Chapter 06: Two Decades Overseeing Human-Subject Research

Chapter 06: Two Decades Overseeing Human-Subject Research

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Description

In this chapter, Dr. Freedman discusses his more than twenty years of experience overseeing human subject research on the Institutional Review Board (IRB). He sketches the history of human subject guidelines and clarifies IRB procedures, potential conflicts of interest (between IRB members and the institution), and the kinds of research protocols of concern to the IRB, whose primary function is the protection of human subjects. He then discusses his belief that regulation is very necessary, but that it has currently gone too far. He points out that different protocols represent different levels of risk, some of which may not require IRB regulation, such as experiments in which the main risk is to patient privacy. Dr. Freedman offers rich detail about the challenges to researchers and describes systems that might satisfy the public’s need for privacy and information security while easing the burden on researchers who want to move ahead quickly with their work. “We needed these systems yesterday,” Dr. Freedman asserts. He gives examples of how his understanding of the need for regulation and its potential complexity evolved as his experience as a researcher grew, then expands his focus again and discusses how regulation can influence how a researcher focuses his or her career.

Identifier

FreedmanR_02_20120301_C06

Publication Date

3-1-2012

City

Houston, Texas

Topics Covered

The University of Texas MD Anderson Cancer Center - Building the Institution; Building/Transforming the Institution; MD Anderson History; MD Anderson Snapshot; MD Anderson and Government; Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient CareLeadershipEthicsProfessional PracticeThe Professional at Work

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Disciplines

History of Science, Technology, and Medicine | Oncology | Oral History

Transcript

Tacey Ann Rosolowski, PhD Now here we’re starting to broach your work on the Institutional Review Board. Would you like to dive into that area and—?

Ralph Freedman, MD Yeah, well, that—

Tacey Ann Rosolowski, PhD When did you start on it?

Ralph Freedman, MD Yeah, well, I guess I’ve had about twenty-five years of that, although it may be more. When I came to the department they asked me to––like they often do is the person at the bottom of the totem pole gets––well, which committees can we put you on that aren’t the best board to be on? Or maybe they do want to be, but they haven’t got the time to do it. So I ended up on the research committee, and at that time, it was early in its development,’74 or ’75, and that’s when Congress came up with their regulations on human subject research. So it actually took from ‘45 to ‘75––that’s almost thirty years––for us in this country to develop our own principles for conducting human subject research. When I was overseas we really didn’t know too much. We just did what we thought was ethical, but we didn’t have any guidelines, so our consents were very rudimentary. We asked the patient, “Do you consent to have a biopsy or do a procedure?” Here, it’s been evolving to what it is today, where it’s a very regulated process. And there are strict rules, and what was regulations and now policies, based on regulations as to how research should be conducted in an institution. So in ’75 when I came to MD Anderson, we had a research committee which had started in the ‘60s, so that committee actually had started off even before the Bellmont Report came into place, and that’s dealt with really nicely in Jim Olson’s book. He talks about the origin of the research committee; so basically, the committee was there to review human subject research–– There was one committee at that time. It was the–– It was called the Surveillance Committee. That’s right. They called it the Surveillance Committee. What does surveillance mean? It means just––

Tacey Ann Rosolowski, PhD Oversight, yeah.

Ralph Freedman, MD

––oversight, and it used to review all clinical protocols that could be conducted at Anderson. And of course, they were a much smaller number than they are today. There were a number of events that happened––and I don’t want to go over this because it’s all well-described in his book––but there were some events which embarrassed the institution. Dr. [Charles A.] LeMaistre had to go up to Washington and appear before Congress with Dr. [James] Bowen, because a drug that was given to patients, one of the departments that had been obtained from NIH in order to do pre-clinical studies in animals––it should’ve never gone into humans––and it ended up going into humans, and—

Tacey Ann Rosolowski, PhD Just for the record, I wanted to say that James Olson’s book is Making Cancer History, so we have that on the recording.

