Event id: 1638018 Event Started: 11/8/2010 7: 45: 59 am et douglas Throckmorton, md



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Murray Lumpkin, MD

While there getting my slides are there, I want to say that some of the data you're going to be seeing, some of the examples I'll be giving you primarily come from the world of drugs. I think that shows my own bias, coming out of cedar. I actually had a job that -- now has. I had it for eight years back of the 1990s that the general principles and general messages you'll be getting about this particular issue. Are equally applicable for devices or drugs. So what I wanted to talk to you about, the impact and reality of -- on this enterprise that we are all a part of. I think it is quite common various can unity is to talk about the impact of globalization when you talk about the actual products themselves and the fact that many of our medical products, devices are Biologics or drugs are now coming from outside the more traditional areas that they came from the 20th century. North America, Western Europe. And the part that people do not talk about as much, is the fact that clinical trials data that supports the authorization of these products, both in the night estates in many countries around the world, is actually also impacted by the reality of globalization. I think the first statement here is not here in the medical product discovery, development, manufacturing and marketing promotion and used by consumers practitioners and patients in geographic isolation simply does not exist. In the world of the 21st century. The entire enterprise is affected by globalization as it is something that we are all involved in.

for a data and what we are supposed to do to it. For products that are marketed for the American population and there are regulations that really are four major characteristics and in the same kinds of things that data has to me. Firstly FDA has to be able to validate the data for on-site inspections, if necessary. Not real different. The clinical investigators have to be investigators with recognized competence and training to make the assessments. In doing the clinical trials. The trials have to be conducted in accordance with good clinical practices, ethics Board review, continuing oversight from an ethical perspective.

The data has to be applicable to the US population and US medical practice and one thing people don't realize, these trials do not have to be conduct did under an IND. An IND was for trials. Legally, you have to do it, as the clinical trial is going to be done in the United States. You can put clinical trial protocols that involve foreign investigation sites but those sites do not have to be under IND. We get data from trials outside the United States which have been submitted and those who have not.



I want to talk about for a few minutes, some of the real challenges that trying to see these particular issues, how they affect the job that we do and particularly thinking of going forward, where it appears very want to get more more trials from outside the United States in the first has to do with the ability to do inspections. As I said, where these trials are done is the decision of the company. This is the corporate decision were the reasons we have discussed. Again, this is the Center for new drugs. Shiny over the past decade international side inspections we have had to do in order to validate the data and ensure the veracity of the data in the various NDA that we had submitted during that period of time. This is to give you an idea of where we send our investigators and the bottom line is, we send them where the trials are. It is kind of basically the roll call at the United Nations and he will see some very interesting countries where people have chosen to do their clinical trials and countries that are not surprising that the bottom-line take-home message is, to do the same kind of assessment of the clinical trial data for reducing their US site and over the 30 years that we have been doing for clinical trials, that is the pie chart on your left. We have done 900 to 1000 of these inspections and not surprisingly, a great majority of these were in Western Europe. The other graph, 2006 2008. And a third and fourth involving foreign inspections we have ever done, you'll see that Western Europe goes down in importance and Eastern Europe is much more of an act of site great Asia is much more of an active site and Latin America so it really is Eastern Europe, Asia, Latin America which is where we are saying a majority of of the offshore at this point in time. And it is not just we were doing the inspections. Many of the counterpart agencies have JCP inspectors, particularly counterpart agencies in Europe. The agency that uses the inspectors at the national inspector is in Europe.

