I have been asked to talk a little bit about informed consent and address it as a philosophical rather than regulatory construct. And take that in terms of the research.] . This is like going to a restaurant and just getting a tasting, I am afraid. I have entitled this "the Grimm Reality." I have entitled it that way on purpose because it is somewhat like a fairytale. It turns out to be something we try to approximate as well as we can. And we often have to tweak for certain circumstances. The overarching consideration, when you are thinking about consent, is that every research subject
While full of addition -- while solicitation of informed consent is an important way, it is -- it respect the entire integrity. Not just asking someone before you do it but how you conduct the whole thing which sets the entire state. If you want to fix the problem, and you want to be truly informed, if the research is not fully designed and well conducted and free from bias and honestly reported. Things that we have just referred to. The responsible conduct of research is the RCR. If you are thinking about this in a more structured way.
What really matters is the integrity. Paying attention to making sure that you really doing what you say you're going to do and promising what you're going to. -- to do. That depends upon the integrity of the person conducting the research. If you like "text bites," don't get so wrapped up in the compliance you forget the ethical imperative. It is not just roles that they violated -- rules that they violated. A favorite quote from our Schweitzer -- Albert Schweitzer, "the first step in the evolution of ethics is a sense of solidarity with other human beings."
Randy Cohen made the point that "individual ethical behavior is likelier to florist within a just society." In order to lead an ethical life, for a just society, making it just, it is one of the best ways to make it in an ethical manner. If you act as well as your neighbors, it is incumbent upon us to create a decent neighborhood. When you start talking about your responsible conduct--
It involves human research protection. Protection for research subjects that are not human. It comes from looking at the supervisory relationships or within the research enterprise. And involves telling the truth about who did what would you are publishing your results. It involves peer review. For publication or for grant money or for whatever. That is done fairly and critically. And data management should be done responsibly. Interestingly, there are reasonable rules are when data will be shared. Finally, reasonable conduct and collaborative science -- in collaborative science.
Human research protections are part of the informed consent piece. I have done some research on this because I was an editor for about 15 years. It is quite interesting to see how people -- people's regular in evaluating other people's man scripts -- manuscript and you would be expected to agree with or disagree, there are some interesting papers and -- done. It's pretty natural.
An important piece of this is an institution fostering an environment that promoted the -- this. There should be formal programs of teaching. Making sure people are taught about responsible conduct in they are reminded of the concept. Of research. We move on to the fairytale of informed consent. This is a piece from one of the original Grimm's fairytale books. It was lying around the house and easily scanned. It is plenty old enough to be beyond copyright.
I like to start out with a few anecdotes. When discussing informed consent. One of which is a careful situation for -- terrible situation for informed consent and one was one of the best. The first one was a patient with newly diagnosed CML, which happen to be the wife of a family physician. This was in the days before new tyrosine kinase inhibitor with activity against CML. She went to get information from the Wall Street Journal and investor advisory sites and for the manufacture -- manufacturer.
She declined to enter into a consent dialogue because she had are gone through -- already gone through these are out decisions. I found it very difficult in conscience to enter her into the study. The second patient, who came to me 10 years -- 10 days later, she had it for several years. She was controlled with interferon and hydroxyurea. She came to the clinic with almost the same identical packet of information from the Wall Street Journal and chat groups and the manufacturer. She also decided she wanted the new drug but she wanted to know how reliable was the information as you count? -- that she had found?
As a result, her homework allowed us to have one of the best informed consent discussions I have ever had with a research subject. She was entered into the trial. She had her illness control for 13 years. We are kidding ourselves if we think we have control over the information that is presented to a prospective subject. They have lots of information and lots of sources. If you put a piece of information in front of them and that is what they're running with him a that is -- with, that is not true. Anytime information is received by patient in a context and it is delivered or received with a set of biases.
Information even if it is reliable can distract or mislead rather than help the decision. Information that is all on the peripheral issues for the rest and benefit assessment they actually make it harder to make a decision. Sometimes, if you make it with consent material, there is more chat then we -- chaff than wheat. It doesn't really discuss what they will likely go through. And it's hard to make complex information intelligible to a diverse audience.
