My name is Robert Bissonnette. I'm a dermatologist from Montreal, Canada. I've been active as an investigator in clinical research for close to 30 years now. I've been audited several times and I've been inspected by both FDA and Health Canada. This is my disclosure slide. I won't be talking about any drugs or products today, but I served as a consultant and obviously as an investigator for several pharmaceutical companies and biotech companies. Let's first talk about audits. Audits and inspections are different. Audits are conducted by the sponsor or the clinical research organization helping the sponsor manage the study. Inspections are conducted by regulatory authorities such as FDA. What are the objectives of an audit? Audits are done to assess site compliance against good clinical practice, applicable regulations, and site standard operating procedures. Audits are also conducted to verify the CRO and sponsor oversight, including study management and clinical monitoring activities. Therefore, the auditor will look at both what has been done by the investigator, the site, and the CRO sponsor. How are sites selected for an audit? First, high enroller sites are more at risk of getting an audit. And this is for several reasons, including the fact that high enroller sites tend to be inspected by health authorities. In addition, the impact of a high enrolling site on the overall data is much more important than a low enrolling site. If your site has been able to put 30 or 40 patients in a study, the impact on the overall data is much higher than a site who only enrolled one or two. If it's your first participation in a clinical study with a given sponsor, if you're starting in clinical research, if you're starting in a new therapeutic area as a clinical investigator, then your risk of being audited are high. If you make mistakes, if you're different from other sites, if you have more protocol deviations or violations, if you're an outlier based on what the clinical research organization or sponsor is monitoring related to safety or efficacy, then you're at higher risk of being audited. Audits are different from inspections. Audits are usually less formal. They're more collaborative. They're performed by a quality assurance representative from either the sponsor or the CRO, and usually they have no impact on health authorities. We'll see in a few minutes that they could, but this is very rare. So, what's the outcome of an audit? Some, but not all sponsors, will provide a written report. However, all sponsors will provide a normal opinion, a verbal report, at the end of an audit. There's usually an exit meeting where the investigator is invited to attend and the auditor will share his or her impression and areas where improvement is needed. If important GCP or protocol violations are noted, the sponsor may stop enrollment or even terminate the study at your site and may inform health authorities. As I mentioned before, usually the outcome of an audit is kept between the sponsor and the investigator, but if during the audit several important violations or deviations are noted, then the sponsor may decide to inform health authorities and the ethics committee. Now, let's talk about regulatory inspections. As I mentioned before, these are conducted by regulatory authorities. If you practice in the U.S., it will mostly be FDA, but other regulatory authorities can also come and inspect. What are the objectives of an inspection? First, to verify subject safety and data integrity, to ensure that a data supporting and marketing authorization is accurate. And it could also be sometimes to investigate cases of serious breaches, including serious safety issues, fraud, misconduct, or respond to a complaint made to regulatory authorities. So, for example, if a sponsor alerts FDA of serious issues going on at a site, then the site might get an inspection. If a patient complains to FDA or regulatory authority, then the site might get an inspection. There are three types of approach, a system approach, a data approach, or an investigative approach. The system approach is usually used when the inspection happens during the conduct of a study. For example, Health Canada likes to inspect trials during the conduct of the study. So they will look mostly at how a site is following GCP, how a site is following the protocol, which systems are in place to ensure quality of the data that is currently being generated and that will eventually be submitted for marketing authorization. The data approach is different. This is usually used when the inspection happens after submission of marketing authorization. FDA, for example, often use the data approach. So they will come to a site after they have received marketing authorization. And one of the reasons why they do these inspections is they want to make sure that what they receive in terms of data from the sponsor about patients seen at your site is exactly what happened at your site. So they will look at your search documentation to make sure that all the adverse events have been entered in the CRF and eventually sent to FDA to make sure that the data that is in your source is what has been sent to FDA and to make sure that everything that has been sent to FDA is really in your source document. An investigative approach is used for a forecast audit. So if FDA or a regulatory authority receives a complaint, then they will use an investigative approach when they do an inspection. How do you prepare for an inspection? The first rule is to always be inspection ready. You need to have up-to-date investigator site files, standard operating procedures, calibration logs, deviation logs, CAPA documentation. If you have a person that is in charge of your site, a non-physician that is in charge of your site, make sure that this person organizes on a regular basis quality controls of those documents to make sure they're up-to-date and they're ready. What to do upon announcement of an inspection? The first thing to do is to contact the sponsor immediately. So the inspector will inspect your site, what you're currently doing or what you have done in the past, but they will also look at what the sponsor has done. In addition, sponsors can help you prepare for an inspection. If you work with a site management organization, contact the quality assurance or administration department. They're used to inspections and they can also help you. The