Radioactive Materials Licensure and Clinical Review Boards for IVB
Mr. Michael Bohan B.Sc.

I am making a presentation today on how to get your intravascular brachytherapy protocol up and running, and today we're going to be talking about the things that need to be addressed to get your radioactive materials license and your clinical review boards set to get an IVB program up and running.

First of all, I'm going to talk about the institutional review board process. The primary regulatory agencies for the institutional review board are the Department of Health and Human Services.

They have an office within the Department of Health and Human Services called the Office of Human Research Protections, and the main body of their regulations is in title 45 of the Code of Federal Regulations 46, which is specifically on protection of human subjects.

In my PowerPoint presentation today, I've linked those parts of the regulations that are available on the Web, and by clicking on the underlined hyperlinks, you can go directly to these sections and see the regulations for yourself. In addition, the FDA, the Food and Drug Administration,

has their own set of regulations regarding the same issues, 21CFR50 specifically is on the protection of human research subjects, and 21CFR56 is specifically on institutional review boards and the requirements regarding setting up an institutional review board and what their review requirements are.

Additionally, with regard to intravascular brachytherapy, since we're going to be using radioactive sources, the Nuclear Regulatory Commission also has regulatory authority. The part of regulations that the NRC regulates medical use of byproduct materials is 10CFR35. Again, there is a link to this,

so you can see it, although 10CFR35 covers medical use, there is not really too much in there that regards research uses of radioactive materials. Well that gets handled in your licensing. When you apply for a license from the Nuclear Regulatory Commission, you will be given a license,

either a broad scope license, which is a license which allows both clinical and research use of radioactive materials or a specific scope license, which is a license which is restricted to just clinical use. So if you have a specific scope license,

you can only use radioactive materials for proved clinical use, you cannot do research involving radioactive materials in humans. To do that, you need to have your license upgraded to a broad-scope type license, and we'll discuss that a little bit later in the presentation.

Going back to the Department of Health and Human Services in 45 Code of Federal Regulations part 46, protection of human subjects, this part of the regulations apply to all human research that is conducted, supported or regulated by federal departments or agencies, the FDA, the NRC, any other federal agency.

They all have codified this into their regulations that you must abide by the protection of human subjects requirements if you're going to conduct research, and it requires a sponsoring institution to establish an institutional review board to oversee any proposed research to ensure that appropriate

thical requirements for human research are complied with. The purpose of the institutional review board is to ensure that human research subjects will be treated with respect, beneficence, and justice.

This basically falls from some infamous occurrences in the past in both the experience of the Nazis using prisoners to perform human research and also other human research that has been done in the past like the Tuskegee people who were knowingly exposed to syphilis to see what the difference would

be between people who were given appropriate medical support and those who were not, and in that particular case, the research subjects were not given appropriate informed consent and were not treated with either respect, beneficence or justice.

So all human research now is required to comply with the spirit of what's known as the Belmont Report, which is a document that was codified, and it covers the ethical principles and guidelines for the protection of human subjects of research.

The institutional review board is a generic term used by the Department of Health and Human Services and the FDA. You may find in your own institution that it may have an alternative name, for instance, some of them are termed the human investigation committee or the HIC,

but there may be other nomenclature in your specific institution. The FDA allows institutions a lot of leeway in how they set up and organize their institutional review boards, but they do have to submit their institutional review board makeup and their policies and procedures to the FDA,

and the FDA periodically will inspect institutional review boards to ensure that they are following through on the requirements of an institutional review board.

The primary thing that they're looking for sponsoring institutions will have to provide assurances to the Department of Health and Human Services that they will protect the rights and welfare of human research subjects.

An interesting thing just occurred in that there was a research subject death at Johns Hopkins University and the FDA very quickly came in and shut down their entire program, so this can happen,

and you want to make sure that when you set up your programs that you make sure that you follow through on all the ethical requirements and that your institutional review board takes those requirements seriously in their oversight duties.