There has to be, as you carry out the research, some kind of balance for which they bear and the ballot -- and the balance to that individual person where they may end of the -- benefit. The investigator comes to us with some biases and they may not necessarily be the best person to be the arbiter of this balance. There is a role for someone outside the process to look at it. That is where independent ethical review comes in. And is part of the process. The ultimate arbiter, once it is within what is acceptable, and it is reasonably presented, it is the informed consent.
It is important because the principle management or ethical or respect for persons is a broader term. People suddenly have a right to say what will be there. This is not a particularly new ID -- idea.. He showed that citrus and apple cider were made for scurvy. And he was criticized for experimenting on his Majesty's sea men. But they all knew it was a study. And they were talk to about it.
That was one of his defenses. And then William Beaumont, in 1833, actually got into a bit of a public relations firestorm over some of the course of things -- coercive things he did to keep the patient in a study. He said later that you had have an important question and be going after information that was requiring this experimentation. In the consent of the person -- it was important. Initially viewed it as a contractual obligation. To constrain them to stay in the study. It was only later that the white -- the right to withdraw was important.
With the Berlin code. There were some interesting things, including the delivery -- deliver it -- deliberate--. There has to be some legal standards for when it's okay. And the Prussian government said there must be a release for anything that was done for treatment. Interestingly -- If you are not the director of an Institute, you had oversight in your process.
Walter Reed also did his study -- He wrote, in addition -- if I get a longer talk, I showed the consent form. Although it showed the risk of death, it was double spaced on one page. He said that the special thing about his research is that he was exposing people to risk. And almost no prospect. The risk included the risk of death. And he said he needed different criteria. Maybe the investigators were willing to be subjects. I think that risk is important are people to look at for societal good. And you want to be in the boat.
He was never bitten by one of those mosquitoes, by the way. And it gets more sobering when you look at the ones that become. They published a series of guidelines for conduct research. They were remarkably modern. They had a risk benefit balance for the search. And informed consent. And special concerns for minors. And they might be liable to exportation. -- exploitation. Gets special respect for the dignity and privacy of the subjects involved. And the reason this gets sobering is they rescinded these rules. But he gave us some of the more striking atrocities.
It was designed with the idea of how we researched was applied what we do now, it was interesting that the 10 points in the card -- and a code, -- in the code, it's almost 30% of the document. And the takeout the incident informed to consent. It called for having an appropriate risk benefit balance. Subsequent codes have allowed that it may be waived. Surrogate consent of one form or another may be allowed when the research activity is a direct benefit in the subject cannot give consent.
But most circumstances, the ethical and regulatory norm remains that. And informed consent. The research participation is a gift. If you have that mindset, you can see the participation for the research. Which includes the rights of that person in mind and body. And he used the word sacrosanct. And almost wholly respect. Okay. As I said in my first minute or so, it's actually an elusive goal and they don't always achieve this.
There are several reasons for this. People seeking consent-- You don't always get the best consent of fashion. -- best consent discussion. We talk about threshold. Are they able to give consent. Is it a circumstance the requires consent? If you want a third subcategory, you had asked how formal the process has to be? The second part of the information. What does the person actually need to know to make a decision? And how is it received? The third point is the actual consent. You need to give consent and you're willing to give consent and I'm satisfied with the information and let's do it.
Jeremy Sugarman and Ruth Fagerman -- Fagerman have written quite a bit about this. There are a lot of issues that arise in medical trials. The nature of the risk can be exotic. Someone may not understand what they feel is -- cell is. It could be that the context diverts attention. If they have just come in with new acute leukemia, they probably only come in with one thought in that is "holy shit, I have a life-threatening disease!"
It can be very hard to get informed consent in that circumstance. That is why consent has to be an ongoing circumstance or process. And sometimes the patients are too sick to address it. A maybe, does. -- may be comatose. In terms of the informational issues, there may be a couple of things. It was the informant? -- Who was the informant? Are they knowledgeable? Are they skilled at layspeak? Does be informant know the elements of consent? -- Does the informant know that elements of consent? Is there supporting me which that could be understood in the language -- by the subject?
