Adherence to Standard Operating Procedures (SOPs) to ensure Good Clinical Practices (GCPs), in conjunction with the Food and Drug Agency (FDA) regulations, is essential to running a successful trial and minimizing FDA findings post inspection. Proper preparation for an FDA inspection requires an intimate knowledge and understanding of the regulations, as well as awareness of the repercussions – including Form 483s, warning letters, or worse – if your organization is not up to code. Without prior experience with real-world inspections, it can be difficult to know if your site will pass the agency’s scrutiny.
I spoke with Janet E. Holwell, CCRA, CCRA, TIACR clinical research consultant, to understand why many clinical trial professionals dread FDA inspections, and how they can be better prepared to deal with one and its potential aftermath. Janet will be facilitating the upcoming Xtalks eCADEMY on FDA Inspections on December 9th, featuring the simulated environment of a clinical trial response team. This highly-interactive, virtual workshop will give participants the opportunity to be engaged in real-world scenarios, where they will be tasked with solving the dilemmas experienced by both sites and industry, when faced with discoveries from regulatory authorities or auditors. Sign up today and take the first step to ensuring FDA inspection success.
Do you think you’re prepared for an FDA inspection as well as what comes after? Take the Xtalks FDA Inspection Quiz and test your knowledge!
What do you think are the top fears associated with an FDA inspection?
If people have not experienced an inspection before, there is fear of the unknown, and they are unsure of what to expect. That is number one. Number two is fear that they’ve done something wrong and that there are going to be repercussions. I always advise that sites or sponsors really have nothing to fear as long as they’ve followed Good Clinical Practice (GCP) and adhered to the proper regulations.
If there are errors, we always want to make sure that we have corrected them appropriately and that they are transparent. I think many people just freeze up, and since it’s an inspection they fear the worst, even though they might be a really good site or sponsor. I think we need to approach it with the understanding that we are human and mistakes happen, and as long as those mistakes are corrected appropriately there is nothing to fear.
What assumptions do clinical research professionals tend to make about FDA investigations that are incorrect?
Some may assume that having their subject matter expert (SME) meet with FDA investigators, given their trial and/or topic knowledge, or the fact they have experience undergoing a past FDA inspection, would make them the best choice. However, if this individual is not an excellent communicator, able to provide information in a clear and concise manner, or if this person is not always calm ‘under fire’, this could be problematic.
What is an example of an FDA inspection gone wrong?
Where we get into some deep trouble is where people have committed intentional fraud, or have done things that are less than honorable in terms of enrolling subjects that should not have been enrolled in a study, or did not report all adverse events.
I know that Root Cause Analysis (or RCA) is key to the process. Can you explain its significance?
RCA is something I teach that is really important. Sometimes we put a band-aid on an issue but we’re not really fixing the true problem – we’re fixing something on the surface but not really getting down to the root of why something has happened.
For example, let’s say that patient enrollment is not meeting a sponsor’s goals. Sites are not enrolling as many subjects as they were supposed to, according to the timeline that was prescribed. What frequently happens is that the sponsor will add more sites. They think that if we throw more sites in the mix that we’ll get more patients. Well, that may work, but in many cases it doesn’t.
The thing is to really get to the root cause of why people are not enrolling. By digging down more deeply – in terms of what is the root cause – we could find out that it’s a really tough protocol. If we keep asking these questions we may find that some sites don’t have enough time and that’s why they’re not recruiting; maybe they have a lot of other competing protocols and they just don’t have time to recruit efficiently for the particular protocol in question.
It could also be that the inclusion/exclusion criteria are too strict and they just can’t find enough subjects that fit the protocol. This would represent a system-wide problem, and by throwing more sites into the mix, it may not solve the immediate problem. It could also be that there is a misunderstanding about the protocol requirements, or it could be a very tough protocol from the standpoint of the patient – the patient may have to make too many visits [to the study site] or there may be too many procedures that are considered difficult.
For example, it could be a GI study in which there are a number of colonoscopies that have to be done and patients don’t want to undergo that many procedures over a certain period of time. By questioning sites to get at the real problem, we might be able to resolve this more effectively than putting a band-aid fix on it, like putting more money into advertising, or adding more study sites when that may not be the issue.
