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Slide #1
SANDRA HORNING, MD: Our next area on the agenda is "Making the Best Treatment Decision: Part One," and we're going to focus in on when are clinical trials the best treatment decision. And our order of speakers is going to be first Lori Kunkel, followed by myself -- and we're doing this mostly, whether it's on a Mac computer or another type, then Dr. Joseph Connors is joining us from the British Columbia Cancer Agency, followed by Dr. Stabler. So I'll introduce now Dr. Kunkel, who is Vice President of Medical Affairs at Genitope Corporation. [APPLAUSE]
LORI KUNKEL, MD: Thank you, and I'd like to thank the Lymphoma Research Foundation for including me in this session. They probably don't know it, since it's gone through a change, but I was originally when I was at UCLA, a Lymphoma Research Foundation grantee back when I was a fellow. So I have a long history tied into this foundation. I think they've really helped me develop my interests in the area.
I think what this session is about is the recognition that the individuals in this panel all share Sandy's passion with developing new drugs. And the fact that when I came to recognition once I went in the industry that I would be able to contribute to bringing new drugs forward, not only to help the hundreds or thousands of patients that I had been treating at UCLA, but also I would have the ability to help bring drugs forward to treat tens of thousands of patients that were already existing and actually the future patients, and I think that that's what clinical trials are all about, is the ability to bring these agents forward. So I'm charged with actually trying to give just a basic overview on why there are standards and what the standards are in clinical trials.
Slide #2
So I just wanted to start out with a history. The highlights of U.S. drug regulation goes way back into the 1900s. Basically, before that time, drugs were bought and sold just like any other consumer good, just like Tide or Ivory Soap. You could just buy drugs off the shelf. And then I think it's important to recognize that our current regulations are really prompted by bad things happen by that premise.
So in 1906, the Pure Food and Drug Act was instituted. And that was actually prompted by the fact that some of the agents you could buy off the shelf actually contained things like ethylene glycol, which is antifreeze, and cause death in patients. So that is an example of what happened before regulations were implemented.
So 1938, there was a federal Food, Drug and Cosmetic Act, and as I mentioned, this was because -- that ethylene glycol was being used as an example. And what this act did is require drugs to be cleared by safety. Before the consumer could purchase them, they had to at least undergo safety testing in a controlled manner. The drug act was actually fairly basic and didn't require efficacy at that time, and corporations were allowed to market these agents if they filed the safety with the agency and there were no comments back in 60 days.
The next big bad thing that happened actually occurred in the mid-'60s, which -- some of you were around during that time. This was prompted by the thalidomide tragedy, and thalidomide was marketed as a sleep agent. And in fact, it was a very good sleep agent.
Slide #3
You could get a good night's rest on it. But unfortunately it ultimately began to be used to treat morning sickness in pregnant women, and it was very effective in that, but subsequently it was found to cause birth defects in these pregnant women, and that was another example of how the drug hadn't been studied, not only thoroughly for safety but also efficacy.
So this prompted an act called the Kefauver-Harris Drug Amendment in 1962, where the government said we now need a defined use of drugs during clinical trials. The patients need informed consents if they're going to be treated with an investigational agent. We're going to require not only that this agent is safe, but also that it's useful and efficacious, and that a government agency was established to review all of the details of these studies in an independent fashion before these drugs came to market.
It also -- and this is probably not recognized by most of the patients, but one of the big requirements is that there has to be a consistent manufacturing of these agents, which is very important so that you know you're getting an agent that is not contaminated, and you're also getting the same agent, to some degree, that was manufactured in the same way that another patient would be receiving it.
And then another part of this amendment was the requirement that adverse events be reported and collected in a central manner so that we could learn about the toxic side effects of these new agents being investigated. And then the final portion of the amendment is that package inserts were created so that when new drugs are released the doctors have basically a summary of the trial data and the expected side effects that may occur with these agents. So this was really a very important act and has really set the stage for clinical drug development.
So why are clinical trial standards currently in place?
Slide #4
One is that it really is very important that you have the independent group review for the patient protection, and that when you get an approved agent, the safety and/or efficacy before that approval has really not been established, that we conduct trials that are based on data versus just a theory or a belief that this may work.
And probably the most important issue that is around clinical trials and centers around informed consents is that the patients may be directly getting products that are indirectly harmful in that they may not be given full information, and that they may be led to be delaying or rejecting proven therapies. This is something important to consider, that if the unproven therapy doesn't work and there is a proven therapy out there, your disease may progress beyond the point where proven therapies can help, and that you may limit your future options by going first onto a treatment that is just believed to work, and not being rigorously studied.
