Guidelines for ethics-related problems with “non-invasive research on human brain function”

4. Ethical characteristics and testing guidelines for each non-invasive research method

C. Positron Emission Tomography (PET) / Single-Photon Emission Computed Tomography (SPECT)

1) Overview
Both PET and SPECT are methods that administer a diagnostic agent labeled with a radioactive nuclide into the body and reveal its mode of aggregation as a tomographic image. Their characteristic is that they allow various kinds of information relating to brain function, such as blood flow, metabolism, and neural transmission and function, to be derived from the distribution and behavior of the administered indicator agent inside the brain. However, their usage has limitations, since they require the use of radioactive nuclides, and there are problems concerning its management and radiation exposure to test subjects participating in the research and the persons engaged in the research.
PET uses radioactive agents that are tagged using a positron-emitting radionuclide with an extremely short life-span, such as carbon-11 (half-life 20 min), oxygen-15 (half-life 20min), nitrogen-13 (half-life 10 min) and-fluorine (half-life 110 min). It is characterized by its ability to qualitatively measure metabolism or function within an organism, which cannot be measured through other testing methods. Because using these nuclides with an extremely short life-span requires setting up a small-scale cyclotron at the test site facility to produce the positron indicator agent, PET entails a large amount of expense and manpower for installation and operation.
By contrast, SPECT testing uses gamma ray-emitting radionuclides, which have a relatively long life-span, such as technetium-99m (half-life 6 hrs) and iodine-123 (half-life 13 hrs). While the quality of qualitative measurement obtained from SPECT is inferior to that obtained from PET, it has the advantage of using radioactive agents that are used daily in clinical nuclear medicine tests. In addition, because it uses nuclides that have a longer life-span than those used in PET, this method allows their dynamic states to be traced for long hours, and is useful for imaging synaptic receptors and transporters.

2) Effectiveness
Since PET and SPECT allow qualitative measurement of metabolism or function within an organism, they are useful for assessing brain function of healthy individuals, ascertaining the clinical condition of individuals with various disorders, performing early diagnostics, and determining treatment effects. These methods are used in brain science research for measuring blood circulation and metabolism in the brain, testing brain activation, as indicated by the cerebral blood flow, and imaging neural transmission and function.
Because it is thought that changes in cerebral blood flow and glucose metabolism occur in parallel to localized neural activity, it is possible to measure changes in localized brain activity by measuring the changes in localized cerebral blood flow and metabolism. The testing of brain activity, which is indicated by cerebral blood flow, is a method that compares cerebral blood flow during completion of a task with the cerebral blood flow during a control state, to detect the areas where changes in cerebral blood flow have occurred. Assuming that the area with a significant increase in blood flow plays some part in completing the given task, it is possible to identify the locations where changes in neural activity related to this task have occurred. As a method for measuring cerebral blood flow and metabolism when conducting a test of brain activity, a system that uses oxygen-15 labeled water and PET has been employed frequently as it allows repeated measurements and has good spatial resolution. Even today when tests of brain activation using MRI have become popular, because PET/SPECT allow easy physical access to the test subject during testing, various electrical measurements, comprehension of physiological states, and assessment of task achievements can be performed with precision. They also allow easy access to the deep structures of the brain and act as methods that provide standards for qualitative measurement of cerebral blood flow.
In addition, imaging of various functions associated with neurotransmission becomes possible by administering radioactive labeling agents that uniquely bind to specific receptors and by using PET or SPECT to trace the dynamic state of distribution inside the brain. While mapping of receptors and transporters that exist at neural synapses is being widely practiced, other attempts are also being made, such as using agents to measure the percentage of areas occupied by the receptor, assessing enzyme reactions associated with synthesis and resolution of specific neurotransmitters, and imaging information transmission functions inside neural cells.

3) Problematic points (risks involved during testing)
For tests using PET or SPECT, it is necessary to consider radiation exposure to test subjects participating in the research as well as persons engaged in the research. As a fundamental principle for radiological protection, the International Commission on Radiological Protection (ICRP) issues recommended dose constraints for individuals. ICRP adopts a stance of justification: “Any activities that involve radiation exposure cannot be employed unless they yield benefits that sufficiently cancel out the radioactive damages that are incurred by exposed individuals or societies as a result of such activities.”1) With radiation exposure, dose constraint is set for three types of exposure: public exposure, work place exposure, and medical exposure. For persons in charge of the test, radiation exposure incurred during testing procedures is handled under the category of work place exposure. As far as the tests are conducted as a medical practice, taking the patients’ benefits into account, radiation exposure incurred by the patients falls under the category of medical exposure. By contrast, ICRP issues additional recommendations for healthy volunteers or patients who agree to participate in clinical research even though they do not receive any direct medical benefits.2) In our country, a regulatory body’s standpoint on this issue is indicated only in the guidance by the Ministry of Health, Labor and Welfare (MHLW) on “micro-dose clinical trial” which are carried out under the Pharmaceutical Affairs Act. ICRP recommendations, which define three tiers of benefit that research brings to society, allow test subjects who do not directly receive benefits themselves to be exposed to 10 mSv of radiation in a situation that yields the “substantial” benefit to society. MHLW does not indicate dose constraints and requires that effective dose on human should be estimated based on the results obtained from animal testing. Since test subjects undergo tests voluntarily, it may be thought that their radiation exposure requires standards that are different from those set for public radiation exposure. Yet taking into account that these subjects do not receive direct benefits, considerations should be made: for the institutional review board at each research institute and facility to set the ceiling of radiation dose constraints; to establish a mechanism that prevents test subjects from participating in multiple studies at the same time or without appropriate intervals between tests; to draw up research plans that accommodate the scientific needs of individual research projects while minimizing radiation exposure; for the institutional review board to make thorough assessments and to make arrangements at the planning and implementation stage to minimize radiation exposure to test subjects and persons engaged in the research. Safety issues pertaining to radioactive agents used must be reviewed carefully at each facility. Depending on their type and amount, some agents require precautions as they might have pharmacological effects. Therefore, it is necessary for decisions about the composition, quality control, and dose administration of indicator agents to be made under the supervision of a doctor and pharmacist with specialist knowledge.
Since the test subject is asked not to move his or her cephalic region during testing, measurements that last for a long time can cause discomfort or pain. Therefore, pay thorough attention should be paid to the subject’s condition to ensure that the pain is kept to an absolute minimum. In addition, when taking qualitative measurements of functions, there are cases when it is necessary to collect a sample of arterial blood to obtain the input function from the blood to the brain. While taking appropriate measures can lower the chances of developing complications occurring, these cases should be dealt with by a medical doctor who is experienced in appropriate well-versed in such techniques.

