug Administration (FDA) regulations governing
research with children (21 CFR 50 and 56), as the use of
radiopharma-ceuticals in PET scanning is regulated by the FDA Comparable
regu-lations are found in 45 CFR 46, subparts A and D
The FDA did not adopt additional safeguards for children in research
(referred to as subpart D) until April 2001 (5) In passing the BPCA, the
U.S Congress also commissioned the Institute of Medicine (IOM) to
review the adequacy of subpart D; their report was issued in March
2004 The IOM found that there are problems in the application of
subpart D due to insufficient guidance and thus variable interpretation
of key concepts (6)
The additional safeguards for children in research found in subpart
D can be viewed as a further specification of the general requirement
that the “risks to subjects are reasonable in relation to anticipated
ben-efits, if any, to subjects, and the importance of the knowledge that may
be expected to result” (21 CFR 56.111.a.2) Absent the prospect of direct
benefit, the research risks to which children may be exposed must be
restricted to either minimal risk (21 CFR 50.51) or a minor increase over
minimal risk (21 CFR 50.53), depending on whether the children have
the disorder or condition under investigation (5) If there is a prospect
of direct benefit from the research intervention, the research risk must
be justified by the anticipated benefit to the enrolled children (rather
than by any knowledge that may result) (21 CFR 50.52) (5,7) Thus, to
59
Trang 21determine whether a research protocol involving children mayproceed, an institutional review board (IRB) must assess (1) the level
of risk, and (2) the prospect of direct benefit to the child presented byeach research intervention or procedure (7)
This chapter examines the use of positron emission tomography(PET) scanning in research involving children from the perspective ofthe additional safeguards found in subpart D The risks of the twomajor components of PET scanning (i.e., administration of the radio-pharmaceutical tracer and procedural sedation) are discussed withinthis regulatory framework governing pediatric research In the course
of the analysis, key concepts from the pediatric research regulationsthat will be discussed include the component analysis of risk, minimalrisk, minor increase over minimal risk, and disorder or condition (6).Finally, the relationship between subpart D(5) and other FDA regula-tions concerning the investigational use of radiopharmaceuticals (21CFR 312 and 21 CFR 361.1) is discussed
Component Analysis of Risk
The risks (i.e., potential harms) and benefits of each intervention or cedure included in a research protocol must be assessed independently.The potential benefits from one procedure should not be used to offset
pro-or justify the risks of another (IOM recommendation 4.6) (6) The cation of this principle is fairly straightforward when the performance
appli-of one procedure does not depend on or require the performance appli-of theother procedure However, when the two procedures are dependent oneach other, the analysis is more complex In the case of a PET scan, thekey procedural components for the purpose of risk analysis are theadministration of the radioactive tracer and the necessary proceduralsedation Other risks such as the physical environment (e.g., anenclosed space and the possibility of claustrophobia) are less than thoseassociated with computed tomography (CT) or magnetic resonanceimaging (MRI) scans, as the child can be accompanied (and reassured)
by a parent during the entire procedure All of the other necessary cedures (e.g., venipuncture, placement of a peripheral intravenouscatheter) are appropriately considered minimal risk given the limitedduration (i.e., less than 2 hours) of a PET scan Thus, the following dis-cussion is limited to the risks of the radiotracer administration and pro-cedural sedation
pro-Procedural sedation is usually required for the successful completion
of the PET scan, given the need to reduce motion artifact Thus, for thepurpose of IRB analysis, the administration of the radiotracer, and therisk or benefit of radiation exposure, is the key component of the PETscan If the PET scan, and thus the radiotracer administration, offersthe prospect of direct benefit to the child undergoing the procedure,the radiation risks to which the child may be exposed can be greaterthan minimal risk assuming that the balance of potential harms andanticipated benefits is justified and comparable to any available alter-natives (21 CFR 50.52) (5) As such, the risks of any procedural seda-
