Discussions brought from Linked in platform (GCP group)
Luis Miguel Cuadrado • Thanks very much for sharing this Tina!! It´s been a long time since I waited these first steps into the new ways of monitoring: use of new technologies, new minds, risk based approach.
Times when everything should be checked are simply gone...
Phyllis Kent • I wish FDA had added that they will be understanding and will not penalize the sponsors when errors are found on the unmonitored CRFs. I can't imagine what a site will look like on inspection if there is only one monitoring visit as suggested in one place in this document. Maybe it would be ok at a Phase 4 site. I think most sponsors will not want to risk that their are errors in CRFs or that data may be disqualified because of inappropriate delegation which would go undetected using in-house monitoring. Monitors are the ones who keep the PIs on task and make sure that they are trained, training staff, involved, reviewing data, etc. FDA is just re-stating that the regs require only one monitoring visit per year and it is up to the sponsors to do enough monitoring (either in house, electronic or on site) to make sure that the study is conducted properly. The risk remains with the sponsor as always.
Tina Avanzato Chiodo • Phyllis - It would be "appreciated" if the FDA considers enforcement discretion if a sponsor's risk-based monitoring plan demonstrates systematic compliance, rather than 100% compliance. I will submit my comment to the FDA.
All - Comments on the draft monitoring guideline can be submitted to the FDA at http://www.regulations.gov.
Lynda Cedar, Ph.D. • Interesting Tina!
Nothing new in this guidance.
Monitoring should be systematic and 100% compliance. The monitoring performed should be adapted to the study progress, there should be no minimum. As Phyllis mentionned, it is of the responsibility of the sposnor to ensure the study is conducted properly...
Michael Smith • I wonder what the implications for QA would be. There is an argument that an audit function within QA could continue with its current approach - to validate any new risk-based quality system. Any thoughts?
Carol Bognar • Michael, in my experience changes in monitoring (reduced, risk-based, etc.) have a significant impact on QA audits. I have found that auditing unmonitored CRFs leads to auditors performing more of a QC effort and less QA. One of the biggest concerns I see is ineligible subjects being enrolled in trials and this not being discovered until later in the trial. Monitors (and auditors) will need to be trained on new methods of data review that are more efficient and performed in conjunction with the changes in the monitoring plans. The combination of centralized and on-site monitoring may be the best strategy to ensure data integrity and quality.
Michael Smith • I could imagine that many organisations could make more use of the data review/validation possibilities in their data management groups - perhaps these regulatory guidances will prompt more attention there.
re: new EMA & FDA documents: We can test reactions in the QA world at BARQA's annual conference later in Sept - perhaps at the GCP Clinic. Let's see what people have on their minds.......
Frédérick Therrien • At line 436, the FDA guidance document adress how communication of monitoring results are reported to the sponsor and CRO but not to the investigational site.
Perhaps this guidance document should define what should be the reporting timeframe, to the investigational site and/or the IRB, for findings that could affect the safety of subjects or their willingness to continue participation, or that could influence the conduct of the study or alter the IRB's approval to continue the study. Off course, reporting timeframe should be based on a risk-based approach.
Lorraine D. Ellis • Thanks Tina, for the discussion which I think will continue for some time since some of the directions in this draft guidance are definitely different from the current "gold standard" of monitoring.
It appears that, as quoted by my colleagues above, and according to regulations, the sponsor will continue to be responsible for the quality of the study and the monitoring. Since FDA is now more open to alternatives in monitoring methods, they are expecting the sponsor to outline in a monitoring plan (in more detail then most of the monitoring plans I have seen), the exact methods for all monitoring procedures and how they will ensure proper monitoring. To address one of the points above, perhaps FDA will inspect according to the monitoring plan requirements and expected results as they do with SOPs.
I think that on-site monitoring will not disappear as there is no substitute for visiting a site to determine deficiencies and apply remedial training or other remedial actions. However, centralized monitoring may find some errors earlier so that the monitor can go on-site to repair site performance before the problem grows. We have found that a combination of several monitoring methods proves to be the most effective in ensuring data quality.
Jeffrey T. Taylor, DMD • @Phyllis Kent, I couldn't help but feel a need to comment on, "Maybe it would be ok at a Phase 4 site."
You would think so. I worked with a sponsor who had us do one IMV for a Phase IV which had had no visits since the beginning of the study after over a year of activity. It was an unmitigated disaster with most of the issues surrounding consent. Phase IV require compliance also.
I cannot imagine a pivotal trial which follows these guidance literally. I would urge everyone to express their concerns to FDA. I cannot fathom this approach. I understand the intent. I understand the value in taking a "step back" and doing an overview; a broad based approach. Many of us understand the risks accepted in doing so.
There is no substitute to an on-site visit. The integrity of the study will be greatly compromised by a lesser approach. This is a "lesser approach".
Phyllis Kent • Jeffrey, I agree with your comments. The more I review this, the less I see anything new. The FDA minimum of one visit per year has not changed. But everyone recognizes that the minimum is too risky and therefore we develop monitoring plans to match the nature of each study. So we are already doing risk based monitoring. I think maybe this document was intended to encourage more database review during the studies to identify sites that are outliers and address them earlier. Again, I think many companies are already doing this and, with site monitoring, are aware of their riskier sites. We then increase our monitoring if we see an increased risk. I think FDA intent was not really endorsing less monitoring but a variety of monitoring approaches to use all of the tools available.
Lorraine, with respect to inspecting versus the monitoring plan, they already do this at the sponsors.