4) Testing guidelines
All procedures, from the composing of radioactive label agents to measurements using PET or SPECT, should be carried out in radiation controlled areas. Since radiological protection laws apply when setting up a small-scale cyclotron to produce positron-emitting nuclides and creating a composite of radioactive agents for labeling, it is necessary to seek the approval of the Ministry of Education, Culture, Sports, Science and Technology.
For quality control of radioactive labeling agents used, each research institute and facility must establish and follow its own standards by referring to the guidelines set by the Japanese Society for Nuclear Medicine or by Cyclotron Nuclear Medicine Usage Special Committee under the Division of Medicine and Pharmacology at Japan Radioisotope Association.2-4) Current standards regulate the following aspects of the agents: manufacturing method, properties, confirmation (radioactive nuclides, labeling compound), purity (inclusion of foreign radioactive substances, foreign radioactive nuclides, or other materials), and full weight; and when necessary, its compatibility for thermogenic material testing, aseptic condition, pH, and specific activity.
For SPECT testing, when using agents that have been provided by pharmaceutical companies as radioactive medical products, each agent’s usage standards should be followed. When using labeling agents that have been developed uniquely at each research institute or facility, they should be handled as other labeling agents made of positron nuclides.
When developing a research protocol, considerations should be made to ensure that radiation exposure to test subjects is kept to an essential minimum. The sensitivity and performance of the measuring device used should be taken into account. For the ceiling of dose constraints for radiation exposure to test subjects, ICRP recommendations1) can be referred to, as well as Japanese regulations relating to radiological protection. 2-4) Approval from the institutional review board at each research institute and facility should then be secured. Selection procedures for test subjects should be reviewed, taking into account such factors as their health condition, current medical symptoms, age, gender, and capacity to give consent. As a general rule, the individual becomes a test subject when voluntary consent has been obtained from the test subject him or herself. However, when consent, which is necessary to carry out the test, cannot be obtained from the test subject, consent can be gained from the subject’s family or a representative who can give consent on behalf of the subject. As a general rule, pregnant women are excluded as subjects. All female subjects should indicate whether or not they are pregnant. Although children are, in principle, excluded from testing, in cases where there is clinical merit, approval should be obtained from the institutional review board at each research institute and facility.

5) Explanatory documents for test subjects
As a general rule, Section 6 of the current guidelines should be followed. The test subject should be provided with thorough explanations about the purpose, content, and method of the test, its possible side-effects and radiation exposure. The subject’s understanding of the protocol should be sought, and his or her consent obtained. For matters regarding the amount of radiation exposure, concrete descriptions should be provided by making a comparison with tests that are more generally familiar.

References

  1. ICRP: 1990 Recommendations of the International Commission on Radiological Protection. ICRP Publication 60, Pergamon Press, Oxford, England, 1990. (1990 Recommendations of the International Commission on Radiological Protection, Japan Radioisotope Association Isotope, trans.) ICRP Publication62:Radiological Protection in Biomedical Research.Adopted by the Commission in November 1992.Annals of the ICRP Pergamon Press Ltd.1993
  2. Japanese Society for Nuclear Medicine, PET Working Group: Guidelines for conducting PET tests using in-hospital FDG. Nuclear Medicine 38: 131-7, 2001.
    http://pet.jrias.or.jp/handlers/getfile.cfm/48,9,99,32,pdf
    http://www.jsnm.org/files/pdf/guideline/fdg_guide2.pdf
  3. Japan Radioisotope Association, Division of Medicine and Pharmacology, Cyclotron Nuclear Medicine Usage Special Committee: Guidelines concerning the assessment of safety of in-hospital cyclotron radioactive agents in pre-clinical stage. Radioisotopes 35: 616-8, 1986.
  4. Japan Radioisotope Association, Division of Medicine and Pharmacology, Cyclotron Nuclear Medicine Usage Special Committee: Standards of radioactive agents approved as mature agents by Cyclotron Nuclear Medicine Usage Special Committee and guidelines for their clinical usage (revised 1999). Radioisotopes 48 (12): i-xxvi, 1999.