Trang 22tion necessary to complete the PET scan become part of this balancing
of risks and benefits However, if the PET scan does not offer the
prospect of direct benefit to the child undergoing the procedure, the
risks of the radiation exposure and any necessary procedural sedation
must be no more than a minor increase over minimal risk for children
with a disorder or condition (21 CFR 50.53) or no more than minimal
risk for children without a disorder or condition (21 CFR 50.51) (5) In
effect, the level of appropriate (and allowable) risk exposure associated
with the procedural sedation depends on whether or not the results of
the PET scan offer the child a prospect of direct benefit A common
mistake is to determine that the risk of a procedure that does not offer
any prospect of direct benefit is no more than a minor increase over
minimal risk but to fail to appreciate that the risks of any associated
procedures must also be similarly restricted
Administration of Radioactive Tracers
The risks of administering a radiopharmaceutical tracer can be divided
into two aspects: (1) the risk from the compound to which the
radioac-tive tracer is attached, and (2) the risk from the level of radiation
expo-sure associated with the tracer The risk from the compound itself is
independent of the radiation risk and are discussed below (see
Research Under an Investigational New Drug Application) The
dis-cussion here focuses on the general risks of radiation, and not on how
one would determine the actual effective dose (ED) of radiation
expo-sure to any given organ from individual radiopharmaceuticals The
sci-entific determination of the level of radiation exposure for any given
radiopharmaceutical depends on such factors as the targeted receptor,
blood flow to the area of interest, isotope and carrier compound
half-life, mechanisms of metabolism and excretion, and so forth (8–10)
The Risks of Radiation Exposure
The data derived from atomic bomb survivors in Japan are the best
available on the effects of ionizing radiation on a large human
popu-lation (11) These data support the view that “the risk of solid cancers
appears to be a linear function of dose” (12), perhaps down to a dose
of about 5 rad (i.e., 5 rem) (12,13) Some argue that there is direct
evi-dence of risk at low-level radiation exposure in the range of 600 mrem
to 10 rem (13,14) Others place the lower limit of the range at which
low-level ionizing radiation increases the risk of some cancers at 1 rem
for acute exposure and 5 rem for protracted exposure (15) However,
the risk of cancer is probably overestimated using these data, as “cancer
rates may vary due to other risk factors correlated with the
expo-sure under investigation” (13)
The predominant model for describing the risks of low-level
radia-tion (i.e., less than 10 rem) is the linear no-threshold (LNT) model This
theoretical model is based on two assumptions: “(a) any radiation dose
can produce adverse effects such as cancer or genetic damage; [and]
(b) the severity of adverse effects is directly proportional to the
Trang 23radiation dose received” (16) In support of this model, the response relationship between low-level radiation and “the biologicalalterations that are precursors to cancer, such as mutations and chro-mosome aberrations,” appears to be linear (17) Although the LNTmodel is the customary approach, “existing data do not exclude thepossibility that there may be thresholds for such effects in the low-dosedomain” (17).
dose-The dose-response relationship between low-level radiation sure and the risk of developing cancer cannot be precisely defined byextrapolating from observations at moderate-to-high doses (15,17) As
expo-a result, there is considerexpo-able debexpo-ate expo-about whether low-level rexpo-adiexpo-ation(i.e., less than 10 rem) increases the risk of developing cancer, with thedata concerning the risk of low-level radiation exposure subject to wideinterpretation (19,20) In addition, some data support the view thatlow-level radiation exposure may be protective (12,16,18–20) This pos-sibility of “adaptive responses” (i.e., hormesis) further complicates the
“assessment of the dose-response relationships for the genetic and cinogenic effects of low-level irradiation” (17)