Is it free of indirect messages? By that, I mean that studies are described as an exciting study and they will be a breakthrough. And you see a number of those. And you don't want to pass up on in exciting breakthrough. Is the information presented in a way that action encourages people to ask questions? We had an investigator at our shop that we had to convince that it was a bad idea to have the patients come in increase of 30 and not have individual sessions to make sure that their questions are answered. They don't want to look dumb asking dumb questions in front of other people.
Is the dialogue structured in such a way that the understanding is tested? If they have their consent am a do they ask questions that people would not be able to answer well if they did get the story? If they ask just what you're going to say next? Sometimes, they are just shell shocked sitting there. Okay. That may have that some of the information they come from other sources. It may not be the only thing they have in the hopper and then to integrate with what you have. And explain any discrepancies. Is a decision actually made before the process begins It is often appropriate spend sometime with them and make sure they a good decision in a reasonable way. We talk about the actual consent -- consent process, is agreement given freely? Either by a group interview or familial pressure? If they are not objecting to the study, are you taking that as consent?
Has the context then pours the -- been coercive? It at that too has the signature on a piece of paper and overvalued? -- been overvalued? You're just checking off we need to be done? Consent is sometimes used as a transit for -- transitive verb. It is not. You do not consent people. It is not a piece of paper. It is not a contract in the ordinary sense, you are making some promises to the patient. It is not a quantum event at a single point in time. A lot of them are so complex that an ongoing process has to be in place. That signature on the piece of paper is that they are buying into it and keep me posted rather than buying into everything in the program.
Other the form is not a process, it is unfortunately common they consent for clinical studies is sought by trainees, sometimes at odds hours, and the trainees may not know the study well and may not be skilled in obtaining consent. It is important that the consent form the good and easily understood document. Often, that is not the case. The problems that we see most commonly looking at consent forms -- there are several.
The study only pertains to step you're going to be doing very must on the road. The study consent form should not spend 80% of its time on the risk of the induction their be about whether they will get in the study were not. That is probably the most frequent example icy in my business -- I see in my business. They tend to be written by highly educated people like positions -- physicians and helped by lawyers. They may be impenetrable by laypeople. We did readability study and we score them prospectively. It was scored a four and after IRB review. We compared these documents with social science and medical science.
They must be readable in the eighth grade level. Here are the grade levels or these consent forms -- for these consent forms. We think it probably include clarity but we don't begin made it accessible to those of limited reading skill. It is not that the scale is impossible.
It is documentation and an information source for obtaining consent. But is it a genuine dialogue study? Now, language is kind of an interesting thing. It has to be understood by the subject and we think immediately of -- and six. It is also be dialect they speak -- the dialect they speak in their language. And it may be spoken differently from other people. And it will be understood, in one sense, but not away that is effective for consent. The advisory committee, as part of what they were doing, look at how me people had been in clinical trials and he knew it. Just to get -- and who knew it. Just to get a feel.
Downwind -- it was one of the plutonium release that is. -- studies. I never knew about that until they published the report. They asked people if they had -- . They thought they had been experimented upon but they had. It depends on whether you are an optimist or pessimist. 85% is about that. That isn't that great either. They asked people to respond
They let -- they looked at the term "clinical trial" and "clinical research" and "medical experiment" and "medical study" and "clinical investigation." We often use these is almost synonymous terms. How real people look at these words. Medical experiment had a lesser sense of clinical benefit. Clinical research very do great deal, according to one of the other terms. It looked good compared to experiment. Look bad compared to study. Clinical study seems pretty innocuous.
Clinical trial in clinical mitigation -- We often come back to some old literature. Some of the most aboard insight happened a long time ago Henry Beecher -- a long time ago. Henry Beecher, many of you may have read his work. In 1966, he called some problems to some of the research issues by revealing a large number of research studies and finding that a few hundred were obviously unethical. He summarized that there were 23 of them. He published those as a -- as an essay in the New England Journal of Medicine. Interestingly, it was accepted but the attorneys told him not to publish it.