The institutional review boards have the authority to approve human research protocols, so they approve it in-house, so it doesn't get submitted to the FDA for approval, but in-house the institutional review board has the authority to prove human research protocols.

Also upon reviewing the protocols, if there is something that doesn't meet with their approval, they can require a modification to secure approval or if they feel that the proposed research doesn't meet the criteria, they can disapprove it and not allow the research to go on.

The criteria that they look at for approval or research is primarily they want to make sure that risks to the subjects are minimized. They also want to make sure that the protocol has a sound scientific design, that the research itself has some chance of showing some scientifically valid conclusion,

individual subject risks are reasonable in relation to the anticipated benefits of the research, in that obviously for something like intravascular brachytherapy,

we have patients who have a potentially life-threatening problem and they're going to be subjected to larger than normal radiation exposures as a result of that,

but the risk of the radiation exposure is obviously smaller than the anticipated benefit of intravascular brachytherapy and that's the reason why it is allowed to be performed.

One thing in this type of research though is that you're not going to get a case control where you have someone who is perfectly healthy and doesn't have cardiovascular disease being enrolled into a research protocol as intravascular brachytherapy and that's why instead of using healthy subjects,

we use patients that are either given treatment or not given treatment using the radiation source in a blinded-type study. They also want to make sure that there's an equitable subject selection process. They want to make sure that there is no discrimination in enrollment in that, for instance,

men and women are considered equally, people of different races are not discriminated against, that they have the ability to achieve the benefits of the research goals as well as other groups, and also they want to see that the researchers are sensitive to vulnerable populations, for instance,

pregnant subjects obviously would be a questionable inclusion criteria for an intravascular brachytherapy protocol. But also with regard to sensitive populations,

if you're going to use people like prisoners who might be coerced into participating in a research protocol because they feel that it may give them preferential consideration for parole or other situations,

where you have a person who is not able to give informed consent on their own but are relying on someone with power of attorney or a relative to give consent,

you need to make sure that you take that into account in setting up your protocol and identifying how that's going to be done so that you don't take advantage of vulnerable population. In addition,

they're going to require that you give them a copy of the written informed consent and one of the things they review is to make sure that the consent form is understandable by the subject population. If you write a consent form that is overtly technical, it will get rejected,

because if they feel that the subject population can't read it and understand it fully, it is difficult to believe that they're giving their consent with full knowledge of the risks of the proposed research. The form itself must state that the study involves research,

now the purpose of the research, the expected duration of the subject's participation, and description of the experimental procedures to be followed. And additionally, the description of the potential risks and discomforts to the subject,

and you also need to include a description of any benefits to the subject or to others reasonably expected from the research. You must disclose any alternative procedures or treatments that may be available,

and you need to have a statement included in the informed consent that describes the confidentiality of the subject records. For research involving more than minimal risk you need to provide some type of explanation of any offered compensation, and also if injuries occur,

what treatments are available, what do they consist of and where further information upon those injuries can be obtained.

They also want on the consent form the name and number of the responsible individual to answer any questions that the subject may have subsequent to inclusion into the research protocol and also any late research-related injuries that person needs to be identified so that they can report any sequela

of the research. In addition, they want a statement that participation is voluntary, that the patient at any time can refuse to participate, and that their refusal to participate will not result in any penalty or loss of any entitled benefits and the right to withdraw from the research at any time.

The institutional review board would usually send you an application and this is a copy of the application at Yale University. I have a Web link here, I know it is kind of hard to see, but if you go to this web link, you'll be able to see what an actual IRB application looks like.

Just to go through it in a little bit more detail, the cover page has the type of information they are looking for is they want a title of the project, they want a listing of the principal investigators,

they also want the information as to who is the corresponding investigator and the contact information. If there is any investigational new drug or investigational device exemption numbers they need to be included.