car-Critics argue that the LNT theory “grossly overestimates the riskfrom low-level radiation” In addition, no “statistically sound well-designed studies” (20) support the use of the LNT model at low-levelradiation doses (16,20) The confidence limits from epidemiologicstudies of the dose-response relationship of low-level radiation expo-sure are sufficiently wide “to be consistent with an increased effect, adecreased effect, or no effect” (20) Overall, “the health risk from low-level doses could not be detected above the ‘noise’ of adverse events
of everyday life” (16) Proponents of the LNT theory, however, point out that the failure to find an increase in cancer, and the obser-vation of a reduction in some instances, among populations exposed
to low-level radiation does not contradict the LNT theory given thesmall increase that would be expected and the methodologic limita-tions of the studies These limits are such that “it may never be possi-ble to prove or disprove the validity of the LNT hypothesis” (17).However, there are no data that “suggest a threshold dose below whichradiation exposure does not cause cancer” (21) nor “reliable dataproving that radiation doses as used in diagnostic x-rays do inducecancer” (11)
In summary, there are three general views of the risk of low-levelradiation exposure: (1) the relationship between potential harm andeffective radiation dose is linear, with no level of radiation exposurebeing nonharmful (i.e., LNT model); (2) there is a threshold level ofradiation below which there is no harm, with a linear relationshipbetween potential harm and effective radiation dose above this thresh-old (i.e., threshold model); and (3) there is a threshold level of radia-tion below which there is benefit from enhanced cellular repair (i.e.,hormesis model), with a linear relationship above this threshold Below
1 rem effective radiation dose, there are no data that will discriminateamong these three models Between 1 and 5 rem effective radiationdose, the data are controversial, with the LNT model being the more
Trang 24favored approach Above 5 to 10 rem, the linear relationship between
potential harms and ED is generally accepted (with some difference of
opinion on the lower limit of the range of this linear relationship)
Characterizing the Risks of Radiation
What level of radiation exposure should be considered “minimal risk”
in light of the above data? Minimal risk is defined as follows: “The
probability and magnitude of harm or discomfort anticipated in the
research are not greater in and of themselves than those ordinarily
encountered in daily life or during the performance of routine
physical or psychological examinations or tests” (21 CFR 56.102i)
Given the variability in the interpretation of minimal risk (22), the IOM
recommended that minimal risk be interpreted “in relation to the
normal experiences of average, healthy, normal children”
(recom-mendation 4.1) (6) Children may be exposed to ionizing radiation
during diagnostic radiologic studies; however, no such studies are
per-formed as part of routine physical examinations of healthy children
Absent a disorder or condition, such as an injury, the interpretive
standard of a healthy child appears to exclude diagnostic radiation
exposure However, children are exposed to background radiation
from natural sources that ranges from 300 to 450 mrem per year
depending on the altitude at which they live (19) Children are also
exposed to additional radiation during such normal activities as air
travel Given the absence of data suggesting an increase in cancer at
altitude, a one-time exposure to ionizing radiation that falls in the
range of yearly environmental exposure would appear to qualify as
minimal risk
The IOM also recommended that the risks of research could be
con-sidered minimal if they were equivalent to the risks “that average,
healthy, normal children may encounter in their daily lives or
experi-ence in routine physical or psychological examinations or tests”
(rec-ommendation 4.1) (6) Studies of radiation exposure from “background
radiation, radon in homes, medical procedures, and occupational
radi-ation in large populradi-ation samples” have not demonstrated any
addi-tional health risks “above the ‘noise’ of adverse events of everyday life”
(16) This conclusion is supported by the observation that “exposure to
1 rem [only] adds about 100 more genetic mutations” to the “average
of 240,000 genetic mutations [that] occur spontaneously every day in
the human body” (16) Although younger children are thought to be
more susceptible to radiation-induced cancer (23), two reviews
con-cluded that there are no data demonstrating higher risk to children of
exposure to low-level radiation (14,16) What is the threshold level of
radiation exposure which, if one remains below, could be considered
minimal risk?