Ralph Freedman, MD Right, and he did a great job in describing the evolution of that. So we had two or three people working in the office. Today, there are about fifty, and that fifty have come about basically through unfunded mandates. The government has said, “This is what you’re going to do,” and in the institution to protect the patients and to protect itself has created this structure, which we now have today, with five IRBs that––initially just one. Now they have five: three clinical, one psychosocial, and one executive IRB that I chair. And the executive IRB basically determines policy and makes decisions where they cross department and protocol boundaries. So you have two protocols that have an issue that would affect both––the same issue that would affect them. For example, adverse events—the reporting of adverse events—you want a uniform policy for reporting those events across the hospital. You want for–– When a researcher doesn’t follow the protocol exactly, it’s a deviation, and it may be a minor thing––it doesn’t affect patient safety—but they have to make a report. So you want people to follow that policy across the institution, and that’s what we do is we create the policies which are based on federal regulation and guidances and good clinical practice documents so that they are followed across the institution. So early on we had a very small structure, and then the feeling was that they needed much more. Dr. [Leonard] Zwelling became the vice president for research at that time, and that’s when it was suddenly expanded, and then we landed––we found that the IRB had so much work to do because it had to review a host of new protocols. It’s required to review existing protocols on an annual basis––at least annually—and then it has to deal with all these adverse events—changes to the informed consent based on adverse event-reporting by sponsors and deviations and all kinds of thing—that there was less and less time to discuss the science. So they created a separate committee, or the clinical research committee, which is made up of faculty and scientists from around the institution, and that’s where they discussed the science. And it’s a sort of a seamless process, where protocol gets discussed in the departments we pursue. Then it goes to biostatistical review. Then it ends up in the clinical research committee, when you would expect a protocol to have basically the format and the content that it would have almost in its final form but with the science being discussed and any revisions that are recommended by the committee being dealt with. And then, within a few weeks, it goes to the IRB, where they look primarily at the consent and the form of the consent and any other issues of ethical concern. So that extra effort was really very necessary. I served as a member first, and then I served as a chair. Then there was a situation where I was no longer a chair, and then eventually I came back to be a chair for the committee. This was six or seven years ago, and I’ve been chair of this committee now for about five years. We don’t have term limits for people on the IRB, I think, in part because it’s not easy to get people to serve in this role.

Tacey Ann Rosolowski, PhD Why?

Ralph Freedman, MD Well, it’s demanding. There’s a lot of time involved. It’s largely voluntary, what you do there. There is a small stipend that they give to me, but it’s due to the chairs, particularly. It’s one of the things that they discussed in their recent review––Dr. Hong’s review of the research––whether there shouldn’t be more remuneration given to members of these committees. There’s a difficulty here because the IRB is supposed to function independently, and it’s supposed to serve the interests of the subjects, not the institution. It’s not the IRB’s mission to protect the institution. You have Compliance and other groups who protect the interests of the institution, so if the IRB is going to serve the benefits of the subjects, it has to keep the institution at some arm’s length. So if–– We’re all employees of the institution, so it’s a sort of a––

Tacey Ann Rosolowski, PhD Almost a conflict of interest.

Ralph Freedman, MD ––conflict of interest to be a member, but it’s––

Tacey Ann Rosolowski, PhD What are you going to do? Yeah.

Ralph Freedman, MD I mean, I guess the only other alternative is to have all the reviews done outside the institution by the so-called Central IRBs. Now, they deal with very large studies that are done in multiple institutions, but they also have their own issues––a number of issues––with regard to conflict of interest and how they organize and so forth, so it’s–– What we have done is that we found that the system that works well for us is––

Our primary interest is the protection of human subjects, and sometimes those interests are not exactly in line with those of the institution. The IRB is the only committee in the institution that can approve a study. The institution can decide for various reasons––financial—but if they don’t want a study to be done, in terms of actual approval, no one else can approve a study to be done. No study can commence at the institution without it being approved by the IRB. When it comes to conflict of interest, for example, the president can waive some conflicts of interest, but it will be dependent upon the IRB approval. So if the IRB says this conflict cannot be resolved, we cannot do the study at MD Anderson. It has to be done elsewhere. The IRB has the final say, so this is the only place in the institution, ironically, where a decision by the IRB can supersede that of the president of the institution.

Tacey Ann Rosolowski, PhD Is there–– ? Are you able, without breaching any confidences, to give a kind of example of this sort––that kind of dilemma that you’ve confronted?