If the research is being sponsored by a commercial or an industrial sponsor you need to reveal who is sponsoring the research. If the research involves the use of radioisotopes, there is usually a check-off box at sometimes to flag that and then also they have,

they want to have a spot where you could have an approval of primary reviewer. Once you do your first draft of your protocol, usually, institutional review boards will have a primary reviewer assigned to review it to just check to see whether it is fundamentally sound.

If there are any obvious technical problems, they'd like to clean that up before it gets submitted to the entire board so that it helps streamline the review process with respect to taking care of any obvious deficiencies in the protocol,

and so initially a primary reviewer will review the application, and then, once it meets with their approval it will be shown to the entire investigational review board. They also want you to identify if there is any sensitive populations involved in the research.

They identify sensitive populations as minors, fetuses, abortuses, pregnant women, prisoners or decisionally impaired persons. Also if it is being done in an academic institution, they want to see that the department chairman has approved the research proposal, and ultimately,

there is a place that will be a check off showing that the IRB has approved the research. After the cover page this is where they would just give you these basic things and you need to put in a description that describes all of these things. So the first section,

they have a description of the study. You need to state the purpose of the study, any background information that supports the scientific criteria that the research is a valid area of study and has potential for scientific advancement.

They want to see the specific location of where the study is going to be conducted. They also want you to give a probable duration of the project, so they know how long this project is going to last. You need to give them a detailed research plan and any economic considerations like, for instance,

if you are going to pay research subjects any remuneration for their participation that needs to be revealed in the description of the study. Then, they go on to human subjects, they want to know what kind of subject population and recruitment you're going to do.

You need to give a description of any risks associated with the research protocol, what your procedures are going to be for obtaining informed consent, what types of things you are going to do to ensure the protection of any research subjects, what are the potential benefits,

and what the risk-benefit ratio is for participance in the research protocol, and they also want you to give some assurance that the data privacy and confidentiality will be withheld. They're also going to want you to append a copy of the proposed informed consent form.

This is the form that you will present to research subjects where you usually in an interview process you will verbally go over the written consent form with them and then give them an opportunity to read that form fully and only upon when they fully realize what they are going to be involved in will they sign it and give their informed consent.

One thing that the institutional review boards want you to do though is you need to evaluate people as they sign off on informed consent in that if usually they want to see that you're going to ask them a few questions to make sure that they really truly understand what's going to happen if giving,

if during that process you believe that the subject doesn't fully understand, you need to hold back and go over again until you're fully confident that research subjects are fully informed before the consent.

The institutional review boards will usually require new investigators and protocol personnel to attend a training program. Many of these training programs are available on the Web, and I have links to two of them here. This one here is the National Institute of Health,

Computer-Based Training For Institutional Review Board. Both of the, and then the second one here is the Yale Computer-Based Training Institutional Review Board. Both of these Web pages will allow you to go through the learning process,

learning about what the requirements are for a researcher wanting to engage in human research, and they will provide you with information and then ask you questions after each chapter, and at the end, if you sign up for it,

they will send you a certificate of completion of the computer-based training. You may find that in your own institution they have their own version of these types of computer-based training and, you know, they may insist that you take that one, but the NIH one is,

the NIH offers it to anyone who wants to take it, but you don't have to be involved with the NIH to take it and they will send you a proof of completion of the training on their Web page. For protocols involving radioisotopes, besides dealing with the institutional review board,

once the institutional review board gets to the point where they're going to approve the human research, usually institutional review boards do not have the expertise regarding radiation, and so in many institutions you will find that they have an arm of the institutional review board.

In my particular facility, we have a Radioactive Drug Research Committee.

