Review and Discussion of FDA Guidance Regarding COVID-19

Hi, Elizabeth here, and welcome!

This post relates to a very important soft skill….being able to adapt to change.  There is an example now causing so many changes, affecting all areas of the clinical research industry, COVID-19 which is the Coronavirus Disease 2019.

Because DHHS, the Department of Health and Human Services, and the president declared this a state of emergency, the FDA recognizes that this pandemic is going to impact the conduct of clinical trials. All areas of research are being affected during this crisis from investigators and site staff to sponsors to CROs, which includes CRAs, study management, CTAs, Data Management, Medical Writers, Statisticians, and more. Due to this, the FDA provided guidance for industry, investigators, and Institutional Review Boards regarding the conduct of clinical trials of medical products during the COVID-19 pandemic.

The guidance provides general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with GCPs, and minimizing risk to the trial integrity.  Due to the government mandating social distancing (which we're all going through right now), and the quarantines in order to flatten the curve, the FDA is aware that challenges are going to arise.  For example, challenges resulting from site closures, travel limitations, interruptions to the supply chain of Investigational Product, or what if site staff or study subjects become infected with Coronavirus or COVID-19???  Because of this impact, it could affect study-related procedures being performed, subjects attending study visits, administration of IP, or using IP, or could even affect labs and diagnostic testing being performed. Because of this, guess what will result….Protocol Deviations!!  The FDA recognizes that there may be protocol modifications required and protocol deviations that are just going to be unavoidable due to illness and control measures to prevent the spread of COVID-19.  

Of course, how the control measures impact each study will depend on many things like the disease under study, will it involve a vulnerable population, the design of the trial, the location/region of the study as some areas are suffering from the pandemic worse than others. So, all of these factors have to be considered when making these decisions.

Let's look at some of the considerations that the FDA refers to regarding ongoing clinical trials…..

Like I mentioned before, each decision is based on what is going to be safe for the trial subjects. The sponsors will have a lot to consider. They must evaluate each circumstance, and how it will impact the safety of those participating in the trial. Some of the things to consider regarding the study would be, should we continue with trial recruitment?  Those that are already participating in this study, are they going to continue taking study drug? Will the patient monitoring need to be modified during the trial? And whatever the case may be, the subjects must be kept informed of any changes to the study or monitoring plan that could affect them. This may affect their decision whether to stay in the study or not as well.

So, the sponsor in consultation with the IRB and clinical investigators, will have to determine what is the best way to protect the rights, safety, and welfare of the study subjects. It could be to continue having them participate in the study per protocol, or discontinuing the study drug, or discontinuing their participation in the study altogether.

Again, these decisions will depend on the specifics and circumstances of the study. What's the nature of the IP? What's the disease under study? Can they still conduct proper safety monitoring? Also, can they still receive drug?  What if the pandemic affects the supply chain and the sites can't even receive drug to supply to the patient? These are all things to consider.  A lot of things that the sponsor has to assess because of COVID-19 control measures.

If the subjects cannot come to the site for study visits as specified in the protocol, the sponsor will need to determine if there are any alternative measures that they can implement when necessary in order to assure subject safety. Like telephone contacts, could those be implemented? With technology nowadays, what about virtual visits? Or could there be a possible alternative location for assessments like a local lab?  So, for example, say there was a study visit where a subject had to come in for the site staff to assess for Adverse Events, changes to concomitant medications since the last visit, and collect lab samples. Due to putting subject safety first, and COVID-19 control measures, maybe they could do a telephone contact in order to assess for AEs and conmed changes, and then maybe a local lab could do the collection of lab samples that are required?  Of course, a detailed procedure would need to be put in place, as well as, training…..but maybe this could be a possibility if something happens with COVID-19 and they have to change things in order to put the subject safety first.  Or what if in-person visits are the only way to fully assure subject safety?  When the sponsor is making these decisions, whether to continue the use of IP, if they were to implement an altered monitoring approach, can they assure safety of the trial participants?  So, this all weighs in on their decision. And again, this is going to vary depending on the protocol and the local situation.