We are presently involved in a pilot program with them which involves a great deal under our confidentiality agreements, sharing of reports and preplanning where'er going, trying to use the resources that we have the resources they have to cover more of the clinical trial sites that we are able to do otherwise. As you can see there are many others that are involved in this particular kind of thing. Inspections of having to do more inspections of having to go to many different parts of the world is a very real challenge for one that you see, as far as what we have been able to do so far. Spent the whole challenges the issue of qualifications. You have to be called lies in order to make the assessments that they are making. And for those of us who have grown up in the clinical trials Enterprises, and western Europe, we understand what it means to BPI and the context. We understand what the degrees are in North America and in Europe. We don't understand. We have had the experience of understanding what it means to be a clinical PIM China. What is a man to be a principal investigator in India? Are people registered? Are people license? What are their degrees? What does it mean in the Ukraine? What is amenable of you? These are indeed real challenges and some of the ones that we are working with others on the outside to increase our knowledge but also working with our counterpart agencies in those countries to become better informed and understand how they regulate clinical trials within their own jurisdictions. And what it means to be API within those -- a TI was in those jurisdictions so we can decide if this people are qualified to make the decisions that we have to rely on a trying to figure out what are the data from the clinical trial telling us what is the applicability of the United States? I'm going to touch on ethical issues that have come out because I know Dr. Hammerschmidt and Dr. -- are going to be talking with you about ethics and JCP. But the whole world of foreign clinical trials have brought a whole new dimension into some of the ethical discussions, within the broader committee -- community. This goes to a issue of individual ethics and which we tend to think of historically North America and Western Europe to the whole -- is ethical to do a clinical trial? If indeed the medicine is not going to be made available to the participants after the fact or if it is not going to be made available to the community in which the clinical trial was done after the fact and the reason this is important, is not just for the sake of arguing the ethics, but we legally cannot use data from a trial that is deemed to be unethical. So the question of some of these trials is one that is quite challenging. Also, one of the clinical trial design, the standard of care, the imperative control plot -- trial. If one chooses, because one can do a new treatment arm, because certain jurisdictions, things are not available, to use the data in the United States is that clinical trial design could not ethically be done in the United States because no treatment would not be unethical trial design for us. Again, very challenging and interesting. And the final one has to do with the concept of consent in different social context that we are used to Western Europe or North America. We no trials have been done in countries where men and women to have the same legal status. Without clinical trials are being done and they are made by elders in the community and what does that mean for subsequent consent by people where your elders had made an overall community decision? There are some very interesting ethical issues that come out of the reality of the clinical trials becoming a global enterprise. And as I said, the issue is, do you judge it by the ethical standards of the committee or do you end up judging it by the ethical standards here questioned the final challenge that I will spend one or 2 seconds on, is the final issue of saying, if you choose to do your clinical trials overseas, how do you then make the case that those data are applicable to the US population and the US medical situation, this is not a new issue, there issues that have to do with intrinsic factors such as generic issues between populations are within a population but primarily, what we are seeing, extrinsic factors, underlying illnesses compared products.

Therapies and particularly, cultural issues that come into some of these trials were rare looking at different foods, herbals, and trying to say, what does the state of Maine? And infectious disease, I have to say, it is not always the people that aren't the same. Often as the microorganisms that are the same in different parts of the world and this is just an example from an antiviral agent were somebody generally got it very wrong in trying to develop a product to ultimately market in the United States because of the different viral genetics in different parts of the world. So actually, the end of the day, the companies make the decisions of where they want to do these trials but our message to the companies is, that is fine, you can make these decisions for you have got to make the case to to the database and results are valid, they're ethically obtained, they are complete and that you are able to predict the utility of the product in the US population in the US medical system based on the data that you have a lot of interesting challenges. You see where it is going and I look forward to talking with you about it later. Hopefully. Thank you very much.



Leslie Ball, MD

Thanks for are you loading up my presentation? I will try to move rapidly. Perhaps we have a few minutes for questions at the end. I wasn't here in the beginning saying they have gone through this but to help me understand how many people in the audience a clinical investigators question mark a big chunk. How many people represent a sponsor. Sponsors? How many represent institutional review boards? Sometimes there is overlap anything that I missed? Okay. We will get started. The outline of my talk. I will be talking a little bit about historical perspective and clinical trials on how that impacts will clinical investigators are responsible for an regulations that have requirements for clinical investigators conducting FDA research. I will provide a couple of case examples at the end and provide suggestions on how to stay out of trouble.