Ralph Freedman, MD Well, we’ve had cases where an individual had conflicts, and the president said, okay, they can have a waiver. Actually, what happened was originally the waivers were going through without the IRB seeing them, and then we’d point it out to Dr. [John] Mendelsohn that this could be problematic especially if safety issues occur, so the rules were changed. Conflict-of-interest rules were actually changed so that the waivers would only be permitted if the IRB approved, and all our decisions are made in strict confidence. Even the votes are done electronically and anonymously so that no one knows who said what, and also, we have a limited number of people from outside who are present at the IRB meetings. Sometimes we’ve found that in the past, that sometimes the presence of an official with a significant authority in the institution could influence the decision making in the IRB, and that was not always in the best interest of the patients.

Tacey Ann Rosolowski, PhD How are these externals parties selected?

Ralph Freedman, MD Well, these would’ve been ex officia. In other words, they were there because of their position.

Tacey Ann Rosolowski, PhD Oh, I see.

Ralph Freedman, MD So a vice president, a lawyer from Compliance—we used to have the lawyers from Compliance in the committee, and the problem––as I told Jessica––is the issue for us is that Compliance, their mission is to protect the institution overall, primarily. I mean, they do protect patients. When the patient has a complaint, they take these things out, but I think, at the end of the day, the primary purpose is to protect the institution from lawsuits, from bad publicity, whatever it is. Our role is to protect the subjects and not to––although indirectly, we protect the institution but not to have the protection of the institution as the direct object of our deliberations. Obviously, we’re not going to do anything stupid that would put the patient––the institution in jeopardy, but it’s not our main objective. So what’s happened is those individuals, they get invited on an as needed basis, like if there’s an issue that comes up that we feel the expertise is not in the IRB, we have the authority to ask to bring in those experts from wherever. It could be from Compliance, it could be from across the road, from anywhere in order to assist the committee in making its deliberations, and that is actually stated in the regulations that you can do that. But these individuals would not have voting rights, so they can come and present, and they’ll be asked questions, and then we let them go out, and there’s further discussion. Then the motion comes up, and the vote is taken with these people out of the room.

Tacey Ann Rosolowski, PhD What’s the relationship between the IRB and the ethics and compliance and clinical research? That was the conference that you were talking about earlier.

Ralph Freedman, MD Oh, okay.

Tacey Ann Rosolowski, PhD Is there a link between those or–– ?

Ralph Freedman, MD Yeah, so the IRB––so the vice president, Dr. [Aman] Buzdar got together with the chairs of the IRB, and we came up with a program. This would be after the conference. It’s an international conference, and the idea is to choose topics that are maybe a bit controversial, but they’re not––we feel that faculty may need to know more about the subjects, and the IRB––certainly members––would maybe need to know more about it so that they can make decisions, the appropriate decisions. A lot of what human subject research is, there’s different aspects of it. One is basically the regulation, the law, following the regulation, following the guidance with the intent that subjects are notified, but there’s a lot of education, as well. Our primary role is not punitive; it’s not to discipline people. Our primary role is to ensure that patients are protected through good practices, so often we have to teach those practices. And it may be an individual protocol, issues that arise with that protocol, and a corrective action plan is required, so you hope they go through that experience, that the investigator and the team members will have learned from that, so the next time they face that situation, they won’t have to deal with it. So our last resort is a punitive decision where you close down some research. And in most instances, literally ninety-nine out of 100 instances, we’re able to correct the behavior of individuals and actually provide them with new pathways and new guidelines for doing things. I mean, their regulations are not really guidelines but just change their behavior so that the ultimate result is that the subjects are protected.

Tacey Ann Rosolowski, PhD What’s the landscape of the protocols that come under your eyes? I mean, what percentage of them go through, and they’re well-designed, and they satisfy guidelines? What’s the percentage that need some tweaking? What’s the percentage where people actually need some intervention, and what are the numbers that actually have to closed down?

Ralph Freedman, MD Oh, first of all, there’s virtually no protocol. That doesn’t have some contingency attached to it because there’s always some improvement that people can do. We don’t try to change the science. Once it’s gone through the scientific committees, and the science is accepted, although the IRB has the prerogative to look into the science, and sometimes we’ve sent the protocol back to the science committee to re-review it, but I would say that, in most cases, it’s an approval with a contingency. There are few that are rejected. If a protocol is rejected, that’s a big issue because. For one thing, we have to forward it to the OHRP that we’ve actually rejected a study.