same thing applies if you work in an academic environment or a hospital setting. You need to inform your study team, specifically your co-investigators and the study coordinator, that there will be an inspection. Also, ask your staff to locate all the documents related to the clinical trial. If the clinical trial is ongoing, that shouldn't be too difficult, but if the trial was completed two or three years ago, you may have sent some or all those documents for archiving. So please make sure that all are available. Open the boxes. Look at the source documents. Make sure you have a copy of the CRFs. Make sure that if there's any data on a USP key, it's really readable. Investigator site files, pharmacy log, lab logs, all these must be identified. Read the protocol again. This applies specifically if an inspection is conducted in a trial that was completed several years ago. You might get questions from the inspector and it's always good to have the protocol fresh in your mind. Decide who will be the main contact with the inspector. So the best strategy is to have one person who will be with the inspector all the time or available all the time during the inspection. That could be the study coordinator. It could also be a quality assurance person working for your organization, SMO or hospital. Identify patients who have had serious adverse events. Inspectors tend to focus a lot on safety. So when they come to your site, specifically if it's an inspection that is conducted after the trial ended, they will come with a list of patients who had serious adverse events, and they will probably look at the charts of all those patients. So make sure you spend time reviewing those in advance. If you have time, you may organize a mock inspection. Sponsors and the QA responsible for SMO in your organization may help organize that mock inspection. It's always good to practice the person who will be the main contact or study coordinator. If you never had an inspection and had a few audits in the past, it might be good to practice you as well. Train your staff on what to do and what to expect during the inspection. In addition, you should review the regulatory agency policy for FDA. This refers to the Bio-Research Monitoring Compliance Program. Review source docs of the first patient. I always suggest doing this. I always do this myself because the first patient is usually the one where we tend to make more mistakes because some of the documents generated by the sponsors here might not be that clear. We don't know the study that well. It's our first patient. So inspectors tend to always have a look at your first patient. How to interact with the inspector. Always be polite and collaborative. These are human beings. They do an important job, not always an easy job. If you're polite and collaborative, it may make a difference. Do not try to hide anything. We all make mistakes, sometimes small mistakes, sometimes bigger mistakes. What's important is to understand that we made a mistake, to be able to explain why we made the mistake and what we put in place to mitigate the effects of the mistake and to make sure that the mistake won't happen again. Keep your interest short and focused on the question. And this is something that the main contact person, the study coordinator, must do as well. So inspectors come in to inspect a study. But if either your coordinator or yourself say things like, Oh, we've had that problem in that other study as well. The inspector may decide to stay a few more days and inspect the other study. So keep the answers focused on the question. Do not hesitate to ask the auditor to rephrase or explain. Never try to answer a question you don't understand. What type of questions could you expect on the first day? It varies from one inspector to another. But they often ask questions about the number of patients that were enrolled, if any patients had serious adverse events, how many patients had adverse events. They'll ask you where you practice, what type of practice you have. Do you have academic hospital appointments? How many days per week are you on site and how much time you devote to clinical trials? They're trying to see if you have sufficient time and devote sufficient time to clinical research to really have a good oversight of the study. In the same vein, they'll ask questions about how many studies are conducted at your site and how many studies you're PI on. And it has to be in line with the amount of time that you devote to clinical research. They'll ask you if you work with co-investigators. They expect you to work with co-investigators to be able to cover for you when you're on vacations or you're at meetings. And they will probably ask you questions about how you keep them informed of new developments during the trial. And these could be protocol amendments, SAEs or others. During the inspection. So upon arrival, it's extremely important to train your staff or do it yourself if your staff has not done it, to require identification from the inspector. So patients, when they sign in from consent, they consent for an FDA or a reg authority inspector to have access to their source doc, to their medical chart. However, as you all know, this doesn't apply to anybody. So if the inspector comes in and the staff is a little scared, they put them in the room and they bring the binders immediately without asking for identification, you will probably get a observation from the inspector that this is not correct. Bring the inspector to a quiet room. Again, being polite, collaborative, having the inspector in a quiet room may help. Avoid leaving the inspector to work in the waiting room or in a cafeteria. Be available. So the inspector will like to meet with the investigator on a regular basis. This is usually at the end of the day. So you will see all your patients. And at the end of the day, it's expected that you will be able to see the inspector. Be open, honest. Do not provide answers if you're not sure. One thing that is important is to be able to debrief with your coordinator before talking to the inspector. So at the end of the day, your coordinator will probably have interacted a lot with the inspector. He or she will know what the inspector looked at, what the questions were. There were issues. So don't get into the room before talking to your coordinator. Always review a document. And this applies to both the investigator and