Several weeks ago we honor Dr. Frances Kelsey. Does everybody know Dr. Frances Kelsey and what she was responsible for? The cast upon others honored for contributions and I think it is so important with respect to this course, many of the regulations that are currently in place stem from some of the activities that Dr. Kelsey kicked off. She was responsible for denying the application in 1960, 15 years ago -- 50 years ago, and some of the activities that went on around that time, there was a series of congressional hearings, that culminated with amendments to the food drug and cosmetic act and a picture on the right hand bottom was up to her Kelsey testifying before Congress back in the early 60s. So I will speak very briefly because some of the regulations that clinical investigators are responsible for today stem from the strategy. In 1961 in 1962, the drug for the mine was sold to a drug is a hypnotic but it was investigational in the US. It was so common that it was actually referred to as West terminates babysitter. -- West Germany's babysitter. At the time, they started noticing an epidemic, a deformity called focal million. More than 10,000 children in 46 countries were affected by this deformity. But there were only 17 children born in the United States and Dr. Frances Kelsey, the FDA medical officer who was -- approval. They kept asking for more information and more data. What was apparent at the time, around this tragedy, there were loopholes in the food drug and cosmetic act of 1938. Companies could distribute unapproved drugs for experimental purposes better to not require notification to patients that the distribution was investigational. It did not require companies or doctors to keep track of the distribution. In fact, win -- was distributed throughout the early 60s, after the disaster became apparent in Europe, was difficult to track down where the fillet him I'd was. -- Thalidomide was. It did not require records to be kept and do not require demonstration of the drug effectiveness. So in 1962 the Harris amendments and the Food and Drug Administration amendments come you heard about this earlier today. Relates to the responsibilities of the investigators. One of the most important things is the approval of new drugs is going to be based on the efficacy and safety. There is often a -- also expanded authority, FDA could inspect company records regarding the development and clinical testing of new drugs. There is also the requirement that FDA had to be notified before clinical trials could be conducted. There is expanded rule-making over investigational new drugs and authority over clinical trials for this also gave the FDA the power to help clinical trials. Within the framework that was enacted or passed after the food drug and cosmetic act, amendment of 1962 was passed, it really is responsible for the current clinical trials in the US. And it provided investigators had to be adequate and well controlled and investigators must be identified by scientific training and experience. It provided for recordkeeping requirements you have today. And informed consent.

So within the overall legal framework for the conduct of clinical trials, there are four important things that clinical investigators have to keep in mind. First these -- food drug and cosmetic act legislation and section 5 statutory authority for FDA oversight of the investigators to test safety and effectiveness. The statute is not something that we, that the world for the FDA regulators live every day, it is the federal regulations. The regulations are promulgated under the act and describes FDA authority in more detail the conduct of investigations. Includes responsibilities for sponsors as well as investigators. The third thing investigator should keep in mind is in a guidance document.

Is important to remember that guidance is advisory only. They don't date actual requirements that they are meant to assist clinical investigators and sponsors and trying to understand how to comply adequately with the regulations. And how many people have assigned a form FDA 1572? Is that familiar? It is good to know because this is really your Bible as well as your investigators. By signing this form, the investigator agrees to conduct the study with protocol, applicable regulations and adequate supervision of the study. So another terms of developing safe and effective drugs, without approvals are risk-benefit decisions. No drug is currently 100% safe. What we do rely on is his data from clinical studies that have been properly designed, conducted, and analyzed and reported to the FDA. This whole process relies on public participation and public confidence in the clinical trial and applied -- and pricey ultimately, approval is based on FTA scientific review of the data is collected by the clinical investigators are sponsored to the two sponsors and submitted I sponsors. So Dr. Lumpkin mentioned this idea of good clinical practice and it is important to remember, it confused me when I first came to the agency, good clinical crack the adequate medical care. Fact, there is a very specific meaning for good clinical practice. In research and is not the same as good clinical practice and caring for patients. For example, FDA regulations have specific requirements for following the protocol, recordkeeping, drug accountability and things that you might not have to do to the same extent in clinical practice. And what are these regulations intended to do? They are designed to ensure the quality and integrity of the data in the clinical trials as well as ensuring that the right safety and welfare of the centers have been protected. So we alluded to the guideline, guidance for industry, chemical practice and if you want to have the standard definition for good clinical practice, it is the standard design conduct performance, monitoring, biking, analysis, clinical trials, and provides assurance that the data and reported results are credible and accurate and the rights, integrity and confidentiality of trial subjects are protected. So there is good news and bad news in terms of clinical investigators. The good news, one area in the practice of medicine were clinical investigators are still in charge. But the bad news is that clinical investigators are in charge and the ones that are held accountable if things go wrong out of sight.

FDA regulations permit sponsors to delegate responsibilities to contract research organizations. But they do not permit clinical investigators and responsibilities to -- site management responsibilities and some are steady staff. The new study investigators overseeing a clinical trial something goes wrong, and it was the conduct of a study -- is a clinical investigator to be held response under FDA regulations. Indeed include morning -- warning letters that are posted on the website and the advent of Google became a powerful thing and we get calls from clinical investigators, and we are applying for privileges and a new hospital and Google and they are coming as a powerful motivator. And in terms of clinical investigators who failed to comply with investigations and significant compliance of FDA regulatory research, they can also be a broader penalty and it means that the clinical investigator cannot be involved in any aspect of the trial, including the sub investigator. In addition, there can be criminal prosecutions and prison time as well as mine. In the cases that I mentioned, will include examples of that. Within the regulations, what is a clinical investigator defined as? The FDA regulations define a clinical investigator as in investigator who conducts a study, presenter immediate directory is any subject. In the event they clinical investigation is conducted by a team of individuals, the investigators responsible leader of that team.