Tacey Ann Rosolowski, PhD What is the OHRP?

Ralph Freedman, MD The Office for Human Research Protection in Washington, and the reason for that is that what people have done is they’ve gone around and done IRB shopping to get their protocol approved. And some of the companies have even done that, so they’ll go to a central IRB that’s got a better record of approving studies than others with the least amount of difficulty. So I would say most––there are really few that are actually––so in most cases, you would approval with contingency, and you might have defer––defer which is another action. In other words, there are real concerns about the study but not something that can’t be retrieved and redesigned and amended, and then they’ll come back, and often they’ll get approved.

Tacey Ann Rosolowski, PhD What are some of the issues that come up that can be of concern?

Ralph Freedman, MD Well, is it ethical to do the work? In other words, is it appropriate to have a placebo control? When is it appropriate to have a placebo control in a study? And basically a placebo control, it’s ethical if there is clinical equipoise. In other words, you have a group of experts who cannot decide which arm of a treatment is better. So you might allow a placebo in that situation with an opportunity to cross over for those patients, or if it’s, say, near the end of life, and you’re looking at a treatment that has subjective component to it but is a placebo effect, you might allow comparison with a placebo because it’s over a short period of time and it’s the only way that you can show a difference between the arms. The placebo might be accepted there. Or you might permit a placebo to combine with an active drug, so two active drugs and one arm, one active drug plus a placebo in the other arm where you’re mainly interested in the matching to the placebo with the only arm that has the two drugs––the one drug of the two that’s new, and the one that goes along with the placebo would be a standard drug. So you’d have standard plus test drug, standard plus placebo in the other arm, and that’s done not infrequently today. So there are situations with placebos not only ethical but it’s necessary in order to show benefit.

Tacey Ann Rosolowski, PhD All right. We’re back after a brief break.

Ralph Freedman, MD So I think the IRB actually––if we understand that the test––its role is certainly protection of human subjects—that’s certainly number one—but also educating physicans and their teams. Today, it’s a team––most research that’s done on patients is a team approach—and it should be because it’s––there are few studies today that can be done by a single person. For example, you need a research nurse. We couldn’t do without research nurses because there’s so much documentation and submission of forms, submission of reports, and the physicians are also seeing patients in for standard of care in addition to doing clinical research, so they need as much help as they can get in making sure that they do things adequately. They need all this support, and then, of course, you need other investigators to help you do that work. And there are different levels of research, and they are basically related to risk. The newest drugs first in human trials are going to be at the top in certainIND studies. Investigation of a new drug—which, by the way, all thatIND means is permission that the FDA gives an investigator was sponsor to take a drug across state lines, so they can do the study in different states. That’s what theIND does. This is compared, say, to new drug application where a new sponsor wants to obtain approval for a specific indication related to a new drug. They first have to have theIND in order to conduct the studies, and then they come up with a new drug application once they’ve got the studies underway in order to see if the FDA will approve the indication that’s being approved for that drug. FDA doesn’t actually approve the drug. They approve the indication for the drug.

Tacey Ann Rosolowski, PhD I think it was last time you had mentioned something about how very needed regulation was but that had gone too far, and is this a time to maybe talk about this issue?

Ralph Freedman, MD Yeah, yeah, yeah. I think there’s––look, it’s with everything. It’s like a pendulum, and there comes a point where you’ve had a chance to work within a system and you can see what works and what doesn’t work. I think a lot of the research that we do is so-called minimal-risk research or low-risk research. Basically, the only issue of concern there is privacy, and I think many individuals today––the people who work with computers and have bank accounts and have to work with government or state at some level have an understanding for what is possible to protect their privacy or not. People used to talk a lot about don’t give out your social security number, and now I just heard that from Google, they can actually know so much about you––your profile and more. So when the patient agrees to provide samples or clinical information to an investigator to do research, I think they should have an understanding that the researcher––or the environment where that research is done––will do the best that it can in order to protect their privacy. But nothing is absolute. We cannot guarantee that privacy will be protected. With the new high tech act that came in last year, they’re subjecting institutions to big penalties for breakdowns in privacy, so this––and the problem is that it’s gotten––to protect privacy involves so much technical know-how and technology that it’s no longer fitting that the IRBs be responsible entirely for protecting that privacy. This came out last year when the HHS submitted a proposal to change the rules to broaden the area of minimal risk and they actually raised the question whether IRB should still be responsible for this. For that type of research–– And the other thing is that we’ve got regulation on board, because you were asking me specifically about regulation. The HIPAA regulation––Health Insurance Portability Act––was basically designed for insurance purposes, not for conducting human subject research, so they have different definitions of what a human subject is to what theHHS has. By the way, they’re all in the same group because HIPAA comes under the Office of Civil Rights under theHHS, you’ve got different offices. You got the Food and Drug Administration; you’ve got the Office for Human Research Protection; you’ve got the Office for Research Integrity––and they deal with fraudulent issues––and then you have the Office of Civil Rights.