the main contact person, the coordinator, before bringing it to the inspector. On the last inspection day, the inspector will organize an exit meeting and will share his or her impression and inform you of the outcome that will be recommended for your site. So this will not be decided on the last day. This is decided by a group of people working for the regulatory authorities. But on the exit interview, the inspector will let you know if everything went really well, that you shouldn't worry, everything should be OK. Or if there were numerous major issues that you might expect an outcome that is not the one you would like to receive. Following inspection, you will receive an official letter from the regulatory authorities informing you of the outcome. This is what the FDA does, and it may take a few months after the op. So what are the possible outcomes? One is a no action indicated. This is what you want. So everything was fine, in line, sufficiently in line with what should be done. So that no action is indicated. Voluntary action indicated, the FDA will issue a 483 form. When this happens, every time you have an inspection, at the end of the inspection, once the letter has been sent to you, your name will appear on the FDA website with the outcome of the inspection. So if you receive a 483, it will be on the FDA website. And finally, you could also have an official action indicated, which means that the FDA may issue a warning letter or may take immediate enforcement actions, including terminating enrollment at your site or terminating participation of all patients at your site. So how to prevent inspection findings? How to make sure that you get a no action indicated? Be involved, be involved in the study. Don't let the study be run only by a coordinator. And write, I'll come back to that, write in the source doc. Ask your clinical research associate, the CRA that is monitoring the trial, about the study specific monitoring plan. Few investigators do this, but it's important to know that some sponsors will ask the CRA to look at all the data from all patients. So if you have a very good CRA monitoring your site, you have a very good quality control process in place. However, some sponsors will ask the CRA to look at one patient out of three or even one patient out of five. If it's the case, then you might want to ask your study coordinator to do a little bit of quality control to spend more time on the various documents to make sure that everything is good. This is especially important if you have a new study coordinator working on a study. You might want to ask a more senior study coordinator, somebody you know well, to do quality control on some of her charts. Hire experienced coordinators and reward them well. In my opinion, an average investigator working with a great coordinator will generate data of higher quality than a great investigator working with a very poor coordinator. We as physicians tend to be involved mostly with evaluations of safety and efficacy, but most of the documentation is generated by the study coordinators. So if the study coordinators is not very good, then the overall quality of the documentation, which is what the FDA and other reg authorities will have a look at when they come to inspect your site, will not be that good. Reward them well. You don't want to have a high turnover in that position. Invest in top quality source document templates. So if you do research in the same indications over and over, you may want to develop these internally. You should also consider joining a research network. They tend to provide good source documents because they write it for all the sites in their network. Make sure that non-subject related activities are well performed and documented. So as I mentioned earlier, we tend to be mostly involved in safety and efficacy evaluations. Some documents like product accountability logs, subject identification log, lab calibration logs, we either don't tend to see or we see at the end of the study. So make sure that somebody at your site is looking at those on a regular basis. Somebody does quality control to make sure that the quality is good. Detailed progress notes are key. So the inspectors are expecting to see involvement of the investigator by their progress note. If they only see signature and date for all patients, that's not good. That's not appropriate. This could be okay for a patient that is doing well and has no adverse events. But when patients have adverse events, specifically if they have serious adverse events, when there are important deviations, when patients don't take the medication according to protocol, they want to see that the investigator was involved, was aware, and did something. Make sure all consent forms are signed. Complete and accurate. Inspectors usually tend to look at many or all of those. Written evidence of sponsored decision is very important. If you discuss with a medical monitor eligibility of a subject, if you discuss adverse events, management of a subject during the trial, it's important to document this. If you've interacted by email, you should print the emails and add them to the source doc. If you've interacted verbally with the sponsor representative, the medical monitor, you should document this in your notes, in your source document. If you regularly work with sub-investigators, ask your staff to show you charts of problematic patients. So those with serious adverse events, those with important deviations, patients who don't take medication according to protocol. And just write a note. It could be just a few words, just that you've discussed the case with a sub-investigator, but this shows that the investigator has oversight in the study. And finally, make sure somebody from your site reads the patient chart before finalizing medical history. So we often tend to enroll patients from our practice. Many investigators will only enroll patients from their practice. So we have a lot of documentation on these patients. And patients are not always good historians, as you all know. So we need to make sure that what a patient said at the screening visit is in line with what's in his medical charts. So it's important to review this, to have a good and thorough review of this. So I want to thank you all for your attention and wish you good luck.

clinical trials

audits

inspections

regulatory compliance

data integrity

inspection readiness