Slide #5
What are the benefits of clinical trials? I think we'll touch upon these in some of our other sessions, is that they provide very high standards, and they're really established to provide protection of patients. You're given a fully informed consent, and those of you who are recently being enrolled on trials, these consent forms can often go to six or seven pages. You're monitored very closely at major medical centers, and the investigational agents are generally provided free of cost to you during these studies.
There is always the hope that you will personally benefit by enrolling on a clinical trial, and then what I find when I talk to the patients is that there's a desire to participate in a study that potentially will benefit millions of patients or future patients down the line.
Slide #6 Windows
So I'm touching upon the objectives of clinical trials. We have phase I, which are the earliest stage that occur after animal data, and the phase I trials are really just to determine how much of the drug you can get and what is the toxicity that may limit use of that. These studies also determine the acute side effects, and often in cancer research, they're not just done in one patient population. They may be performed in ovarian cancer, breast cancer and lymphoma patients when a new drug is being studied. There's usually three to six patients per dose level, and these are usually performed at a single institution, so you have very limited experience initially, but you get an idea of how much drug you can give, basically.
Then, if it can be given safely, you move on to phase II drugs, and this is where you're trying to determine antitumor activity. These are usually performed in a more defined population. You may do a phase II study, a single phase II study in ovarian, and then an additional phase II study in breast or non-Hodgkin's lymphoma. You want to identify the activity across different tumor types, and then you're looking once again to further define what are the side effects, because a patient with non-Hodgkin's lymphoma may be taking different medicines. They may be younger patients, they may be older patients, and they may be taking different medicines than a patient, say, with breast cancer, so you really need to define that population.
Phase II studies, again, are generally very small. They're usually 30 patients, and they're usually limited to a small number of institutions, because you want to perform these consistently across sites.
So if the drug shows antitumor effect and has a tolerable side effect, these move into phase III studies.
Slide #7 Windows
Now, the basis of a phase III study is to compare efficacy with a known standard. So generally in a phase III, the patients will have -- one arm will receive a known, proven therapy, and the other arm will generally receive the new agent plus the known, proven therapy. And the other important goal, objective of a phase III clinical trial is to further define the toxicity.
These are generally randomized studies, which means the flip of the coin decides which arm you'll go on. These generally include large numbers of patients, in the hundreds or sometimes even in the thousands. They're conducted at between ten to thirty institutions. They can be conducted across different countries, and during this phase -- again, I'm going to get back to the point that the companies are refining their ability to manufacture these agents for large numbers of patients so that the manufacturing processes are accurate, that in the phase III when you're delivering it to hundreds or thousands of patients, you're sure you can do that, because you don't want to bring an agent to market where you can't manufacture enough of it to meet the demand. So that's another important role of a phase III trial.
Slide #8 Windows
Now, I attended this session last year, and there's always a question, "Well, how come phase II data isn't enough? You've shown that there is some antitumor activity. Why can't we just do phase II studies?" I think Dr. Horning will address this in more detail, but I will use the example of studies that began in the 1980s in large-cell lymphoma, aggressive lymphoma, where we began to look at new intensive regimens compared to the standard regimen, which is CHOP, and the phase II studies looked -- every institution had their favorite combination of drugs, sometimes seven or eight, and all the studies were positive. They all looked better than CHOP when they were performed at a single institution. They looked great. But these were all in small numbers of patients. They were in very selected patients groups, because they were all at a single institution, so it was whoever could come to that institution, and everybody wants it to work. The doctors want it to work because it's their new regimen, and they believe it's a better regimen. The patients want it to work, because they want to believe that they're getting something better than the standard of care.
So when these regimens were then put into a phase III study which compared it to the standard of care, they picked three of the intensive regimens and compared it to the standard CHOP. They weren't any better than CHOP, and in fact the most telling point of this randomized phase III study were that the other regimens turned out to be more toxic, that in fact they cause more side effects without being any more effective. So I think that's one example of why phase III studies are important, is that, yes, in phase II you believe that it's better, but it really takes large numbers of patients across multiple institutions to determine efficacy.
Slide #9 Windows
So the other question that comes up is randomization, and it is a question that we all as physicians deal with. Is it ethical to have a randomized study or use a placebo? And I will say that it's my belief and the belief of many physicians that there are cases when this is ethical. It's ethical when the patients are fully informed in advance that they're going on a randomized study. It's ethical when they're not denied therapy that could alter survival or prevent injury -- i.e., if there's a known therapy that could benefit them, they're not denied it on the study -- that they voluntarily agree, and that the effects are monitored as they're occurring.
One point of randomized studies are that the trial can be stopped if a major effect is seen, so that if there's a major negative effect from the new agent, the trial can be stopped, and if the trial's far enough along to see a major positive effect, the trial can be stopped. I think this is important to understand when we're talking about randomized studies.