The issue I see is that if site monitoring were cut back, then more errors would exist in the CRFs. FDA would cite these errors during site inspections. Some errors will probably always exist. But with reduced site visits and less SDV, these would likely be more numerous. Of course, central monitoring can find blanks on the CRF or inconsistent data. But I do not see any way that increased use of centralized monitoring can minimize data omitted from the CRF (such as medical history, conmeds, changes in meds, adverse experiences) or captured incorrectly from the source (e.g.,start and stop dates, AE severity, etc.,) These are the same items that are likely to impact subject's qualification for a study and protocol compliance as well as safety monitoring.
I agree with Carol that the result of decreased site monitoring will be an increase in audit findings. That should result in increase in monitoring but I'm not sure that the loop is ever closed.
JeanMarie Markham • It's my sincere hope that all of these comments will be shared with agency during the comment period. I am a bit surprised at the somewhat "lax" approach the document appears to take. Especially in light of all the 483's issued in the past couple of years regarding monitoring quality. There are a number of efficiencies to be gained with EDC and EMR and some central monitoring. I agree with Phyllis we are already using "risk based monitoring plans" specific to each clinical trial to ensure proper oversight to optimize this function. There needs to be a balance. Although technology facilitates the capture of data - it is still only as good as what is entered into the system. SDV does require some F2F review to ensure patient safety and GCP compliance. We tend to forget that technology still requires human interaction; and that valid source documentation is only as good as the data being entered. It is still a search for the holy grail.
Jennifer Woodside • I'm writing from a Research Site, and we're very curious about how this might be implemented by different Sponsors/CROs. Despite many electronic records that could be centrally monitored, there is still so much on paper. Having read a few other online articles about how central monitoring would financially benefit Sponsors as on-site monitoring is a huge cost - it seems like they would apply themselves to making paper records more accessible remotely, or finding ways to replace them. I think as a Site, we will absolutely see a rise in "Portals" (basically a way to upload documentation into a online shared database) or other ways to try and chip away at making sites less paper bound, and more electronicly based.
I also wonder, if this change could place an unexpected burden on the Site itself. Potentially, we could be inundated with requests to confirm, verify, copy, check, look up, etc. Things that a Monitor on-site would be doing themselves, but as
a remote presence would require the assistance of the site to complete, or make documents available to them electronically?
10 days ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion1 .
Michael Smith • This deals with monitoring - does anyone know if FDA will issue related guidances on other parts of the "integrated framework" - their analogy, not mine? e.g. protocol design, CRF design, data analysis plan: Quality by Design......
Carl Anderson • I agree with Michael. It really would be great if FDA would give some guidance to study design, probably the number one root cause of GCP violations. Anyway, this guidance document is overdue and is a step in the right direction.
I think that Jennifer raises a legitimate concern about the potential unintended consequences of centralized monitoring. Sites definitely have something to say during the comment period.
Raeda Mustafa • Very interesting ! where a vast amount of clinical trials are being shifted to the MENA region and other emerging markets, investigators and clinical sites are being exposed to the GCP experience for the very first time. We (monitors) are visiting the sites, collecting the essential documents - even sometimes we instruct site personnel how to sign and date every page of the resume provided. The investigator might need a clarification for what an FDF would refer to exactly. After site initiation and prior to the first randomization, we always had to be there to ensure that I/E criteria are clear and not misinterpreted, protocol deviations throughout the conduct of the study is becoming a trend rather than being a single occurrence and most of the time the monitors' early involvement is highly important and I'm wondering if this would happen through the centralized monitoring .. this is not a one time or one visit work, it's considered part of the continuous qualification of the site, not only in our region I guess but everywhere else.
Rebecca Georgevitch • This guidance document is giving permission to run studies without regular on-site monitoring to confirm compliance for patient safety and data integrity. They're way off base. Per the FDA, patient safety is #1 and thedraft contradicts this statement. With the many mistakes that will most likely be found, this will cost everyone in the long run. Within the last 10 years, many drugs have been pulled off the market with on-site monitoring. I can't imagine the disaster with so few on-site visits and centralized monitoring. Huge impact on patient safety.
Paul Gittelson • I must disagree with Rebecca and Raeda. The guidance document really only clarifies what FDA has been saying all along. Namely, there is an undisputed sponsor/monitor responsibility to ensure the integrity of study data and that the rights and safety of study subjects are protected. The methods by which this may be accomplished may be as varied as are the studies themselves. The monitoring plan for a small oncology trial, or neurologic device trial, does not have to look like the monitoring plan for a large, multicenter erectile disfunction, seasonal allergy or weight loss study. If FDA discovers study misconduct or data discrepancies, the Investigator and Sponsor/Monitor will be taken to task for failing to detect and correct them, and a "clean" study will not receive regulatory citations irrespective of the monitoring plan adopted . While Raeda and Rebecca are correct in asserting that some studies will be disasters without regular on-site monitoring visits, that is not the case for all studies. The trick is to devise a monitoring plan that is sufficiently sensitive, robust and flexible to identify problems early on and direct resources where they are needed. For many studies, that will entail traditional routine monitoring visits as part of the monitoring plan, but there are studies that will require fewer, more selective visits. FDA is empowering sponsors and monitors to make those decisions. Don't ask FDA to be your clinical project manager.
Lynda Cedar, Ph.D. • That's true Paul. FDA does not develop the monitoring plan nor manage the study. The Sponsor is the first one who is responsible for the quality of the study, he should put in place the appropriate plan to achieve it. A study conduct involves a lot of tasks, the monitoring is just one of them. The monitoring and the number of visits should be customized upon study requirements. FDA evaluates whether it was adapted and appropriate or not.... that's all.
0 comments:
Post a Comment