The reason why it's called the Radioactive Drug Research Committee is most protocols involving radiation that come through the HIC are usually nuclear medicine protocols involving new radiopharmaceuticals for diagnostic purposes. So in our particular facility,

we call it the Radioactive Drug Research Committee, but obviously with intravascular brachytherapy, we're not really researching a drug or researching a device,

but it would still get passed off to either the Radioactive Drug Research Committee or its analog in your own institution and then they would take care of the radiological safety evaluation of the proposed research. The Radioactive Drug Research Committee is usually but not always,

a subgroup of the Radiation Safety Committee. If it's not a subgroup of the Radiation Safety Committee, you may also have to petition the Radiation Safety Committee separately for a final approval of the research protocol. In my particular institution,

the Radioactive Drug Committee is a subsection of the Radiation Safety Committee, so we do the reviews concurrently. The regulation of byproduct materials in the United States is shared between the Nuclear Regulatory Commission and the agreement states. Just in case you don't know,

byproduct material is any radioactive material that is produced as a byproduct of nuclear energy. So for any isotopes that are produced in a nuclear reactor, those are subject to NRC regulations. However there are artificial sources, such as x-ray devices,

and naturally occurring radioactive materials, for example, radium, and artificially generated radioactive materials such as radioactive materials produced by a cyclotron, and what we commonly use now is positron emission tomography type radionuclides.

Those are not subject to NRC regulations because they are not byproduct materials. The regulations of those types of radiation sources fall to the states themselves. So if you're going to use some type of a novel radiation source that's not one of the ones that are currently under consideration,

you may have to petition the local state authority for any regulatory approval before you go ahead with your research. Within the United States, the states are split up into what are known as non-agreement states and agreement states.

The non-agreement states are states that are regulated directly by the Nuclear Regulatory Commission.

Agreement states are states that have reached an agreement with the Nuclear Regulatory Commission and have shown the Nuclear Regulatory Commission that they have appropriate resources to regulate the use of byproduct materials within their state borders and they've taken over the regulatory responsi

ility from the Nuclear Regulatory Commission. This is a current map of the agreement states and all the shaded states, that's 30 shaded states up there that are agreement states. The non-shaded states are non-agreement states. So if you're located in one of the non-shaded states,

you need to deal with the Nuclear Regulatory Commission directly. If you're in a shaded state, you deal directly with the state regulatory authority, and the state regulatory authority then deals with the NRC.

Now to participate in an intravascular brachytherapy research trial you need to have a broad scope medical license. A broad scope medical license authorizes the licensee to use byproduct materials for medical diagnosis, therapy,

and research in humans in accordance with any applicable FDA requirements, and if you take a close look at your license, you'll see that the Nuclear Regulatory Commission will usually pin you down specifically with that type of wording directly in the license. Also,

in a broad scope license the NRC will have a statement in the license saying that any research use is subject to approval by the Radiation Safety Committee. This is where, this is the reason why even though you have gone through an investigational review board approval,

if it's going to be using byproduct materials, it still must be scrutinized by the Radiation Safety Committee before the final approval and the commencement of clinical research. Now this is a copy of what a broad scope license would look like. This is the first two pages. Unfortunately,

it didn't transfer very well and so it is not very legible, but way that you can tell that you have a broad scope license,

first if you take a look at the front page here this will list all the radioactive materials that the license is authorized for and will tell you what ways and what types of radioactive materials they can be used, and what quantities are allowed under the license.

If you're going to start an intravascular brachytherapy program,

you need to scrutinize the license and make sure that the limitations that exist in the license are large enough that you can still possess the total quantity of radioactive materials that you're going to need for your intravascular brachytherapy program.

The one thing that you need to realize is that you need to put in enough of an allotment for that particular isotope that you're going to use so that you can possess whatever number of sources you need to have on hand for treatment purposes plus any other radiation sources that you'll have on hand d

ring the time that you are switching over or changing over sources. This is especially true with sources that have short enough half-lives that they need to be replaced frequently.

You need to make sure that you have authority to possess at least two or three times the total activity that you're intending on using. So you have enough leeway to possess a strength source or induced source that has just arrived in the program because this is an absolute limit.