Slide #10 Windows
The last issue that I wanted to bring up is how is the FDA really increasing access to new drugs by the clinical trial method? And there has been a lot of work over the last few years, because they recognize that there's -- I think there's over 400 agents in development right now to treat cancer patients, so there's an enormous amount of choices out there. One is that they have established an accelerated approval for new products based on surrogate endpoints that demonstrate a reasonable benefit. And actually, Rituxan was approved with this. It was felt that in a relapsed patient that an improvement in time to progression versus their original duration of response was a surrogate endpoint for survival. Rituxan has not been shown to improve survival in patients, but it has been shown to be able to provide a reasonable, long duration of response, and that study was accepted under an accelerated approval process.
The other is that the FDA, the agency, has a priority review process to direct resources for evaluation of applications with significant therapeutic advances, and I think the most recent and telling example of this was Gleevec, which is used in a type of chronic leukemia for which there was no really adequate treatment, and resources were put on that agent, and it got approved very rapidly.
Slide #11 Windows
There is an expanded access to investigational cancer therapies that have been approved in other countries. Again, drawing from the liquid tumors, arsenic was used for years in China and has recently been approved for use in the U.S. for treatment of acute leukemia, and can help acute leukemia patients who have failed other standard therapies. And that agent was filed basically on data from the Chinese studies. The trials actually -- there were trials conducted in China, but trials were not conducted in the U.S. But the FDA accepted the data that had been well controlled in the other countries.
And then there's another procedure called fast track, which facilitates approval. If it is indeed a serious and life-threatening disease for which there is no good treatment, the FDA will make an effort to get that agent approved in a quicker manner, and Zevalin is actually an example, or the radiolabeled antibody that went under this. So I do believe that there are efforts being made to increase the access to new drugs.
Slide #12 Windows
The FDA also includes cancer patients on the advisory committee that reviews drugs. They also encourage that once a drug is approved, they're trying to streamline the process to apply it to other uses of marketed projects. And the examples I'm listing here is that interleukin 2, initially approved for renal cell cancer, has also been approved by this mechanism for melanoma, and Gleevec was also expanded to be used in gastrointestinal tumors.
Slide #13 Windows
So I work on the vaccine trials, and we have a lot of controversy around our trial, and one recent controversy is why -- there have been issues raised, why do we even have to have human trials? Why can't we just use the animal data? It looks so good. Well, I've gone over the reasons why in the previous talk, but I will say for this particular trial, the animal data does not strictly translate into the humans. We've already seen that we have a different schedule to use in the humans, and we've also seen that actually our effect, we get a better effect in patients that have disease, whereas in the animal studies, the animals could have no disease to get an effect to the vaccine. So that is one important reason.
The other is that in our particular study the current manufacturing process has changed, and we need to make sure that we can manufacture this, and that any company coming forward can manufacture these sorts of treatments so that all patients will have access to them. And there really has been a limited phase II experience, and if you dig through the history, that there have been 41 patients with one treatment regimen at a single institution, which is Stanford, and that treatment regimen is different from the regimen that's currently being used, there was another study with 32 patients using a different treatment regimen than was used at Stanford and a different patient group than was at Stanford, and then we have a smaller study with the technology that has now been moved into phase III. So you can see that there's been less than 100 patients treated in phase II.
Slide #14
I think that within our particular development that there has been a really great collaboration with the FDA, and also with our investigators in that there was no new animal data that was required. They did accept data based on the previous studies. We were not required to find a dose finding because our particular agent doesn't have a limited toxicity that we know about. Our phase II studies began in 1999, and the results from that allowed our phase III to start in 2000, so you can see that things moved very rapidly.
We have right now the belief that the agency will accept a surrogate endpoint, which is time to progression versus survival. So in the example, we're treating newly diagnosed patients, we won't have to follow them for survival to be able to get this agent out there. If we show a significant difference in time to progression versus standard therapy, we will be allowed to bring it forward, and that means that we can have an accelerated approval.
Slide #15
So I think, in conclusion, that if you have a single well designed study in clinical development and a phase III study and it's well controlled and it provides the data to make informed recommendations, that you can obtain fast approval. And I believe that the way, the quickest way to really get agents out to the thousands of patients with this disease is really to increase patient access to clinical trials and to accrue to these trials so that we can get approval and move them forward. [APPLAUSE]
SANDRA HORNING, MD: I'm going to speak briefly, expanding some of Lori's remarks as they relate to the phase III clinical trial. Hopefully our technology will set this up. Thank you.
Slide #1
So as patients and their physicians, we're constantly asked to make decisions about treatment options, and when you're speaking with your oncologist, you're asking for his or her expertise, which is related to the numbers of patients that this person has seen over time, perhaps with your situation, and taking into account all of the things that make you individual. And then of course, your choice is an important aspect of this, and what you're really going to be discussing is what is the evidence on which basis I'm going to be making my choice and you are making your recommendation.