The sponsor may want to consider delaying some assessments for ongoing trials. For example, if the trial cannot be conducted properly under the current protocol, they may want to consider stopping recruitment and enrollment or early terming the trial participants. Now, due to the pandemic control measures, there may be situations where the study subjects may not have access to the IP, or they may not have access to the site. The sponsor will need to determine if additional safety monitoring of these subjects will be required due to the fact that they're withdrawing an active treatment. Again, and you're going to see this a lot in the post, it's going to depend on the IP, and it's going to depend on the disease under study.  

Okay, I thought this next part was interesting…..So, say you have a study site that's part of a health care system and that health care system is mandating screening procedures for COVID-19…..the FDA mentioned that if the health care system mandates screening procedures for COVID-19, this would not require reporting as an amendment to the protocol, even if it's performed during a study visit. Which makes sense because, when you think about it, these procedures would be added due to standard of care, not because of study changes. Now, if the sponsor decides they want to incorporate this data as part of a new research objective, then it would require reporting as a protocol amendment. I thought that was interesting.

Now, as we know in everyday research, changes to a protocol are not implemented prior to IRB approval and sometimes the FDA.  However, due to the pandemic, if there are urgent or emergent changes to the protocol or ICF that are anticipated due to COVID-19, sponsors and investigators should engage with the IRB as early as possible. If the changes to the protocol are required in order to minimize or eliminate immediate hazards or protect the life and the well-being of research participants, like protecting them from being exposed to COVID-19, these may be implemented prior to IRB approval, but required to report afterwards. The FDA does encourage sponsors and investigators to work with the IRB regarding procedures to prioritize reporting of deviations that may impact the safety of study subjects.

Implementing these alternative procedures should be consistent with the protocol as possible, but sponsors and investigators should document any contingency measures implemented. And like with any protocol deviations or issue, they must DOCUMENT, DOCUMENT, DOCUMENT!! In addition to the changes documented, they should document how the COVID-19 restrictions led to the changes in study procedures, the duration of the changes, and which subjects were impacted and how.  Some changes that may be implemented could affect study visit schedules, missed visits, and discontinuation of subject participation. This may lead to missing information like study procedures not being performed. And just like with any missed assessment or procedure, you will want to ensure that it's reflected in the Case Report Form (CRF) as well.

In some cases, depending on how the CRF is designed, sometimes there's a comments page. For this particular issue a comments page would be helpful, as the FDA did mention in the guidance document that it's important to capture the specific information in the CRF explaining the basis of the missing data, and the relationship to COVID-19 for missing protocol specified information. This information then would be summarized in the clinical study report, which is going to be helpful to the sponsor and the FDA.

So what if the subjects can’t get to the site for study visits, which could affect receiving additional IP? 

The guidance does mention that if study visits to the sites are significantly impacted, that certain study drug usually distributed for self-administration may be amenable to alternative secure delivery methods. I would definitely think this would depend on the type of IP when taking this alternative method into consideration.  The site would also require a detailed process to document IP accountability if this alternative method were added. For example, maybe a telephone contact confirming receipt, and if it's a temperature controlled drug, they would need to confirm what was the min/max temperature during shipment and upon arrival at the subject's location.  This, as well as, other specifics would need to be agreed upon and documented in a detailed procedure. For studies that have IP normally administered in a health care setting, it is recommended that the sponsor consult with the FDA regarding alternative plans for administration. For example, would home nursing be a possibility or an alternative site where the non-site personnel were trained (and of course documented) be an option? In this case too, they will need a detailed process of how it will be performed, how will we handled securely, and how they will ensure accurate drug accountability.

In the FDA guidance regarding efficacy assessments, the sponsor will need to consult with the appropriate divisions in order to determine the best alternative method. Like will virtual assessments work, or an alternative collection of research-specific specimens, or would it be better to just delay these assessments?