Proponents of the LNT interpretation of low-level radiation risk
express concern that adopting the view of a radiation threshold below
which the risk is zero may undermine efforts to minimize radiation
exposure (12,19) Others argue that the LNT model imposes an undue
Trang 25regulatory burden that “is detrimental to the welfare of our society”(20) The minimal-risk standard does not require that the risks of theresearch be zero but rather that the risks be no different from those that are experienced by healthy children in the course of everyday life.One possible choice for the level of radiation exposure that presents nomore than minimal risk can be taken from the 1996 Health PhysicsSociety statement that the health risks from exposure up to 10 rem
is “either too small to be observed or nonexistent” (24) A more servative approach, taking into account more recently published data(12), would reduce the radiation level at which there is unobservable,and thus minimal, risk to 1 rem exposure (25) This approach is con-sistent with published research studies involving the exposure ofhealthy children to ionizing radiation that have been approved by anIRB (16)
con-Allowable Research Risk for Children with Conditions
Subpart D allows researchers to expose children with a disorder or condition to more than minimal risk, provided (among other condi-tions) that “the risk represents a minor increase over minimal risk” and
“the intervention or procedure is likely to yield generalizable knowledge that is of vital importance for the understanding or ame-lioration of the subjects’ disorder or condition” (5) The IOM report rec-ommends that a “minor increase over minimal risk” be interpreted “to
mean a slight increase in the potential for harms or discomfort beyond
minimal risk” (recommendation 4.2, emphasis added) (6) Based on theabove discussion of the risks of radiation exposure, one could considerlow-level radiation exposure falling between 1 and 5 rem as presentingonly a minor increase over minimal risk Even so, exposure to this level
of radiation during research that does not offer the prospect of directbenefit is only justified if (a) the child has a disorder or condition, and(b) the research is likely to yield knowledge that is of “vital im-portance” for understanding or ameliorating the child’s disorder orcondition
There are no guidelines on how to interpret the phrase “vital tance.” At a minimum, the enrollment of children should be necessary(i.e., vital) to answer the research question (26) In addition, the require-ment of having a disorder or condition should not be interpreted sobroadly as to encompass all children The IOM report recommends that
impor-“the term condition should be interpreted as referring to a specific (or
a set of specific) physical, psychological, neurodevelopmental, or social
characteristic(s) that an established body of scientific evidence or clinical knowledge has shown to negatively affect children’s health and well-being
or to increase their risk of developing a health problem in the future”(recommendation 4.3, emphasis added) (6) A normal stage of childdevelopment could be considered a condition provided that evidenceexists that our lack of understanding of this condition may negativelyaffect children’s health and well-being, perhaps through the use of aninappropriate medication dose However, the inclusion of healthy chil-
Trang 26dren as a control group (i.e., those lacking the disorder or condition
being studied) would not meet this standard The exposure of children
with a disorder or condition to greater research risk than other children
has been the subject of criticism (27) The ethical justification of such
exposure is not that children with a disorder or condition are otherwise
exposed to greater risk Rather, the exposure to greater risk (although
limited to a slight increase over minimal risk) is justified by the
necessity of such exposure to achieve vitally important scientific
knowledge (26) Although exposing children without a disorder or
con-dition to a minor increase over minimal risk in research would require
review by a federal panel (7), the scientific necessity of such exposure
is one of the “sound ethical principles” required for approval (21 CFR
50.54) (5)
Prospect of Direct Benefit
Children enrolled in research may be exposed to more than a minor
increase over minimal risk provided that the intervention or procedure
offers the prospect of direct benefit, “the risk is justified by the
pated benefit” to the enrolled children, and “the relation of the
antici-pated benefit to the risk is at least as favorable to the subjects as that
presented by available alternative approaches” (21 CFR 50.52) (5) For
example, PET scanning may be a useful diagnostic test for localization
of lesions such as tumors or collections of abnormal pancreatic islet
cells when structural studies alone (i.e., CT or MRI scans) may not be
sufficient (28) The risks of radiation from radiotracer administration
would then be balanced by the benefits of a more appropriate clinical
or surgical intervention and be comparable to the alternatives such as
selective angiography or transhepatic portal venous sampling (in the
case of insulin-secreting pancreatic islet cell tumors) (29) Absent direct