And so, have your signing in 1972, it is important to look at the various responsibilities that are listed under them. I have abstracted the most important ones and the first one, but I wanted to emphasize is that there is an acknowledgment the clinical investigator will be acknowledging that investigator is signing with 1572 investigator commits to following the protocol to ensure the person assisting in the study is important for obligations and that the subjects are informed that the drugs are being used for investigational purposes, there is also a commitment to following the regulations with respect to informed consent. There is a commitment to maintaining adequate and accurate records, and having them available for inspection if necessary.

There is also a very broad statement that compliance with other requirements within the IND regulations.

Who terms of investigative responsibility, the rags to find some general responsibilities, there is a requirement for control of the investigational drugs, the investigator should know where the drug has gone, where it is being stored, and there is a requirement for recordkeeping. And other data pertinent to the investigation. And why is that important? If FDA is in charge of trying to make a decision on the safety and efficacy of the drugs, if they go to a site and the records are no longer there. It makes it hard for us to validate the information and submitted a new drug application. The investigator also has responsibilities for progress reports and there are specific requirements for reporting adverse events and a clinical trial. Both reporting that bad verse at events to the sponsor and the unanticipated problems, to an IRB. Then there is a responsibility for submitting accurate information on financial disclosure. So, briefly mention the investigator disqualification and this is provided under the regulations 21 CFR three 1270 and this is really a circumstance that only is invoked under pretty rare circumstances. Where there is repeated and deliberate failure to comply with the FDA regulations. And in many cases, there is a submission of false information and does not have to involve fraud or fabrication. It may be a situation where the clinical trials conducted so poorly that clinical investigation for disqualification are provided notice of this may have an opportunity to explain in an informal hearing, there also may be a more formal hearing in front of an administrative law judge in this may result in an eligibility to receive investigational drugs. So what are responsibilities? I'm not quite shocked about sponsor responsibilities but it is important to understand there is a distinction and you're serving as a sponsor investigator you are responsible for both the clinical investigator responsibilities as well as sponsor responsibilities. Sponsors are responsible for selecting qualifying investigators, providing them with information they need to conduct it best to geisha properly insuring proper monitoring of the investigation. Ensuring that the investigation is conducted according to the investigational plan. Maintaining an effective of IND. And making sure the participating investigators are promptly informed of any significant adverse events. This particular slide at the bottom, there is a link to the FDA guidance on clinical investigator responsibilities. And outlines expectations for study oversight. Specifically, clinical investigator is responsible for appropriate delegation of study task, responsible for appropriate training -- training of the steady staff and appropriate supervision of the ongoing studies as well as appropriate oversight for third parties in the studies. That might involve other labs or vendors that provide services for that site.

This guidance on investigator responsibilities also outlined the expectations for the right safety welfare and safety of subjects. There is provision for reasonable medical care for issues related to study participation. For example, if the individual experiences and adverse event, while in the study, there is responsibility to facilitate care for other health issues that might arise during the study as well as provide reasonable access to needed care and exposing, avoiding exposure of subjects to vote risks. The FDA also has responsibility for reviewing information collected by the clinical investigators and submitted by sponsors. The primary objectives, and revealing an ING are, in all phases of the investigation there is a consideration on whether or not the safety and welfare of participants is being protected. In phase 2 and three, there is a specific requirements under regulations to ensure the quality of the scientific evaluation of the drug is adequate and to permit evaluation of the safety and effectiveness of the drug. So as part of this process, FDA will review an original IND submission and any information amendments to the IND and also, we will review the IND safety reports and annual reports submitted to the IND.

The FDA, in the process of the review, can institute to something called a clinical hold. They can be several situations that may prompt the FDA from placing a clinical hold on an ongoing clinical trial. The most important is finding that there may be unreasonable and significant risks of injury by participation in the study. This can be applicable to any phase of clinical trials. There also, rare circumstances where clinical holds can be placed in a clinical investigator is not qualified by scientific training or experience. I can think of one situation where a medical officer in the Center for biologic, as part of a clinical hold, and that putting a site on clinical hold because the clinical investigator involved was a psychiatrist and he had developed an investigation new drug to test on patients were inflammatory -- for me to and this project their psychiatrist was not qualified to oversee that particular clinical trial. The other reasons that investigators, investigational new drug, a study may be placed on a whole because the investigational pressure is incomplete or misleading or erroneous.