When this happens, and methods are modified, remember the site should document, document, document! The reasons for not obtaining the efficacy assessments should be clearly documented - due to COVID-19 and what was the limitation imposed that resulted in these assessments not being obtained. If changes to the protocol will affect data management plans or statistical analysis plans, the sponsor should do this when consulting with the FDA.

There were some studies that I had been on in the past, where if it was found that a subject was not eligible (and should not have been randomized into the study in the first place), of course the protocol deviation was documented, it was reported to the sponsor/medical monitor, site retrained, and submitted to the IRB....but in addition, the particular subject would not be included in the final statistical analysis. In this guidance from the FDA, prior to locking the database, the sponsor should address in the statistical analysis plan, how they will handle the protocol deviations related to COVID-19 in the prespecified analysis.

Due to control measures and travel restrictions, CRA onsite visits will be affected as well….And that's the first thing I actually thought of with this….I was like, wow, if I was out there still monitoring, this would be so crazy to all of a sudden be quarantined at home, not able to travel, and all of a sudden all scheduled visits cancelled.  I bet there are a lot of COVID-19 team meetings going on, at every single company, for every single study. My heart goes out to you guys, as I definitely know there are MANY immediate changes. Again, like I mentioned about soft skills, a lot of changes are being put in place, and you have to adapt to it quickly, and very efficiently.  I was definitely curious when I heard about this, how it was going to be handled.  When this happens, the sponsor should definitely consider boosting central and remote monitoring in order to maintain oversight of the clinical sites. I'm curious if this will be documented as an addendum to the CMP, the Clinical Monitoring Plan, or how they're going to put this into place.

Like I mentioned, there definitely needs to be detailed procedures in order to give direction how to handle and perform the modifications that are needed. The guidance document also mentions that sponsors, investigators, and the IRB should implement policies and procedures, or update existing ones, in order to address the approaches that are used to protect study subjects and manage the study conduct due to possible COVID-19 disruption. 

Some of the changes and updates could impact ICF procedures, study visits and study visit procedures, adverse event reporting, data collecting, study monitoring, or changes to investigators/site staff/CRAs. This could be due to COVID-19 itself or the quarantine control measures. The updated procedures will need to comply with all regional and national policies for the management of COVID-19. I would think the stricter policies would apply, and then depending on the changes, a protocol amendment may be required.

Now, like I mentioned before, in the clinical study report, the sponsor will need to document in the appropriate sections: what contingency measures were implemented due to control measures for COVID-19, what subjects were affected, how that participation was altered, and the analysis/corresponding discussions that address the impact of the contingency measures on the safety efficacy results reported for the study (some of these could be early termination from the trial, IP discontinuation, or alternative procedures that had to be performed in order to capture critical safety efficacy data).

It is expected that every effort should be made by sponsors, investigators, and IRBs in order to maintain the safety of trial participants and study data integrity. Remember, I always say our top two priorities are subject safety and data integrity. All efforts should be documented, and again, the FDA does recognize that protocol deviations and modifications may be required due to COVID-19 illness or control measures.

Now, if a study DMC, a Data Monitoring Committee has been established, they can also provide support in assessing if modifications are needed (as a primary responsibility of the DMC is assuring the safety of trial participants). So, the DMC’s assessment of the impact of the trial modifications due to COVID-19 on patient safety is very important to consider.

The FDA's guidance document also has a specific email address if there are additional questions regarding conduct of trials during the COVID-19 pandemic, as well as, links to different FDA review divisions like CDER, CBER, and CDRH.

I hope this information has been helpful, and I know it was a lot to take in. If you haven't reviewed the new FDA guidance yet, you can find it on the FDA's website or via the following link: https://www.fda.gov/media/136238/download. There's also an appendix that's been added now with questions and answers as well, which is really helpful.

Thank you so much!!  I pray you guys are safe out there.  Let's work together to flatten the curve, and stop the spread of the Coronavirus and COVID-19. 

Again, please stay safe! 

XO,

Beth

The CRA Helper