The reason that phase III clinical trials are so important is that they are really the most powerful form of evidence. They meet scientific criteria for evidence, and they establish the standard of care, and more and more, if you've been reading the newspapers, that's what the FDA wants to see for drug approval.
Sometimes, phase III clinical trials don't all agree with one another, and something is done called a meta-analysis, and that's been done over and over in the large breast cancer trials, where they try to get a group of experts together, come to a consensus, and then that becomes a guideline for standard care. So these trials are very important, because they have the strongest influence in what's done on a day-to-day basis.
Phase II clinical trials are sometimes the only evidence that's out there, but they are relatively weak evidence, and particularly if you're dealing with only small numbers of patients who were probably highly selected at the time they went into the trial.
Slide #2
So you're trying to make your choice, and it's difficult, because you're exposed to a barrage of information and misinformation. I don't know how many of you saw it, but there was a wonderful piece that Jane Brody did in the New York Times this last week about separating the gold from the dust in clinical trials. And that does come from the media, it comes from the internet, and it comes from individual contacts. And furthermore, most of you are not really trained to distinguish solid scientific evidence from weaker evidence. You just haven't been thinking that way in your day-to-day life until everything came forward.
Slide #3
So the phase III clinical trial, as Lori said, is generally taking the best available standard treatment and then comparing it with something new that is safe, looks promising on the basis of phase II, and is either put forth because there's an idea that it may have greater efficacy or in some situations that it might be equally efficacious but less toxic.
And I would put forth that a phase III clinical trial is only ethical when there's uncertainty. That is, there's uncertainty that one really knows if one treatment is better than another. That's certainly important for the physician to have that level of uncertainty in recommending the trial, and it's something you need to be convinced about.
Slide #4
But, as humans, physicians and patients, we have hunches about unproven therapies, and we have boundaries on our hunches of presumed benefit that can vary between the agent in question is extremely effective to not effective at all, or perhaps frankly harmful.
Slide #5
I'm going to give you some examples now of what is presumed benefit. And probably the most notable example is experience with high-dose chemotherapy and transplantation for breast cancer in the United States. And early on in the late '80s there were several reviews that came out saying that this was a better treatment, particularly for women who had advanced stage of breast cancer, often recurrent breast cancer. And there were a lot of questions that came out in the press, in time magazine about insurance companies balking at paying for this, and we kind of got bogged down into the financial aspects. But meanwhile, there were clinical trials that were done, and the bottom line is that when we get to the year 2000, it's demonstrated that this therapy was not better, and in fact was significantly more toxic.
Now, that's unfortunate, and it's not because anyone was trying to fool anyone. It was because there was this presumed benefit and the desire on the part of physicians and patients that this was going to be better. But what really makes me sad is that it took 12 years to figure that out. And the New York Times did a calculation that we probably would have had the answer around 1991 if the same number of patients who were transplanted in this entire period of time had entered phase III clinical trials.
Slide #6
As Lori said, we have our own example with diffuse large-cell lymphoma, and again, we had reports coming out on phase II, each of which looked better than the other. We all believed it. Investigators believed it, patients believed it, but it was in fact a four-arm trial that told us this is not the direction to go. We need to go a different direction to improve outcomes in large-cell lymphoma. And the more quickly we can figure this out, which is totally based on the rapidity with which patients are accrued to clinical trials, the better off we'll be in testing this multiplicity of new treatments that we have.
Slide #7
Now, we have examples of proven benefit. Here's Hodgkin's disease, comparing ABVD to a chemotherapy combination of MOP-ABD, and in this case we have equal outcome. But what's important is that patients with ABVD do not have the risk of secondary leukemia, they do not have infertility, which is important for young patients with Hodgkin's disease, and we learned from that we don't need MOP. We can get away from that, and this became the standard treatment.
Slide #8
We also have the example of high-dose therapy and transplantation for recurrent large-cell lymphoma, and here, unlike breast cancer, it was proven that transplantation was in fact a significantly better option. So we changed the culture from just a few patients going to transplant or believers to this now becoming the standard of care.
Slide #9
I believe that there's a cycle of discovery and therapy and that in order to continue building on this, we really need to keep going around this wheel. We have a new discovery based perhaps on biology. You take it to a phase I trial, found out that it's safe, take it to phase II, and we've got some promising information. Then we need to go on and prove it so that it can become the standard of care, but it could also keep this wheel going, because it's not going to work for everyone. We have to figure out the prognostic factors, the clues we get from that that lead back to the biology and keep this wheel going.
Currently in the United States, we have only about 1 to 2% of patients going on clinical trials, and what often happens is that after this phase II it drops off and becomes a standard of care, and if we're going down wrong tracks, kind of like the maze, it's going to take us much longer time to get to the finish line.