BNT does not contain sufficient information to determine what the risks are to subjects. And for phase 2, and phase 3 studies, it is fairly sufficient to meet its stated object is pretty can be placed on hold. I'm going to segue into a few minutes about FDA inspections. The first inspection of a clinical investigator occurred in 1961. In Silver Spring Maryland, you ought miles from where we are today. And this particular situation, the investigation was found to have made up all of the data for all the studies they had conducted at the kitchen table. He had been producing study results for sponsors. Around the same time, in the 60s, there was a MER 29, a cholesterol-lowering agent. It was discovered after was approved, it is a significant safety concern and when they are found guilty of falsifying data and toxicity. And these two events, let's regulations FDA had a responsibility for ensuring data responsibilities to data inspections. We're expecting clinical investigators, sponsors, GOP facilitators and regulatory requirement to record you can investigate a new drug application for cause inspections as a result of the complaint. And surveillance inspections, IRB inspections generally done on a rotating basis.

So what are common mistakes are risk factors for noncompliance? These are things that we have called -- pulled from our most common findings for noncompliance may include poor supervision and training of study staff. Insufficient investigator involvement in the steady contact. Inappropriate delegation of the tasks in the clinical trial to unqualified persons. Failed -- failure to adequately protect the rights of subjects. One thing that we found was an overworked clinical investigator in the study staff, there may be too many subjects, enrolling them too quickly, too complex and study protocol was large number of data points that are being collected. And sometimes we see in clinical investigator who is quite honestly connecting to many clinical studies at one time.

So let's move on to a couple of case studies. This particular one, I don't want it to end up on the front page of the New York Times, this was one that was back from 2005. The gentleman and the taxi it out in the middle, was a patient who died as a result of their participation in a clinical trial. The individual, his picture was on the left-hand bottom, was a steady coordinator who was masquerading as a physician. And he was inappropriately enrolling subjects as well as possible by information. So, in this particular case, it is a push for the clinical investigator who failed to provide adequate and supervision of the clinical investigation in the coordinator enrolled in eligible subjects into an oncology trial at the coordinator altered documents, created fraudulent case report forms to make the subjects appear eligible they were not. There was data manipulation that was pretty late and -- blatant and should have alerted a clinical investigator. The subject that was a knowledgeable and was enrolled had renal and liver function, was diagnosed in as a result of this.

The steady coordinator did not -- receive prison time, 71 months, and was barred from any future involvement in FDA regulated research. The clinical investigator who had oversight of this clinical trial received a five-year probation prison time and had to provide $500,000 in restitution. To the defrauded drug companies and he was disqualified from serving as a clinical investigator.

Moving onto a more recent case, this particular press release was from August of this year. This clinical investigator played guilty in federal court before -- 15 counts of failing to prepare and maintain adequate records. With intent to defraud and mislead in connection with clinical trials, to evaluate efficacy of adolescence and children with excessive compulsive disorder. These particular bullets I took exactly from the press release and this particular defendant had agreed to conduct the studies and accordance with the protocol, only to change the, make changes in the protocol, and the safety of the subjects, the defendant also agreed to personally conduct and supervise the investigation and maintain adequate records. The trial also noted the 1572 and what they had agreed to.

Says more detail about the particular case. But this investigator was sentenced to 13 months in prison to bring current with other charges that she had pled guilty to on Medicaid fraud.

So, after all that bad news, I end with a couple of suggestions about how to avoid getting into trouble. They're a couple of key points here. A couple of points to emphasize, the need to -- the conduct of the study. To create systems that limit the opportunity for errors. One of the things that we have noticed, increasingly the protocols are more and more complex. And it was to collect for more information. In light this provides a lot of problems at the site. Simplify the protocol is possible and the outcome assessment of standardized assistance and forms were possible, use validated instruments for collecting data and key protocol amendments to a minimum but check if you are making amendments against the case report forms to make sure accurately collecting information that adequately training at the site is critical. So you can -- to make sure the study staff know what they're responsible for. They also have a disaster plan, a backup and Hurricane Katrina caused a lot of havoc among clinical trial sites have a disaster plan and make sure that it can be implemented.

It is a clinical investigator responsibility, as well as a sponsor responsibility to make sure they are qualified clinical investigators involved in stuff and training. And make sure that the study staff are not performing tasks that they are not qualified to do. For example. A coordinator with no medical training assessing adverse events or -- events.

