Lead CRA Q&A: Meeting with a Principal Investigator

Anonymous commented in... "Routine Monitoring Visits":
Could you please give advice about how to deal with the "difficult" Principal Investigator who doesn't want to meet you despite the numerous efforts to persuade him? Any recommendation would be very appreciated! -May 26, 2011 2:54 PM


NadiaBoBadia responds...
Thank you for a great question.  I've partially addressed it before in a post from the archives called "Who's Running this Study?"  Even though Principal Investigators (PI) have made a commitment to personally oversee the safety and conduct of the trial (In the US, see FAQ for FDA Form 1572) they often can't find time to actually meet with the monitors during our visits.  This happens quite often so I definitely want to address your question.  Remember, that there is no regulatory mandate that we talk to the PI but certainly it is a best practice.  However, I don't want to understate the importance of regularly briefing with the PI.  Remember from my post on Routine Monitoring Visits that the PI discussion is an opportunity to address important topics that affect conduct, can positively impact data reliability and validity, and ensure vigilance in reviewing ongoing subject safety.  If your trial is still recruiting, meeting with the PI can be instrumental in influencing study enrollment (related post).

My interest when I am monitoring is to meet all of my objectives as efficiently as possible and leave the site as soon as I have met my goals.  Guess what though, doctors are busy.  In turn, I offer my PIs flexibility where I can.  I do not insist that they drop everything and meet with me each visit.  Generally, I have more success when I schedule an appointment time (say 15-30 minutes) in my confirmation letter and confirm it a few days before arriving.  If the PI truly can't meet though, a telephone contact within 10 days of the visit will be an effective alternative for communicating important findings during the visit, pending items for resolution, or general study updates or training.  I document the call in my report, in a separate telephone contact report for the TMF, and/or an email recap.

Trick your PI into a meeting! Tell the
doctor there is a party they must attend and then tackle
them with your visit findings - just kidding!

Part of our goals as monitors are to prepare PIs for audits and also to influence operations of a trial.  We help bring corrective action for any missed procedures and help them document anything that may need to support the record of conduct down the road.  We help them defend their data and demonstrate that patient safety is protected.  The PI meeting furthers these goals so it is important to budget time for it.  Don't use the meeting just to criticize the "difficult" PI and the study site staff.  Give them kudos and tell them what is going well and also where improvements may be needed.

If you pitch the PI meeting like this, act accordingly, and are respectful of the PI's time then the meetings are more productive and more likely to occur.  As you build a relationship with your PIs, they will see that you are committed to helping them conduct the trial properly.  As your PIs grow to trust you as a partner to their site, they are more likely to make time to meet with you.


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You may also like...from The Lead CRA archives:

• Selecting Qualified Investigators April 2010
• Pre-Study Visits January 2008

Selecting Qualified Investigators

The focus of this post will be selecting adequately performing US clinical trial sites for Investigational New Drug studies.  Depending on the nature and size of your clinical trial, you may be targeting private practices, specialists, academic centers, purpose-built dedicated clinical research facilities, or a combination of any of these to find your principal investigator(s) (PI).  Certainly, there is great cost associated with opening and maintaining a study site so you are well advised to be thorough and thoughtful when evaluating the potential investigators.  As monitors, we may provide input on the clinical operations of a study and assist or manage projections of how many and what types of PIs will be selected and this article will discuss some of the important considerations for qualifying and selecting study sites.

As qualified CRAs, we use our instincts and training to predict and choose the most qualified and motivated PIs.

Inevitably, some study centers will perform better than others and deliver the ideal study candidate while strictly adhering to the protocol.  Careful site selection is absolutely critical to limit the time and resources that will be required during study conduct to manage poor performing sites; I refer to my non-enrolling or poor performing study centers as “duds”. Duds require additional monitoring oversight, coaching, and avoidable cost for continued participation, therefore, these sites are often closed before enrollment or conduct is complete.  Closing a non-performing site is an attractive option to suspend the siphoning of time and resources, but forethought and a well-coordinated site selection exercise can help ensure dud sites are never opened in the first place.