These included things like having to these studies with a placebo controller. When it was really known about the rapid eradication. It involved things like injecting cancer cells into elderly patients to see if they would survive. They usually didn't. On and on like that. [ Indiscernible -- speakers words are echoing, making it difficult to understand ] . It is a bit of a danger to assume There is no choice. He also pointed out that if the request is coming from the patient has inherent trust, like your long-standing division, that covers all process. Patients will a seat on the basis of trust Joe Muster any quick -- to almost any request their position may make -- physician may make.
The usual patient one agree a list there is something in it for them. I like this one. There is that "r" word. Responsible. That truly responsible investigator will design experiments that minimize risk. And they will make information available for the subject to make a sound decision about participation. And that it is presented in a way that maximizes understanding. They will make sure that the information is presented in genuine I look. Affording opportunity for discussion. And they will give time for reflection and consultation before decision is required if appropriate.
I am ready to hit my last slide. I often like to close my presentation with the fact that a lot of this is not new. Commitment to a desired research result poisons a product. Went you know what you want to find, you design it differently and choose the subjects differently and you analyze the data differently. The study you are doing in which you're trying to very something is much different than where you're trying to study whether something is really good. Those are not always the same. Second, pride and ambition are just as bad as the commercial perspective.
The desire for respect and promotion. And keeping your data secret guarantees that they will be held suspect. And deprives you of the insight that someone else looking at it may provide. And the researcher owes a duty of protection for the subject. Interestingly, he always called them "patients." Whether he was muddied by the therapeutic perspective all the time or whether he thought it was the challenge, and that experiments, they are not often that we -- that way.
If you're going to send to your data for some sort of -- censor your data for some particular result, you have to know what you doing it. Finally, it is easier to be critical of research that challenges your own police. -- own beliefs. Inc. you.
Sumathi Nambiar, MD
Before going to my presentation, I want to give you my bio. words are echoing, making. I want to keep the presentation fairly general. I hope you find it applicable to these areas that you're working. The order of my presentation is a follow -- as follows. We would have the general considerations, we will spend some time discussing animal toxicities versus toxicities and humans. And we will briefly describe how we do the starting dose for first in human studies. And conclude with a study on safety monitoring.
The main objective is to really assess the safety of the products. Studies tend to be study does -- single dose studies. And we will also be tolerant studies as well. They are conducted in healthy volunteers. On occasion, they have to be done in patients, especially when the drug you are using is expected to be toxic. For example, the cytotoxic agent. Sometimes they have to be done in special populations.
Before one proceeds with these studies, it is important to understand these non-clinical studies. What is the disease that you are talking about for treatment because it is very important. We publish in will be used once it is marketed? What population is it likely to be used as a drug? In the pediatric population? Is this a systemically administered drug product? Another important question --
Do they provide sufficient safety for the child? Will the animal species chosen be appropriate or relevant? Will we be altered identify his target positions for toxicity? By the dose and regulation and administration support what you plan to do in humans? I will give some examples of toxicity that we have seen in non-clinical studies.
These are actually approved marketed drugs. The other was, I cannot give you the name of the drug because they are still under investigation.
In animal studies, the following was noted. Bone marrow. In these findings are noted but the juvenile in animal studies. In phase 3 is trials -- they three trial -- phase three trials, increased frequency of thrombocytopenia were noted. They did have information about the development of this. Be pharmacology section did describe the hematopoietic effects noted in animals. In cases of myelosuppression were reported. This is another example of predicable toxicity. I cannot name the Tom to -- the compound here.
It has been associated with toxicity before they reached the targeted does -- dose, toxicity was reached in the study had to be halted. Animal studies have identified the kidney at the detention -- potential level of toxicity.
