One of the issues raised by the new FDA Draft Guidance on Risk-Based Monitoring is the training and qualifications of clinical investigators, usually referred to as the PI. Veteran GCP training specialist David Montgomery questions whether the draft guidance document is consistent with the previous final guidance document on Supervisory Responsibilities of the Investigator (2009). David raises some interesting points as he enlivens the discussion on the draft guidance. Since this is a significant change in how FDA is giving its current recommendations on monitoring, it deserves a certain amount of scrutiny. And David is certainly up to the task, with a Latin lesson thrown in for good measure!
Guest Commentary by David Montgomery
Facile Descensus Averno
This latest proposed guidance from the FDA is a constructive move forwards but like the ancient Greeks seeking guidance at the Oracle at Delphi there will inevitably be points for interpretation.Somewhere between sponsors perception of what the FDA is saying and the guidance they actually provide lies a vast expanse of mythology which can, on occasion, be attributed inappropriately the badge of best practice — itself a context specific judgement in an increasingly global enterprise. It is axiomatic that the FDA is taking a stance by providing its current thinking and therefore challenging sponsors to apply some critical thinking to their own processes and procedures. Sponsors need to be confident that they the necessary structure in place to enable their staff to fulfil their tasks in accordance with regulatory guidance. Moreover, and at of least equal importance, sponsors need their quality systems to achieve the goals set out in ICH GCP in terms of safeguarding trial subjects and ensuring that credible data are generated.
Certain phrases from the latest guidance stand out and all those involved in the planning, conduct and monitoring of clinical trials of drugs, biologics or devices would do well to take note of these, whilst at the same time recognising that they are not cast in stone.
(all numbered lines are from FDA draft guidance document)Lines 62 – 64 “Quality is a systems property that must be built into an enterprise and cannot be achieved by oversight or monitoring alone.”
Comment: See text from lines 207 – 209
Lines: 97 – 99 “For major efficacy trials, companies typically conduct on-site monitoring visits at approximately four- to eight-week intervals, at least partly because of the perception that the frequent on-site monitoring visit model, with 100% verification of all data, is FDA’s preferred way for sponsors to meet their monitoring obligations”
Comment: we are talking efficacy trials
Lines: 188 – 189 “This draft guidance strongly encourages sponsors to tailor monitoring plans to the needs of the trial”
Comment: One size does not fit all
Lines 207 – 209 “A poorly designed or ambiguous protocol or case report form (CRF) may introduce systemic errors that can render a clinical investigation unreliable despite rigorous monitoring.”
Comment: Attempting to remedy a bad protocol with copious doses of guidance is an exercise in futility and the tale of Sisyphus springs to mind.
Lines 209 – 210 “Study-specific training of investigators, other site staff, and monitors also contributes significantly to study quality (see sections IV.D.4. and VI.A). “
Comment: (209 – 210) What is meant by training?
464 – 469 “Training should include principles of clinical investigations, critical protocol-specific requirements, the study monitoring plan, applicable standard operating procedures, and appropriate monitoring techniques.”
Comment: Protocols have objectives and endpoints – in the interests of quality will training adopt the same model?
Lines 531 -532 “On-site visits should include sufficient time for mentoring, feedback, and additional training, if needed, during the conduct of the study.”
Comment: Feedback is always valuable but how are monitors qualified for study specific mentoring roles or is ICH GCP 2.8 to be ignored?I must take issue with the FDA on their use of the term training. It blurs the responsibilities of what was stated in its own guidance from 2009 for Investigator Responsibilities and what was intended in ICH GCP, particularly in relation to multicentre trials.
The term training is already over used in clinical research, particularly when what is often intended is instruction or guidance. Furthermore, the use of the word mentoring is certainly a bridge too far. This is not what Homer had in mind – in what way are sponsor’s monitors qualified to fulfil these roles or are we going to waive the requirements of ICH GCP 2.8 for those undertaking a role which “contributes significantly to study quality.”
The 2009 FDA Guidance on Investigator Responsibilities takes the trouble to define what they consider necessary in terms of adequate training and puts the onus on the investigator to ensure that there is adequate training for all [their] staff participating in the conduct of the study.”
Compare this to ICH GCP 5.23.4 which states that “All investigators are given instructions on following the protocol, on complying with the uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.” Interestingly, the purpose of an initiation as it is “To document the trial procedures were reviewed with the investigator and investigators trial staff.”Providing instructions is rather different to providing training — a point well made Dr Robert Mager, world-renowned expert on training who said, “If telling was the same as training we’d all be so smart that we can hardly stand ourselves.” All those with an over weaning dependence on the use of the weapons of mass instruction, such as PowerPoint, would do well to read his works. But in the context of the training described by the FDA, particularly as it is directed towards clinicians, it is also helpful to consider an article in the British Medical Journal some years ago in relation to the teaching of doctors.
“There has always been an assumption that if a person simply knows a lot about their subject, they will be able to teach it.” Few persons responsible for providing effective teaching and/or training would disagree with this point of view. However, if it is truly the intent of the FDA that sponsors provide training then the latter would be wise to read that BMJ article in more detail, since it goes on to state that “understanding the learning process will help clinical teachers to be more effective.”
The real question is what the FDA expects sponsors to provide: a review of study specific procedures and documents coupled with feedback during monitoring visits, as stated in ICH GCP or training complete with intended learning outcomes and evaluations?
If you employ an architect and a builder to renovate your house you will ask them to provide plans and a schedule of work which comply with building regulations and other applicable regulatory requirements. Reviewing and agreeing their plans prior to implementation coupled with checking on their progress of their work would be the actions of the prudent — yet I wonder how many builders or architects would consider this training?
Fa·ci·lis de·scen·sus A·ver·no [fah-ki-lis des-ken-soos ah-wer-noh; Eng. fas-uh-lis di-sen-suhs uh-vur-noh] Show IPA
(the) descent to hell is easy; it is easy to take the downward path. Vergil, Aeneid, 6:126.
How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!
Next week: Guest Commentary by Len Grunbaum and Emma Barsky on:
“One Way to Avoid a Warning Letter … Maybe“
There have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.
GxP Perspectives on twitter: @GxPPerspectives
On The Blogroll: Rebar Interactive has an excellent blog for clinical sites. If nothing else you MUST check out their post on:
“Patient Recruitment: Think That You Might Be Wrong,”
if for nothing else than the photo. A great blog post by Rahlyn.
Please comment on the new draft guidance on Risk-Based Monitoring.