And HIPAA is controlled by them, but all of this falls under the general umbrella of theHHS, so you’ve got agencies for all, and yet, they have different sets of rules and different sets of regulations. So for example, we have a federal-wide assurance, which says that we will be compliant withCFR45, 46, which are the regulations that relate to human subject research that is funded by the government. We could actually opt out of that by just signing one little box, but we haven’t, and so in the federal-wide assurance that the institution official signs, it says that we will comply with all these rules and if there are unanticipated problems, that we will report these to the government. They have––the first part of this is what’s called the common rule, which basically talks about definitions of human subject research, IRBs, how they should be formed and the responsibilities of the individuals, and then we get to vulnerable populations and so forth. In theHHSdefinition it says that only a living person is a subject. According to HIPAA, even if you’re deceased, you’re still a human subject, so the problem then for researchers who do a lot of edemiology-type research is that the population that they’re studying includes deceased people who, because of the research––and you’ve got to get authorization from family members in order to get access to that information, whereas under theHHSyou don’t need it because a deceased person is not a human subject, so then they allow you to get waivers––HIPAA will allow you and the other will allow you to get a waiver for informed consent or authorization. Informed consent is what we generally get from a participant. Authorization is what we require under HIPAA––authorization to access their records, authorization to use those for research—and the HIPAA requires you to be very specific about what you’re going to do with it. So whereas theHHSrules may be satisfied if you said I was going to do the laboratory research or there’s nothing going into patients––there’s no risk to them; it’s just privacy issue and protect the privacy the best we can—HIPAA will say no, you got to say exactly what lab experiments, and then if you want to change your research by adding different reagents or something, you’re supposed to come in and get their permission. That’s the way it is, so you can get a waiver if it’s not feasible to do the research without accessing the private information, and they use that the terminology, practicable––they use the word practicable, which means that it’s impossible, basically, to do it without getting access or without getting thePHI––the private information. Well, it’s always possible, and that’s where the problem is because it may take you two months to get authorization, find out who the family member is who’s responsible, who’s the legal authorized representative in order to grant you access when what we’re talking about is not any research that’s going to affect either the family members or the community, perhaps, because in those cases, we treat it separately, and we might actually require consent. For example, the Huntington’s chorea is a genetic disorder, and it occurs in families, so if you’re going to do research on that type of situation, you would want to get permission from them and also inform them how you would deal with that with the results, how you would disseminate them back––that problem happened with that in a South American country some years back––so there’s no harmony between the two groups. Basically, what we need is a system that the public can have confidence in. So we’re talking about hardware; we’re talking about software; we’re talking about processes––hardware computers, so now they are busy installing Windows 7––Windows 8––

Tacey Ann Rosolowski, PhD I think eight.

Ralph Freedman, MD ––onto all the computers. Not all the computers can take it, so they’ve got to abandon those computers and now get new ones, but those can be encrypted––the information can be encrypted at least, so there needs to be––and we’ve talked about this––it needs the institution to come up with systems in place. This is the equipment that you are permitted to store patient information on. It has to be in a password protected area; it has to be encrypted. If you happen to have this on your laptop and you leave the facility and your laptop gets stolen, gets lost, nobody can get access to that information or it’s unlikely––really difficult. And then you have to have software that can be––also protect the individuals, and in the case of the FDA, they want you to be compliant with part eleven, which is that nobody can manipulate data. In other words, there’s signing in and signing out for every event that happens where that data’s taken out––if it’s worked on, calculations done with it, there’s a signature pathway that goes with it, so you’ve got information security; you’ve got information technology; you’ve got the people who buy the equipment––the contractors. But most of this is outside the domain of the IRB. Institutions should really have to pick up the ball here and provide the resources to the investigators or provide the investigators with solid guidelines as to what is acceptable practice to protect the subjects’ purity. Once we’ve got all this in place, I think you could come to the public with a strong argument and say we’ve got processes in place, which are equivalent to what your government has, what your state has, what your bank has, and we can’t guarantee that your privacy be protected, but if you want to participate in this research, this is what we’ve got in order to protect your privacy.