Slide #10
So what do patients need to know? I think we all have to admit there's uncertainty about many treatment options, and there's a difference between solid scientific evidence and weaker evidence. As a patient, I think you're entitled to know the basis of your physician's preference, what evidence that's based upon, what are reasonable alternatives and if there are clinical trials in existence for which you are eligible, what they are. In some cases, a clinical trial may be the best option. Thank you. [APPLAUSE]
Slide #1
JOE CONNORS, MD: We've already reached the lunch hour, so I'm going to go through this fairly quickly, and I think the way things have been set up actually is very good, because we have breakout sessions this afternoon, and the questions that are in your minds that we don't address, there will be plenty of time to talk about them there. And I hope to develop my perspective on thinking about clinical trials and how they're done, and I'm going to have to page back, because for some reason have my last Slide #. So let's see. When you're nervous and your hands are shaking before you give a talk, it's the last time you want to be making these little gidgets jump around on the screen, but I'm there. There we go. Okay.
I sat back and thought about why might a clinical trial -- and it's emphasis on "might" -- why might a clinical trial be the best treatment decision for some particular person? I wanted to emphasize some aspects of how clinical trials are put together and the standards that they have to meet.
The first of them is that the clinical trial itself must qualify. It has to meet standards that are sufficiently high to satisfy the regulatory agencies and those of us that are eventually going to analyze that trial and decide whether it demonstrated something unequivocally or not. So the treatments that are going to be used within a clinical trial, as I show you up here, are reviewed themselves by experienced experts, and we don't carry things on into clinical trials. We don't expend the resources in terms of money and patients' time, energy and effort unless we've managed to identify that there are interesting questions or questions of general clinical relevance, scientific evidence that are necessary for us to resolve.
The two aspects that I reviewed most carefully are, one, the science, and this is approved both at local and national levels. So a clinical trial doesn't go forward unless these experts have sat down, looked at it carefully and said, "Yes, this is a scientifically well conceived project and has the potential to advance the field or advance our ability to treat patients." In addition, clinical trials today are scrutinized very carefully for the ethical acceptability of the way in which they're going to be conducted. And I'll return to that as I emphasize some of the protections that are built in so that your privileges and rights as a patient, as a subject in a clinical trial, will be respected.
Other people or places have to qualify. The investigators have to qualify. Not anyone can just say he wants to sign up or she wants to sign up and start enrolling patients on a clinical trial. Your credentials are examined, your capacity to do this kind of work is examined and has to be verified, and you are centrally registered in one way or another with sponsors and regulatory agencies when you're going to go ahead. And so this is an additional level of qualification that must be brought on behalf of the investigators to the conduct of the trial.
The investigators aren't, having once been accepted, never again looked at. Your actual performance while you're doing the trial is monitored, so every time I see a patient that I have on a clinical trial, I have to sign off on case report forms that describe everything that's happened up to that point in time and certify that these things are true. What I say goes to a central place and is inspected to determine if my performance, the way I'm doing things on the clinical trial, meets the rules and criteria. And I hear quickly if I'm falling short of that goal and my performance is encouraged to improve, or I'm not allowed to continue to participate in that or future clinical trials.
And finally, the institution where the clinical trial is to be done must qualify. The facilities have to be appropriate, we have to be able to offer not only a comfortable and safe environment in which to do this, but the whole apparatus has to be there, with a sufficient guarantee that it will still be there in the future, when the analysis is going to have to take place. The laboratories where the tests are done have to be accredited by the appropriate bodies, and they have to prove that they have built-in quality assurance that will guarantee that the results being produced in those laboratories is reproducible, accurate, precise and relevant to what's going on in the trial.
You've heard an elegant talk earlier from Dr. Said about the importance of pathology. When clinical trials are done, the biopsies that are used to base enrollment are inspected by local experts first, but almost always in one form or another by additional experts, and especially in lymphoma trials. Hematopathology, which is so important and I'll return to in a second, has to be guaranteed to be of the highest level, and this is built into clinical trials as they're done.
Diagnostic imaging is another area. When an assessment is to be made as to whether a new drug works, we have to be able to tell if the tumor changed. Often we can only do that with appropriate scans, and those have to be performed up to certain standards and read by experts who know how to interpret the changes that are evident on the diagnostic imaging. Local imaging departments are certified, and in most trials, especially where response is important, all the x-rays are collected, brought to a new place, centrally reviewed by an additional set of radiologists and doubly certified to actually be showing what's been claimed in the case report forms up to that point.
Slide #2
There are various different standards that we have to live up to in conducting clinical trials, and I wanted to emphasize one called the Good Clinical Practices Standard. What I've done over here is to list the specific aspects of clinical trials that are addressed by these clinical standards. In the interest of time, I'm not going to go through each and every one of them. I'll just emphasize a couple of them.