The NRC license will not allow you to possess any more than what's been specified on the first page of the license. On the second page of the license over here, you will find that the NRC will list what we just covered in the previous slide, that if you're going to do any research use in humans,

you must comply with the FDA requirements and also it will say that any research use is under the review authority of the Radiation Safety Committee. If you do not have a broad scope license, you have a specific scope license. If your institution has a specific scope license,

you're limited to byproduct materials that are approved for clinical use only. As of July 2001, there are two sources that are currently approved by the FDA, and so a license that is a specific scope license can use the Novoste strontium 90 base system or the Cordis iridium 192 system, but the,

you wouldn't be able to participate in any research trials because your license doesn't authorize research use in humans. On a specific scope license, the use is limited to authorized users that are listed specifically in the license. That means,

while in a broad scope license you don't see individual physician's names listed in there as authorized users, on a specific scope license, every physician who is considered an authorized user by the Nuclear Regulatory Commission will have his name specifically listed in the license, and then also,

next to his name will specify what parts of 10CFR35 he is authorized to practice medicine in using byproduct materials. For instance,

a physician who is listed specifically to use radioactive materials for diagnostic and therapeutic purposes in nuclear medicine would not have the criteria the NRC would require for him to use sealed sources in intravascular brachytherapy. If you had a physician who wanted,

who was a nuclear medicine physician and wanted to participate in intravascular brachytherapy, he would have to, not he, but he would have to submit his training and qualifications to the Radiation Safety Committee. The Radiation Safety Committee would then have to submit that data to the NRC,

and you would have to wait for the NRC to modify the license and send back the license showing that he would be authorized also for brachytherapy. FDA-approved intravascular brachytherapy devices can be specifically added after a license amendment.

So if you have a specific scope license and you want to participate in approved intravascular brachytherapy devices,

you are going to have to again petition the NRC for an amendment to the license and you're going to have to specifically add those devices onto the front page of your license so that you can start a clinical use program. This is an example of a specific scope license.

Here you can see that there is a listing of the different forms of radioactive materials that are used, what they specifically can be used for. You'll note on a specific scope license that there is no mention of any research and then also here there'll be a limitation of what the quantities are,

and on the second page this is where you'll see where the physicians names are listed and what types of use they are authorized for. In the license, it's going to list what isotopes you are authorized for, in what chemical and physical forms, and maximum allowed activities.

If the license activity limits are less than the proposed IVB source requirements, you need to amend your license before beginning any trials, so that means on some broad scope licenses, you may not have enough headway for let's say for instance, strontium 90, and if that occurs,

you must amend your license and tell the NRC that you need more of a possession limit for strontium 90 before you can start on your research trial. You need to make sure that the licensing authority allows possession of at least one treatment and one spent source at a minimum. If you can,

you might want to try to give them, get another source on there, just so that you have one new source, one current treatment source, and one spent source limit on your license so that you don't run into trouble if you don't ship out your spent source in time.

Another little ticker in here is some isotopes with long half-lives and greater radiotoxicities, for instance any bone or thyroid seekers, may require filing a decommissioning plan with the NRC. This was a problem with the Novoste system initially,

when it was a research device in that if a sealed source hasn't been submitted for approval and hasn't been listed in the Sealed Source Device Registry, which is part of the agreement state program with the NRC,

you must consider that source as an unsealed source even though it is technically a sealed source, and that drove up some licenses above the levels that would require you to file a decommissioning plan with the NRC. Basically what that meant is that,

the NRC wanted you to put away somewhere in the order of a 1.5 million dollars in some type of an escrow account so that if your license, if your institution went bankrupt and basically left behind a contaminated area, there would be money available to properly decommission a facility.

Many medical licensees did try to avoid having to put away that much money and may have modified their license so that they wouldn't have to file decommissioning.