Along with the elevation… drug development was in suit. And adverse event were more prominent. The way we can mitigate this information was in the product label, warnings and percussions noted the increased level of toxicity. In the animal toxicology for the product level describe the changes. Know I will go to some of these levels of unpredictable technology. There were two products. Both of the members for which we have a lot of safety information. And abuse were few decades. Both of these products, and now it would cover some resistant organisms. The effect for these battery of animal studies for the doctor 30 noted. The responses of these respective products resulted in phase 1 studies.
In single dose studies, there were no problems. dose When they moved into multiple studies, the subjects developed moderate to severe skin reactions. Such that the product development could not be pursued. This is another example of an unpredictable toxicity. Were subjects are actually -- were subjects -- where subjects were actually hard to describe. They did not identify the node system.
Whether or not that conflicted in the system. Now calculated what is the recommended study. Is just as important that you have the quality of the investigation.. I will skip over that slide. I think you'll hear more about this in the next couple of days.
There are some important steps in selecting the maximum recommended study does -- dose. You take the dose from the animals and put it into an equivalent dose -- I don't have it to go over the calculations but there are tailorable -- tables available that you can derive the human dose. And you choose generally the most sensitive species. Because you have done them in more than one species. And some you have to use the most appropriate species based on the target develop. Once you have tabulated the human equivalent dose, you apply a safety factor. What is a factor -- safety factor? It issue a margin of safety. This is a new compound. The default safety factor tends to be-- . Why does that happen? There could be difference -- a difference in sensitivity. I cannot difficulty in detecting certain toxicities. Like a hypersensitive reaction. Or an adverse event that is very subjective. It's very hard to identify that in an animal see she's. You can have it raises in receptor densities and affinities. And sometimes you do see the unexpected toxicities. There can be a variation between animal species and humans with respect to this. There are some instances where you increase the safety factor.
They are easily monitored and predictable and reversible. This is just a simplified version of the flowchart of the steps that I have discussed so far. The first up is to determine what your know of served at first level -- observed level.
You choose the safety factor. And divide the human equivalent dose by that factor advantage of the maximum recommended starting dose. I will review if you are couple of examples of calculations of recommended safety doses. For this product, the argument that they put forth for the safety factor is less than 10. This was a number of a well-characterized class of drugs. In the toxicity study has the two species that they study. -- that they studied. These toxicities were reddish early -- readily monitorable.
On the other hand, we were a little concerned because even though the apparent class was generally... Members of the subclass -- we had evidence of toxicity.
I will be quick. Taking me to the last part of my discussion once you have reviewed this studies and you have preceded humans and you come up with a dose that you want to use, what are some important considerations you should have before you actually start your study? Again, these are questions that you probably have to ask yourself.
The clinical protocol even to you, is it appropriate? Is it designed a partly to ensure safety and needed objective? Are the starting dose is appropriate -- doses appropriate
In the first week following initial dosing, you need to follow the more closely. Any many to monitor them more frequently at frequent intervals. You also need to remember that you may have to follow them long-term in some cases because of some undetected toxicities.
When you look at the lab test data, as part of your phase 1 study, yet ask yourself about whether it includes an assessment.
You have to have a list of acceptable toxicities which they may occur. You on such a list some toxicities that are certainly not acceptable in may result in altering the conduct of the study. What are the options for safety? Stopping for safety reasons? Sometimes you have to do subject dosing or you have to have additional subjects in a particular cohort. And you may have smaller increases in doses between the words -- cohorts or you may have to exclude certain subjects that you may feel are at higher risk.
I have modified the slide a little bit what you have in your head out. -- hand out. It seems like the older version is up here and it didn't get updated. On September 29, the suit -- new safety reporting where crime is were published in the registry. There was some mention of that. There was also a guidance that was published in October of this year. Which discusses the new safety reporting requirements. In the roles and definitions have changed a little bit. In the requirement have been modified a little bit. The older version has been uploaded here. I apologize. To summarize my presentation, I have given you an overview. And we have discussed the relevance of animal toxicity. And it is important to keep in mind that some of the toxicities that you see in humans are predictable but you have to be prepared for some of the unpredictable toxicities. I have reviewed with you several examples for these tabulations in the importance of safety factors. And very briefly touched upon safety monitoring and stopping rules. I will stop there.