First of all, the trials have to be designed properly from the beginning, or you're not meeting this standard. They have to be conducted or performed in accordance with the way that the trial was laid out in the beginning, and so you're not allowed to slack off as you go on through the clinical trials. You can't start taking shortcuts and cutting corners. You have to do it the way you said you were going to do it.
Trials are monitored in real time. As the results are coming in, feedback is going back and telling us, "That's great. You're doing it just right when you do it that way," or perhaps, "No, you didn't meet the standard of this trial, and you need in the future to be doing it in a different way so that the results will be as believable as they can be."
Eventually, everything is well recorded and analyzed, and clinical trials are reported. That is, when the end of the day comes, the trial results are in. They don't just get tucked away someplace and gather dust, they actually are presented by physicians at meetings where they can be criticized and re-inspected, and finally published in the medical literature. So all of these things are required by good clinical practices, standards, and when they are met, in ensures that the results from trials are credible and accurate, that in the conduct of the trials that the rights and integrity and confidentiality of all of the subjects enrolled has been protected. So you have these standards being built in that are reasonably high, and in meeting them guarantee that you'll be passing through a high-quality experience as you participate in a trial.
Slide #3
Pathology review, I'm going to show you why I think that specimens are so important, as Dr. Said was emphasizing, by showing a couple of pictures.
Slide #4
This is a different listing of the different entities that a patient can be found to have when they're identified as having a non-Hodgkin's lymphoma, and the emphasis here is the large list. Each of these, a different disease with a different natural history, a different way of spreading about the body, and a different way of responding to treatment. If we don't know which of these diseases a person has, then we can't tell whether they're on the right track in what they're being treated with, or whether they're eligible for a particular trial or not. You can see the kind of problems that can arise.
Slide #5
This is a close-up picture of a particular kind of lymphoma called follicular lymphoma, and the very characteristic, very darkly stained, crinkled-up or cleaved cells are scattered throughout this area here, and you could take a sample from up here or down here or over there and you would see rather the same thing, and in each of those cases have some confidence that you are correctly categorizing what kind of lymphoma this is.
Slide #6
But this is what that same lymphoma looks like if we back up to a lower power looking through the microscope, and what I wanted to emphasize here is that the lymphoma is distributed in these light areas. These are the nodules or follicles that give it its name, follicular lymphoma, and in between you see these strands of normal cells -- T cells, B cells, connective tissue cells, endothelial cells from blood vessels, all different kinds of cells are here.
Well, if you take your sample from right in the middle of one of these nodules, you'll get what I was just showing you on the previous Slide #. But if you took your sample from these strands of normal cells elsewhere, you'll get a very different picture, and therefore what you're looking at will depend very much on how the specimen was obtained. I emphasize this because in the hurly-burly and rush of trying to get things done quickly, have patients go through the least invasive procedures and have the most convenience to getting on to their diagnosis and their treatment as fast as possible, there's a strong temptation to cut corners and to rely on smaller biopsies that can be more easily obtained or that might be accurate, and often do turn out to be accurate, but there's a danger that they might not.
Slide #7
Take a look at a Hodgkin's Reed-Sternberg cell here. That's the isolated malignant cell. All the rest of the cells in the picture are normal cells. In many Hodgkin's disease biopsies, only 1 to 2% of the cells are malignant, and all the rest of the cells are normal. Suppose we tried to diagnose this with a needle aspirate, and when the needle was put in position, it sucked out a collection of cells from over here and none of the Reed-Sternberg cells. Every cell aspirated would be normal and no diagnosis made.
It needs an adequate specimen to start with. Once the pathologist gets a very good and adequate specimen properly obtained, wonders can be worked with it using the modern immunohistochemical tools available. But you've got to start out in the right way.
In a clinical trial you can't cut corners like that. You have to get a proper biopsy, and it has to be reviewed by an expert who's willing to certify that this definitely is the disease that they say they are, that the patient has. The quality is being held up, and the enrolled subjects in the trial are benefitting from it.
Slide #8
So how does this affect you? Well, let's just look at some of the aspects of clinical trials. One of them is what's called adverse event reporting. When we do a trial, if anything bad happens, we're required to report that. When we report it, it goes back to the central agency that's sponsoring the trial, and there's the potential that this can be then rapidly -- in a standardized format can be rapidly shared with all the other participants in the trial. And before that goes out, before we just willy-nilly say this bad thing happened, experts can take a look at it and see, does this make sense? Is it sensible to blame this adverse effect on the experimental treatment, or might it have been due to something else, and so provide an interpretation for the reporting of that adverse event.
If that happens, then across the entire trial subjects are assured that they will be informed of anything bad that happens and protected in any way that we possibly can in the conduct of that trial from that moment on from experiencing that kind of adverse event, or at least be made familiar with the fact that this is an additional risk that they're undertaking by being enrolled in the trial.