Tacey Ann Rosolowski, PhD What’s the situation with all of those components at MD Anderson right now?

Ralph Freedman, MD Right now, it’s evolving. Unfortunately, I think when a person view––and that is not mine or any others––is that we’ve lost a lot of time building these systems and building these processes. It’s taken events to happen, to get into the media to encourage us to do these things. There are committees that are working on this. We needed it yesterday––the moment we started working with this private information, so that––

Tacey Ann Rosolowski, PhD But why has there been such a slow process to come up with–– ?

Ralph Freedman, MD Well, it changed after 2003. HIPAA was enacted in 2003, and HIPAA changed everything because things were much easier. Now I don’t know that HIPAA has solved problems or has prevented problems from occurring to a great extent. It’s an extra layer of––it’s become an extra burden, basically, to researchers, and IRBs have to spend so much more time reviewing these things, so instead of taking care of physical and other risks to subjects, we’re spending a lot of time on privacy risk, where if the systems were in place, we shouldn’t be bothering about this. We should allow somebody who wants to submit a study to look at data from the institution, and if they’re going to comply with all these things, it should be able to go through on a templated-based system, and there may need to be a record of access and release, but the risks basically would not be very––they’d be very minor. So I think this is part of the thing is to have the systems in place for the researchers to use, and then regulations, so these regulations which we’re not sure protect anyone or they are certainly burdensome, and there should be a way of removing unnecessary––or there should be at least a very careful look at what we have to see where these things can be amended or changed so that patients can still be protected but not with additional burden to the researchers. That way, the research can get done more quickly. You can access the necessary patient information. We talk about honest broker systems––honest broker systems, which can––we don’t have any such thing at Anderson, but data tissue banks basically could be operated by honest brokers, and they don’t have to be a person, but it could be a technical thing that allows people access to only certain information but keepPHI back.

Tacey Ann Rosolowski, PhD Okay. Because I have not heard that phrase before. I wasn’t––

Ralph Freedman, MD Yeah, so that’s––I mean—it’s one of the recommendations of the NIH for developing tissue repositories as the honest broker system’s being placed. The only problem with the honest broker system that I see is that investigators need to have access to a lot of information, and the honest broker––if you’ve got many investigators, you may not have enough people doing––separating thePHI out from the information that the investigators are requesting, so it may not be feasible. On the other hand, if you have secure computers and secure programs, that may cover it, and I would say a lot of research today, you need more than just a pathology diagnosis. You may want to know, for example, what happens to these patients long term, so you may need a followup. If you only need the tissue in order to study something there, and that’s probably a minority of research that goes on, then it’s okay, because you can go to the tissue bank and say I want x number of tumors from certain a type of cancer, and I don’t want the identifiers, so they give them to you, and then you do the research. You probably should go with research exempt, so the exempt category, you don’t continuing review. You can be administratively approved, and you can go through, so the idea that was submitted in the federal register last year was to broaden this category—somehow to broaden it so that there were less barriers in the way to separating the investigators from the research material. So this is a major issue––getting to grips with the privacy issue, even case reports.