This was about 8 to 10 years ago without having an inkling that we would need to have enough strontium 90 around to be able to participate intravascular brachytherapy trials. If you need, if you had this particular problem,

I have set up a link here in the PowerPoint presentation so you can go through the specific parts of the NRC regulation, that is 10CFR part 30, where they cover the requirements for decommissioning. Once the sealed source though has been submitted to the Sealed Source Device Registry,

usually if it's an agreement state where the source is produced or an NRC state, the state authority or the NRC authority will review the source construction and testing to ensure that it has the integrity required of a sealed source. Once it's listed as a sealed source in the device registry,

it's no longer considered an unsealed source and the decommissioning requirements for a sealed source are much less restrictive for sealed source, so that is one reason why once the Novoste's source was listed in the Sealed Source Device Registry,

you didn't have to worry about filing decommissioning to participate in using that type of source. Again unlisted sources are considered unsealed until they've passed that review process and are listed in the device registry and you'll find that most investigational IVB sources are not listed.

The reason why is they're usually new sources that have just been constructed and they haven't been subjected to the testing requirements to achieve listing in the Sealed Source Device Registry. Also before any IVB source can be used clinically for non-research purposes,

they're going to have to be listed in the registry and so you find that the manufacturers are all working on that prior to their achievement of FDA approval so that they're ready to go for clinical use once they've received the final approvals. If you're using an unlisted source,

the NRC puts the onus on the licensees to do their own safety evaluations before embarking on research use.

One thing you should realize is that vendors of research sources that are trying to get them approved will come in and make a presentation to you telling you about what a great device they have, and you bet it's very true, it may be a great device,

but you have the responsibility of making sure that the device can be used safely and without harm to the individuals both in the clinical laboratory doing the procedure as well as the patient.

Usually the Radiation Safety Officer and the Radiation Safety Committee will review the source before approving research protocols. The device representatives are not always knowledgeable about the rigors of the clinical environment.

I've seen this happen a couple of times in our experience where they told us that everything would work great and everything else and then later on when we had a chance to fool around with it a little bit,

we found out that there were some areas that needed more focus on to make sure that this device can be used safely. So, it's very important you need to do an independent safety review before starting new research protocols and you need the time to do it.

Many times a vendor will come in and bring in the source and they will set up a demonstration for the first research subject and they basically want to do it the next day after the source arrives on site. You don't want to be under that kind of a pressure.

You want to have enough time so that your physics personnel can go in and review the device and make sure that they understand it fully before implementing, going ahead and implementing the research program. This will save you a lot of heartache later on,

because if something does go wrong and you're not prepared for it, the consequences could be misadministration, which will get the NRC on your back, and if it results in any injury to a research subject, you'll have the FDA on your case too, as Johns Hopkins recently had occur.

The Radiation Safety Committee will review the intravascular brachytherapy research protocols for radiological safety purposes. They have their own application form. It's similar to the intravascular brachytherapy form, but you'll find that it's more focused on the radiological safety issues.

The one thing, good thing about it is for most of it, you can usually cut and paste portions of your institutional review board protocol into your Radiation Safety Committee application and any radiation safety protocol,

any radiation safety committee protocol must be sponsored by a physician who meets the NRC subpart J criteria as an authorized user for brachytherapy. Again I have a link here to the part of the regulations that contains those requirements,

and so that cardiologists on their own cannot do intravascular brachytherapy. It must be done currently with the affiliation of an approved authorized user in brachytherapy.

One of the things that you won't have to do so much in the institutional review board protocol but the Radiation Safety Committee protocol will want to have the detailed dosimetry information for critical organs as well as the target organs and many will also want to have some type of a summation of

the doses from the fluoroscopy involved in the intravascular brachytherapy also. Some additional references regarding NRC regulations I've listed on this slide, Regulatory Guide 10.8 is basically the NRC's guide for applying for medical license.

NUREG-1516 is a nice overview of the NRC's perceived way of going about managing radioactive material safety programs at medical facilities and then NUREG-1556 volumes 9 and 11 are program-specific guidance about medical licenses and broad scope licenses which will give you some further information

that you may need in the licensing process. That's the end of my talk and I'd like to thank you for your attention.