benefit, or a justified balance of potential harms and benefits, the risks
of the radiation exposure would need to be limited to no more
than a minor increase over minimal risk Although a restriction of
radi-ation exposure to less than 5 rem likely would not prove limiting to
research using PET scanning (30), the approach to procedural sedation
would vary depending on the category of IRB approval (as discussed
below)
Adequate Provisions for Parental Permission
Subpart D also requires that “adequate provisions are made for
solic-iting the assent of children and the permission of their parents or
guardians.” The child’s assent can be waived only if the child is not
capable of assent (e.g., too young or cognitively delayed) or the
research offers a prospect of direct benefit that is not available outside
of the research (21 CFR 50.55) (5) Setting aside the question of child
assent, communicating the risks of low-level radiation exposure to
parents is particularly challenging given the controversy over the
inter-pretation of the data At EDs below 1 rem (and some would argue
below 5 rem), a consent document could state the following: “There is
no evidence that radiation doses in the range that you will experience
Trang 27in this research cause any harm above that caused by the backgroundradiation you experience every day.” For higher doses where theassumption of the linearity of risk has greater merit, risks can be com-municated in either numerical terms or in days of life lost For example,
in numerical terms: “Participation in this research study will increaseyour chances of getting cancer (dying) by 2/1000” (for a 5-rem EDexposure) Alternatively, this same risk can be expressed as 11 days oflife lost over the next 15 years The variation in background radiationover the course of 70 years is 7 rem (i.e., ±100 mrem per year), suggest-ing that this estimated difference of 11 days may be undetectable whencompared to the effects of natural background radiation over thecourse of a lifetime (31) Thus, at the doses that may be considered topresent minimal risk (<1 rem) or a minor increase over minimal risk (<5 rem), the consent document should reflect that the evidence to dateshows no increase in the risks of radiation exposure when compared
to natural background radiation
Procedural Sedation for PET Scans
A child must remain still for the duration of a PET scan, which canrange from 15 to 30 minutes or more Thus children (especially youngchildren) will need to receive some sedation to ensure that motion arti-fact does not undercut the quality of the PET scan Depending on thetype of scan and radiopharmaceutical used, the tracer may need to beadministered prior to the sedation The risks of procedural sedationthus need to be considered when evaluating the appropriateness of thePET scan
The level of appropriate risk exposure during procedural sedationdepends on whether the PET scan offers the prospect of direct benefit
If the PET scan offers the prospect of direct benefit, the procedural tion may present more than minimal risk and should be performed insuch a way that the PET scan is completed successfully The risks ofthe procedural sedation should be minimized while a sufficient level
seda-of sedation is achieved to ensure a successful scan If the PET scan doesnot offer the prospect of direct benefit, the risks of the procedural seda-tion must be restricted to only a minor increase over minimal risk Chil-dren who are at increased risk from sedation (such as those with adifficult airway) should be excluded The drugs used should have awide therapeutic window between the dose necessary to achieve theneeded level of sedation (i.e., without the loss of protective airwayreflexes) and the risk of upper airway compromise and respiratorydepression Absent direct benefit, the end point of procedural sedation
is to restrict risk even if the scan must be canceled due to an inadequatelevel of sedation Finally, the provision of procedural sedation does notmeet the criteria of minimal risk, thus restricting the performance of anonbeneficial PET scan in children lacking a disorder or condition tothose capable of remaining still without sedation for the necessaryscanning time
Trang 28Investigational Use of Radiopharmaceuticals
The investigational use of a radiopharmaceutical may proceed under
one of three FDA regulations: (1) the limited use of a
radiopharma-ceutical for basic research under the local jurisdiction of an authorized
Radioactive Drug Review Research Committee (RDRC) (21 CFR 361.1),
(2) the investigational use of a radiopharmaceutical that is exempt from
the requirements for an investigational new drug (IND) application (21
CFR 312.2), or (3) the investigational use of a radiopharmaceutical
under an IND application (21 CFR 312) In all three cases, the research
use of the radiopharmaceutical must be reviewed by an IRB In the first
case under 21 CFR 361.1, the FDA has authorized the local RDRC to
approve the “research only” use of a radioactive drug under specified
conditions that classify the drug as “generally recognized as safe and
effective.” Otherwise the radioactive drug is considered to be an
inves-tigational new drug
Local RDRC Review and Approval