I mean, you may have someone who was treated at MD Anderson with an unusual history and the investigator wants to publish a case report. Well, according to the HIPAA law, you’ve got to get authorization even though the patient is deceased. You’ve got to get authorization from the family. Now, they’ve gone through a tough time maybe, and maybe they don’t want to talk to anybody over here about things at this time, and we’re going to bother them now with forms which do nothing to protect the subject. I mean, it’s a case report. There’ll be no identifying information in the case report, no pictures. If there are pictures in there––and, of course, you require authorization––but it’s just a case report. It’s important for teaching. The fellows often will want to write case reports, and there are some journals that like to take them. They may be hypothesis-generating, but they don’t prove anything. One or two cases that are reported of a certain condition doesn’t amount to a proven statement on that disease, but often, it’s very useful for people who are learning to study these cases. So those things have to get authorization, and you think from the other side, well, that’s––so this is all low risk research, basically, getting access to tissues, getting access to clinical information from charts, records. Then the other side of it is you have the higher-risk research, and we start to talk about that, and it’s related to––first-in-human studies carries the highest risk––and then you go through those studies that have already been done before. So there’s information about not just animal data, but human data, and in finding you end up with the Phase II studies where you’re looking at some efficacy and safety, and then finally the definitive PhaseIII, or the randomized control trial, which may be placebo controlled or not. Those studies require a lot of expertise in doing them. Investigators who do those studies have to be very familiar with the drugs that they’re using because you get a look at toxicity effects. You need to be able to know whether it’s the disease or the drug that may be contributing––is this a new toxicity so that you can report it as an unexpected event related to the treatment. You have to be experienced enough to do that, so these are individuals who’ve been recognized by the FDA as investigators. An investigator with trial is the individual who’s responsible for the conduct of the trial. The sponsor is a person who––or the company, organization that supports the conduct of the trial, maybe provides the drug, so a sponsor can be a company that wants to market the drug, and then they are identifying investigator around the country. Maybe MD Anderson will be––they have a principle investigator there, and this person would sign a 1572, which is a form that says, I will follow the good medical practice and all the regulations that relate to the administration of this drug and then sign any other individuals who would be necessary to participate. These are called sub-investigators. They don’t sign a separate form. And that investigator actually has the total authority and is totally responsible for the management of the study, for the assessment of the effects, the end points or the toxicities, and for any problems that happen during––for the consenting process, for delegation of authority to others, that person is the principle investigator and special role. If there’s a problem, the principle investigator takes the responsibility. Now MD Anderson can be a sponsor, also, of studies. If we develop a drug and if we––well, let me not put it that way, but some studies we cannot do, where we develop the drug. We are apt to get another institution to do them because of the conflict of interest. But if we have a funded study that’s, say, funded by the NIH, NIH can be the sponsor or we can be the sponsor. If we submit theIND––that’s the investigational new drug exemption––then we are––MD Anderson is the sponsor, so we would be the sponsor. We would also have a principle investigator responsible for the study. The trials require a lot of input, and a lot of this has evolved over years of learning how to conduct these studies—what resources you need, the support personnel that you need to do these studies. And in the old days, they were done with a shoestring, so as a result, a lot of things were missed––toxicities were missed or end points were missed.

Tacey Ann Rosolowski, PhD Since you’ve had such a long relationship with this process and then finally with the institution or review boards, what is your special interest in protecting patients’ rights through these mechanisms? How did that start, and why have you kept up with it?

Ralph Freedman, MD Yeah, I think––I actually saw it evolving with me as I was learning to do––become a better researcher. I saw a necessary or––these are necessary rules that we need to comply with.

Tacey Ann Rosolowski, PhD What kinds of things did you notice?

Ralph Freedman, MD Well, I would say that we noticed you probably learn from others’ mistakes more than our own because that probably prevented us doing things that we aren’t correct just by learning what others had done and what they’ve done to correct. We saw events happening where, for example, a principle investigator took on the responsibility of being principle investigator but wasn’t familiar with all the interventions that were being done in the study, and as a result, patients were potentially harmed. And so I think learning that the responsibility of an investigator––someone who wants to be an investigator on a trial––you have to be certain that you have the resources to do it. If you don’t have the resources, you may not be able to do the study. Maybe someone else can do it but not you. But to go back to your questions, I guess I like a certain amount of order in things. It’s nice when you have an instruction about what to do and what to do correctly. I familiarize myself with guidances and, of course, with the regs over the years, and I still go back to them from time to time to––when a certain situation comes back and see what is the guidance for this particular issue. And they’re always coming out with new guides, so we’re learning––well, I’d say we’re learning continually how to conduct trials, how to conduct them correctly, and—I mean—conflict of interest, for example, has become a very big issue today. It wasn’t ten years ago. We only had our conflict-of-interest committee established something like––I think it was about ten or fifteen years ago. We didn’t have a committee at the institution. Now we have very, very strong regulations. I sit on that committee, as well, as an ad hoc member from the IRB, so when a human subject issue comes up, I don’t vote with it. But after the Gelsinger case––that was the case from University of Pennsylvania. I think it got a lot of attention. [James M.] Wilson was a scientist who developed a gene therapy to transfer a gene for enzyme deficiency into patient. He had a nineteen-year-old whose name was Gelsinger––the investigator’s name was actually Wilson––and he went to U-Penn. It became so successful that the university got interested in it and he was able to develop a company. He was conducting trials at U-Penn himself as an investigator until one day he took a nineteen-year-old boy––his name was [Jesse] Gelsinger––his father didn’t accompany him, went up to the hospital. He got this gene therapy, and he died from liver toxicity, and they went back and found that some of the animal experiments had suggested that this might happen. Well, it was a big problem––problem for the University of Pennsylvania––and I don’t know if you know about the case.