Slide #9
I wanted to give an example of the way that this can play out. In Hodgkin's lymphoma, as Dr. Horning was just pointing out, ABVD has become the standard treatment. Let's just suppose that a new drug comes along, X, that shows lots of promise. All by itself, half of the patients get better when they're exposed to it. This looks like a very promising drug that might be useful to insert into this combination. And instead of using ABVD, we'll start treating patients with ABVX.
Well, this is now done. Twenty different centers are participating in this trial, and at each of three different centers, three different subjects experience fairly severe pulmonary toxicity. Well, think of what might have been happening if drug X was simply available for some other purpose and clinicians, knowing of its 50% response rate here, were on their own outside of clinical trials deciding that for their particular patient maybe the D is undesirable -- the D happened to cause a fair bit of nausea -- so they're going to substitute this other drug which actually works well.
Off trial, after a while, they might encounter one of these patients with lung toxicity. That experience is confined to that individual clinician. He might share it in his local hospital, but certainly the word won't spread beyond that, and it remains an oddity until many such cases arise and finally people start to make the correlation. Outside of a trial, it remains an oddity for a long time. On the trial it's reported, the pattern is recognized. All the subjects are protected because the investigators are informed. And so it works to your own protection to have been part of the trial.
Slide #10
I'm going to end up by pointing out that, being human, we all hope to leave our own legacy in this world, and one of the ways that people who participate in clinical trials can leave a legacy is by way of what I'll say is never being forgotten. This is sort of the long memory of clinical trials. If you enroll in a trial -- and I'm giving you sort of an example of how this can play out -- let's suppose you participate in a trial and we're comparing standard treatment X versus taking X plus some of Y. So Y is the variable here that's being added.
Well, it turns out in this particular trial, as in many, it's a tie at the end. X by itself works no better or worse than adding Y to it, and 60% of the patients are cured regardless of the two approaches. Well, the conclusion would be, you don't need Y. If X can do that all by itself that's great.
But let's suppose that many years go by, and ten years later clinicians start to recognize that having been exposed to Y causes your thyroid to stop working, and half of the patients become hypothyroid. Actually, this is real. This is the sort of, kind of time scale that it takes to figure these things out. We notice that a lot of the patients are becoming hypothyroid. Well, off of the trial -- you're not part of a trial -- you've moved twice, you've changed doctors three times, you're off on your own. You're about the only person that really remembers well that you participated in this trial at all. Eventually, having become hypothyroid, if you're one of the 50% of people that do that, your thyroid stops working so well and you finally become sick. The right test is done, and it's seen that you're hypothyroid and it's corrected.
On trial, all the subjects are tracked, the pattern is recognized, the subjects are notified, a simple treatment is started and nobody had to get ill at all. It's prevented from happening.
Slide #11
And the last Slide #, your experience becomes part of the record. You can see the list that I've put up. It's recorded locally, across the group, central repositories, and in addition, the results from the trial are presented in sessions like this and in publications and become shared with a wide number of people, but patients and clinicians.
Off the trial, the memory of what becomes of you resides in the heads of a few people. On the trial, again, everybody's tracked. The results are accumulated, and group decisions are affected, other researchers are affected, and a permanent point of reference is created. So you do get to leave a legacy that helps other people and has the potential to even help you. I'm going to wrap it up there and let Dr. Stabler have a talk with you. Thanks. [APPLAUSE]
BRIAN STABLER, PhD: Those of you who follow Monty Python will know what I say when I'm saying "And now for something completely different." It might be a while. I hope you're not very hungry.
Q: ... question ...
BRIAN STABLER, PhD: I certainly would.
Q: The question I have has to do with the standard treatment versus the standard treatment plus the thing that is being investigated, and one fear that I have is that since the standard treatment is not the same or it's not widely accepted in some lymphomas, joining a trial seems to have a fixed standard treatment, and if you join a trial like a year into it, for example, the standard treatment may have already progressed to a better cocktail, if you will. And so the question is, how do you put your mind at ease of someone who's considering a trial, but perhaps the standard treatment is not as good as perhaps the current treatment is. Do you understand my question?
JOE CONNORS, MD: Well, I'll answer it partially. When we conduct a trial, we have in place continuous monitoring of what's going on inside the trial, and I think the thing that most protects people from having happen what you said -- that is, that the standard changes and some new standard comes along which actually works better -- is that the trial and the available medical literature and evidence are being monitored by a data safety monitoring committee, and if new information becomes available that indicates that the standard genuinely has shifted -- not just that people's opinions have drifted or a new fad has appeared, but the evidence has changed -- then the data safety monitoring committee actually tells those conducting the trial that you have to consider or may even have to stop the trial, because a new standard has emerged, and it isn't any longer reasonable for the experimental treatment to be compared back to the standard.