It is important to fully understand the scope of responsibilities and the protocols are in best interest of the patients and monitoring for subject safety. If the clinical investigator, problems with the way the protocol reads, consider amending the protocol or steady treatment under emergency treatment usage doesn't have the same specific requirements of the steady conduct in terms of actually having to follow the particular protocol. I think it is important, also to make sure they have a system for implementing and implementing corrections in correcting problems in real time and not waiting until the studies are done. Pay attention to monitoring queries and respond promptly for systemwide correction. So define one problem, but one particular patient, make sure it is not a more widespread program were protocol monitoring needs to be adjusted. This is my summary slide in the key messages are the clinical investigators play critical role in ensuring high-quality studies.

Good care patients is not the same as good clinical practices, GCT, in research. It is important to have a clear understanding of what responsibilities are in FDA regulations if you are to serve as clinical investigator in FDA regulator trial. Ultimately, at stake is public confidence and participation in the clinical trials and the availability of safe and effective drugs.

How would we do that? Somebody serving as clinical investigator or a sub investigator?

I think that is a problem. FDA would, that would not be something we would find acceptable -- acceptable and with respect to that particular, there are some variations about who can conduct medical care. And that is in the United States dictated by state, the state will say, does not just a physician, other individuals that can provide medical care and the undue degree outside the US, would be aware of, to conduct physical examinations of subjects. That would not be appropriate. I think with respect to your last point about individual owning a phase 1 facility, I think there are no requirements that somebody who is conducting research can't own the facility. But in this particular scenario, he could not be functioning as an investigator or sub investigator and conducting medical examinations and so on.

I think that is a scenario. I'm trying to think of one regulation -- what village that would fall under I think that is outside the scope of FDA regulations on terms of regulatory requirements, that would actually be an ethical consideration that I think we bear some degree of reflection about what would be appropriate in terms of the particular conduct our enrollment of the individual in a clinical trial.

I'm sorry, the question was, an individual, as a donor to a site or an institution conducting clinical trials of the individual subsequently wanted to enroll in a study, whether or not there was any problem with that. My answer, does not, that is not a scenario envisioned by the FDA regulations but it would be something ethically and perhaps even legally to consider at the institutional level.

Is a clinical investigator, we go to investigator meetings all the time that we set for countless GCT lectures, which all essentially say the same thing. And while this fundamental abstract principle is important, as an investigator, what really would be very helpful to me are more specifics. What does the FDA really want us to do as far as how we monitor and follow up an adverse event? Understand why your guidelines can be very abstract very general but has investigator, sometimes we would like more specific guidelines for is there somewhere we can go for that? That is why I'm here today. Is there somewhere we can go for, how do you not just become adequate? Have you become excellent at what you're doing?

That is an excellent question. -- That is a good question. When we write guidance documents, we are always trying to balance between being too explicit inner guidance and -- and our guide us to take away individual autonomy versus being explicit in the to provide the guidance that someone like you would like. There is some guidance, related to adverse event reporting that is coming out. There is a new rule that has, that will be implemented in March of this year in the guidance document that safety reporting is quite explicit and includes things like FDA does not want investigators to do with respect to safety reporting. That is the type of thing that as we move forward in guidance documents, we keep in mind the are you familiar with the guidance document it on the FDA website because generally, to provide examples of best practices. How to implement that.

-- Talking about keeping the documents. We know the CRS, forever, what about regulatory binders, can they be electronic. First of all, does the FDA allows and secondly, do they have to be compliant?

When you're talking about electronic regulatory binders, are you talking about, we go to do an investigation on the clinical investigator in the documentation related to IRB review and monitoring of the site and that kind of thing? The main concern we have, and we can address us as well, we are spearheading the effort to provide additional guidance on electronic source documents. And the guidance is still under development. It is not under development yet. But what is required in terms of the site, I think the important thing is, we will make sure has investigator has responsibility for that what would you like to get, at the site, is the disc from a sponsor, the clinical investigator had any input into.

We recognize that keeping voluminous paper records of the site, in the future, that is not going to happen. I think as long as there is an assurance that the investigator signed off on the study in

Does that answer your question?

There was some additional guidance back in 2004 that talked about radio story discussion is hard -- regulatory discretion. As far as important. And we're you may get in trouble for part 11 noncompliance. It is really in respect to data for safety and advocacy. We are more than likely to look at the rules -- within the electronic system. Been actually trying to ensure compliance. I hope that answers that question. Great.

I believe my e-mail is on the first slide. If you have any questions that have not been answered today, I am happy to answer them. In terms of best practices, we get a lot of questions about this. And we get this at the FDA.



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