A local RDRC may approve the use of a radioactive drug in a basic
research protocol if (1) the administered compound (absent the
radioac-tive material) is “safe and effecradioac-tive,” and (2) the radiation dose is below
specified levels The drug may be “generally recognized as safe and
effective” only when the “amount of active ingredients to be
admin-istered shall be known not to cause any clinically detectable
pharma-cological effect in human beings based on data available from
published literature or from other valid human studies.” Alternatively,
“the total amount of active ingredients including the radionuclide shall
be known not to exceed the dose limitations” under an IND
applica-tion or the approved drug labeling (21 CFR 361.1) In effect, an RDRC
cannot approve the use of a radioactive drug (even in trace amounts)
without the knowledge gained from previous testing in humans under
an IND application The second condition is that the radiation dose fall
below specified limits For adults, the radiation dose must remain
below 3 rem for a single dose or 5 rem for an annual and total dose to
the “whole body, active blood-forming organs, lens of the eye, and
gonads,” and 5 rem for a single dose and 15 rem for an annual and total
dose to “other organs.” For research involving children less than 18
years of age, the radiation dose should not exceed 10% of these levels,
e.g., 300 mrem and 500 mrem for a single dose to the “whole body,
active blood-forming organs, lens of the eye, and gonads” and “other
organs,” respectively (21 CFR 361.1) The RDRC is not authorized to
approve the use of radiation doses above these levels, but must refer
the protocol to the FDA
The radiation limits for local RDRC approval bear no relationship to
the levels of radiation exposure that an IRB may approve under subpart
D as either minimal risk or a minor increase over minimal risk An IRB
may approve, for example, a PET scan with an effective dose of
560 mrem in a 5-year-old child (30) under 21 CFR 50.53 (i.e., a minor
Trang 29increase over minimal risk given the procedural sedation necessary forpreventing motion artifact), even though an RDRC would refer theresearch protocol to the FDA Some investigators have argued for anincrease in the upper limit on radiation exposure to be an effective dose
of 2 rem for a single dose and 5 rem for an annual and total related dose for children with cancer and other chronic life-threateningdiseases (32) However, these levels of radiation exposure may beapproved by an IRB under 21 CFR 50.52 (absent direct benefit) or 21CFR 50.53 (with direct benefit), provided that the radiopharmaceutical
research-is considered under the IND regulations Thus the regulatory hurdleper se is not the radiation limits of RDRC approval, but the require-ment for an IND application (or exemption) under 21 CFR 312.There are some additional criteria for RDRC approval under 21 CFR361.1, including the following: (1) the amount and type of radioactivematerial that is administered should be the smallest amount necessary
to perform the study; (2) the radiation exposure should be justified bythe quality and importance of the resulting information; and (3) thestudy meets other requirements regarding qualifications of the inves-tigator, proper licensure for handling radioactive materials, selectionand consent of research subjects, quality and purity of radioactivedrugs used, research protocol design, reporting of adverse reactions,and approval by an appropriate IRB All of these additional require-ments are consistent with the general criteria for IRB approval ofresearch found in 21 CFR 56.111 In addition, for a research protocolinvolving children to be approved by an RDRC, the study must present
“a unique opportunity to gain information not currently available,”involve no “significant risk,” and require the use of children to answerthe scientific question These additional RDRC protections for researchinvolving children are also consistent with the safeguards of subpart
D, provided that “no significant risk” is interpreted to mean no morethan a minor increase over minimal risk Finally, the RDRC is required
to submit an annual report of all locally approved protocols to the FDA.When a protocol involves children (i.e., subjects less than 18 years ofage), this report needs to be submitted immediately upon approval (21CFR 361.1)
Research Under an Investigational New Drug Application
The investigational use of a radioactive drug falls under the IND ulations (21 CFR 312) if it does not meet the criteria for local RDRCapproval as “generally recognized as safe and effective.” A clinicalinvestigation involving a drug product that is “lawfully marketed inthe United States” is exempt from the requirement for an IND appli-cation if (among other requirements) (1) the study is not intended tosupport a new indication, any other significant change in drug label-ing, or product advertising; and (2) the study “does not involve a route
reg-of administration or dosage level or use in a patient population or otherfactor that significantly increases the risks (or decreases the accept-ability of the risks) associated with the use of the drug product” (21CFR 312.2) As of January 2005, the only PET tracer that has been