While exploring what the true root cause is, you may find that there are different root causes at different sites. Some may not have the personnel to address all of the calls that come in from the advertising they’ve placed. Maybe they receive 200 calls but they can only return three of those calls a day due to their workload. Some sites may have inadequate screening of the target population. There may be one solution, or more than one solution, to get to the bottom of the problem.
How do Corrective and Preventive Actions (or CAPAs) come into play?
If we find that there is a problem – such as data not being completed in a timely fashion by a site – we’ll do an RCA to find out why that is. The immediate response would be to correct the situation, ensuring the site has now recorded all the data and is up-to-date. That is the corrective action. A lot of people stop right there because they believe that they have corrected the problem, but they haven’t performed a preventive action – what is going to prevent this from happening again in the future?
If we’ve done our RCA, we might see that the person responsible for entering that data is overworked, or there’s no backup. If the person is out on maternity leave – or perhaps just out sick for a day or two – and no one is there for backup, things can get pushed back in terms of the timeline.
There may be a variety of issues, but unless we dig down to determine the problem, we won’t know if it’s a resourcing issue or whether the assigned person has not been educated about the timeline for the expected completion of data entry. The RCA, and the action of putting something into place to correct the action, are sufficient; but to go a step further and prevent it from happening again, is the best practice and what is expected by regulators. This might mean having a backup person trained, or retraining the person who was supposed to be doing this in the first place, to ensure that they do know what the timeline is.
A common example [in the clinical trials environment], are problems with informed consent. So let’s say the investigator does not sign the forms at the time the consent was obtained. Let’s assume the investigator is the one administering consent and, for some reason, they forgot to sign or date each consent form at the time it was obtained. We could go back and explain in a note why we didn’t capture the signature at a particular date or time, but this doesn’t get to the root cause or put a preventive action in place.
If we go through the process we might find that the investigator is not always on-site. We may need to put an SOP in place stating that the principal investigator is signing to show they have oversight, but that the signature may come a day or two later because the principal investigator will not be at the site at the time this particular informed consent is to be obtained from the study subject. The task could be delegated to another sub-investigator, but if a principal investigator’s signature is required, we may need to put an SOP in place to state that the PI is going to be signing all of these consent forms to demonstrate this oversight.
In your experience, what surprises have even the most seasoned clinical research professionals experienced when dealing with regulators?
I think they are surprised to find that regulators are just regular people. You’re very fearful when you hear that you’re going to have a regulatory inspection – and of course it is very serious – but the inspectors are just like you and me. You can have some that are tougher than others but they are just doing their jobs. They are trying to ensure the same thing that you are trying to ensure – patient safety and that the regulations are followed and research is conducted in a proper way. That really is sometimes the biggest surprise for people to realize – that maybe the experience was tension-producing, but these people really are doing their job with the same goals in mind.
What is the real take-home message for sites wanting to ensure they are FDA inspection-ready?
In terms of sites and sponsors, they need to have good procedures and policies in place and adhere to them. It’s not good if they have SOPs in place but don’t follow them. Along with policies and procedures, if quality checks are in place, the likelihood of passing an inspection without any major or critical finding, is much more likely. You can have SOPs in place but if you are not going back to check to make sure everybody is following them and understands them, and that new people are trained on them, there is a good chance that things will fall through the cracks.
How is attending the eCADEMY online workshop more valuable than simply reading about the FDA regulations?
Any kind of hands-on practice is invaluable. In this particular case, this online workshop will engage participants with examples of real-world inspection situations. It’s one thing to read about the regulations, but it’s another to take part in a practical exercise and receive feedback from peers and the instructor in a workshop format. I think it’s good to have these things discussed and to exchange ideas.
I also think it’s critical to participate in these types of workshops so you can get feedback, ask questions and get input from colleagues around the globe. That gives a lot more depth [of understanding], than simply reading the regulations and how to apply them. We all have different learning styles and, if you’re not a visual-based learner, the hands-on piece and the auditory piece of the [eCADEMY online training workshop] enhances the learning experience.
Register for the FDA Inspections eCADEMY coming December 9th where Janet will discuss appropriate strategies for responding to FDA inspection findings and how to implement realistic, and appropriate, Corrective and Preventive Actions (CAPA). She will also share how to employ the right corrective actions to resolve the major and critical FDA inspection findings. And all from the comfort of your home or office.