Now, this doesn't happen anywhere near as often as you might worry. What does happen is the first thing I mentioned, and that is that the fads or opinions change without new evidence emerging, and the standard seems to drift around. But if new evidence actually does emerge, if a new standard of care emerges, then the trial is brought to a halt and a new trial might be launched compared to that new standard.
Slide #1
BRIAN STABLER, PhD: Looking for a clinical trial, says he with great alacrity.
Slide #2
I have become convinced -- what I'm going to do here is I'm going to talk about what it takes for a person to be an effective consumer of the services of oncologists, and I came up with this little ditty the other day, and I thought I'd put it down because it said to me everything I need to know. "There once was a man who had cancer, who searched high and low for an answer, until one day he found, in a moment profound, that he himself held the answer."
Slide #3
Effective patients, those who look for and who do well in clinical trials have these characteristics. This is one of my patient friends who has a high level of this phenomenology called emotional intelligence, the ability to know how you feel and to talk about that with other people. It indicates that you are in touch with, as they say in California, your self, your true self. Two other factors come out very, very often, either in my own life experience or in that of patients that I've worked with. Curiosity and sociability are by far and away the best psychological predictors of how well a person is going to do throughout treatment or whether or not they're in a clinical trial.
Slide #4
But it comes down, as you've heard many times from my colleagues in the last hour, to risk, and some people enjoy adventure and risk. Some people prefer safety first. So if those are temperamental traits that you have, regardless of any of the evidence, you may find yourself backing away from a trial that might even be good for you because you perceive it or you feel it to have too much fear attached to it, and nobody likes to be afraid. But, as we will talk about this afternoon, risks can be rationalized.
Slide #5
The decision-making tree, when you listen to the evidence about cancer and cancer trials, it is very heavy in information. It is saturated in information. But as part of the cognitive tree that you use, I use every day as we go about coming to a decision, at least two thirds of what we do is subconscious or unconscious. It's either held in our belief systems or in our intuition. And finally, I'd have to say that intuition is a thing that has guided me more than any data set in my life as a patient.
I talked to Paul Tsongas, the Senator, who was trying to help me early on, and he said -- he put it this way. He said, "You get a chance to be in a clinical trial" -- that we were talking about -- "Just do it." Do the Nike thing. That was his approach to things.
Slide #6
As you already heard, in Europe, many, many, many more cancer patients get into clinical trials than do in the U.S., which puts us, in terms of developing a body of knowledge, a standard of care, a new gold standard, maybe a new platinum standard, at grave risk.
Slide #7
When you look at how long -- and this was frightening to me when I found this out -- that it takes 15 or more years for a drug product to come from the concept to anywhere near a patient. Now, if patients were more actively engaged or involved or proactively engaged and involved in clinical trials, I would imagine, guessing now, that that number would reduce quite a bit.
Slide #8
My criteria for whether or not I'm interested in a clinical trial are essentially these: Is it better? Does it scratch and sniff and smell better than two thirds of all available options? That's my rule of two thirds. Will it replace or will it add to standard of care? That's something that I think is exciting and interesting to know. And of course, depending on how desperate I am -- and I, thank God, have never been that desperate -- I'm looking at a phase III trial, preferably, more than a I or a II trial.
Slide #9
What have I got to win or lose? Well, I've got an opportunity for improved outcome, and I'm always looking for that. But I might have the same opportunity by exercising myself better. I may improve the quality of life. That to me, at this moment in time, is probably more important than the quantity of my life. I hope to improve my health status, and I hope to improve and add to the amount of time that I have left. But on the other hand, by taking a clinical trial, like I did in going to Boston for a bone marrow transplant, I could have severely limited both my quality of life and the amount of time I had.
Slide #10
What worries me? Safety. The primary issue is my safety. Will my program of care, however it's written, be complete? Will I still get the other therapies that I need? Will my present physician be on board with me? Will he stay in some, or she stay? Will I understand? Will I be educated about what is happening in this process? And will eventually the trial be successful? Most of these questions you can't answer easily, but they must be asked. They're part of an internal dialogue that I think good, effective patients have with themselves.
Slide #11
Finally, to move this rather rapidly, all things are possible. All things, including alternative and complementary cancer therapy trials. But not every probability statistically is acceptable to us, and those are two different phenomena. There is a time when you come to giving it all over, giving it up, not giving up, just disconnecting and letting the system run, and knowing that you are not alone is critical. I've said that to a couple of people already here. People connected to people is the most positive way of making decisions, of following through after treatment, and of maintaining the quality of life that we all seek. And finally, any decision well made, well thought out, is a step forward. Thank you. [APPLAUSE]
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