Tacey Ann Rosolowski, PhD No.

Ralph Freedman, MD He was suspended from research––well, they found the conflict of interest, that he had his company––he shouldn’t have been involved. He ignored certain experiments––pre-clinical experiments––so he was suspended from research initially from a certain amount of––from getting grants from NIH. Then he had to write a paper, which has been published––that’s Dr. Wilson. He had to write a paper describing what he had done wrong. He actually wrote it, and that was one of the corrective action plans, so after––I guess that case was a wake-up call to a lot of institutions around the country—I mean—the many other instances where physicians are getting large amounts of money from industry to––even in standard of care––orthopedics, cardiology, example––and these you see in the newspapers all the time, but it raised the question whether these conflicts could actually contribute to safety issues in subjects. In most cases, conflict of interest is a perception. It’s a perception by the public—somebody else—that the conflict could interfere with the objectivity in research, and sometimes the safety, but the problem is that once the perception is out there––in particular when it gets into the media––it ‘s irretrievable. You cannot recover easily from that, and there have made many academics who’ve lost their careers because of discovery of conflict of interest.

Tacey Ann Rosolowski, PhD Do you suspect that the conflict of interest is sometimes overblown, that it maybe is not so much of an issue or–– ?

Ralph Freedman, MD It can be, but the problem then is it’s a perception that’s created in many cases. We’ve had our own situations, which have been very clear, and actually, they have been the potential for harm to subjects as a result of those situations, and they take a lot of time to try to repair the situations. We’ve had 483’s, which is a notice of concern that the FDA gives you when you have a problem that they come and inspect and they find the problem. It isn’t a warning. It isn’t the same as a warning from them, but it’s a notice of concern. And then you have an opportunity to fix––and in most cases, we’ve been able to do that, but with a lot of effort––is to give them a response, which shows that we can adequately take care of the problem, and then you don’t end up with a warning because once you get a warning, that’s hard to recover from that. In response to your question, there’s no––there’s limited amount of evidence that conflicts actually have harmed people. Mainly, it’s created a perception that objectivity can be a victim, and there could be harm, but there are some cases where you say it’s very likely that the subject could’ve been harmed––Gelsing case is one example––so as to try to avoid this problem. So all of this has actually been amplified now because of the Bayh-Dole Act––the Bayh, B-A-Y-H––Senator Bayh and Senator Dole, responsible for that in the ‘80’s. Basically what that act did is they said that there were lots of patents being developed for universities, but they were not being exploited. And a Democrat and Republican coming together to pass this act which enables institutions and individuals––inventors––to get some financial reward from the inventions— Institutions like it because it increases the size of their coffers, but itself, it created a dilemma now because now that this act has been passed and been around for some years, theHHS has come back and said now you have to have rules dealing with conflicts of interest. So when it comes to first-in-human studies or even definitive studies, we cannot be the lead site anymore with those trials. So it’s one of the things that I wonder about, and I know that Dr. [Ronald] DePinho was interested in developing new drugs, but I’m not sure where they plan to test all these drugs because under the current conflict of interest rules for the institution––

Tacey Ann Rosolowski, PhD MD Anderson can’t be the site.

Ralph Freedman, MD ––and we may not be able to be the site, and maybe that’s not what he’s thinking of. He’s interested in the developing of the drugs and marketing them for institution and is having the trials done elsewhere, which can be done, but it does raise some issue about where the––for faculty, what their emphasis should be in their academic careers.

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Chapter 06: Two Decades Overseeing Human-Subject Research

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