Consider the therapeutic area of study and recruit PIs with relevant experience, the right study tools and equipment, access to the target subject population, interest/motivation to recruit, and availability to participate.  

You needn’t only consider PIs with prior clinical trial experience, but you may gain some considerable efficiencies by targeting PIs who have performed well in prior studies and audits.  Some PIs pay to be listed in clinical trial directories, you may be able to obtain names of doctors to approach through online physician directories, reviewing PIs you or your colleagues have worked with in the past, internal company databases, conference attendee lists, patient advocacy groups, journal article author searches, pharmaceutical sales personnel, medical association websites, telephone directories, the internet, trade journals, other networking contacts, etc.

The FDA maintains lists of disqualified investigators and those that are prohibited or restricted to conduct clinical trials.  You can also review any previous warning letters or license restrictions using publically available databases (Click on the hyperlinked text and see additional links below for further information).  Your investigators will need to adhere to all ICH/GCP guidelines and relevant CFR sections including 21 CFR 312.53.  Check your potential PIs against these lists and also gather anecdotal information regarding the investigator from colleagues and the internet. Read physician review websites like yelp.com or clinician directories.  Determine if there have been previous inspections at the study center.  Some doctors have their own websites and you can also search news databases to find information about a potential PI you are considering.

http://www.fda.gov/ICECI/EnforcementActions/FDADebarmentList/default.htm
http://www.fda.gov/ICECI/EnforcementActions/DisqualifiedRestrictedAssuranceList/default.htm
http://www.accessdata.fda.gov/scripts/cder/cliil/

http://silk.nih.gov/public/cbz1bje.@www.orilist.html

Relevant official FDA guidelines are available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf  and Section C of http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070291.pdf

Here is a checklist from one of my trusted colleagues:
http://www.ehow.com/how_2352851_choose-good-clinical-research-investigators.html

Finally, you can contact the physician and his staff to inform them of the trial, determine their interest, and request that they fill out questionnaires or provide a copy of their CV or a summary of their experience.  If you do develop site selection questionnaires you can ask them for their input on the trial design, to describe their facility, to quantify their qualifications/experience/availability/resources/staff, to identify if they have the proper equipment, to comment on their previous clinical trial or audit experience, to give details on their IRB process, to project potential recruitment and access to the target subject population (double check that there aren’t competing trials at the facility or within the same geography www.clinicaltrials.gov), to detail translation and advertising needs, and to inform you of any anticipated barriers to recruitment.  Much of this work can be done via telephone/fax/email but you may want to schedule a time to visit their office and evaluate whether they are a fit for your trial. For more information read my post on Pre-Study Visits.

Beyond the questionnaire, you can use the site selection process to gauge the communication style, organization, and responsiveness of the site staff.  

Beyond the questionnaire, you can use the site selection process to gauge the communication style, organization, and responsiveness of the site staff.  Ensure there are no conflicts of interest, lack of objectivity, or other reasons to avoid a specific PI.  You will be able to determine the PIs experience conducting other sponsored trials, develop a feel for the turnover at the site, and sniff out any additional red flags that may steer you away from choosing that site or anticipate issues that might creep up during conduct.  Be tactful, gracious, and considerate of their time.  The PI will be evaluating whether they want to work with you as well.  It is very much a two-way street since you may be working closely together for a considerable amount of time if they do join the trial.

Good luck selecting qualified investigators. Definitely take the time before the trial starts to be thorough and deliberate with the site selection process.  There is always pressure to get sites up and running as quickly as possible, but you must balance that need with the requirement to spend adequate time selecting qualified investigators. Hopefully spending enough time choosing your PIs will ensure your trials will be easier to enroll, your studies will be conducted with less protocol deviations, and your study team will be more likely to avoid unnecessarily costly “dud” sites and achieve all of your study objectives.

You may also like...from The Lead CRA archives:

• Routine Monitoring Visits March 2008
• Investigative Site Recruitment Plan Sep 2010
• Motivating Study Coordinators Feb 2011

Home from the Investigator's Meeting

I've been assigned another study and attended a kickoff and Investigator Meeting on the East Coast last week. As I mentioned in my last post, an Investigator's Meeting is basically a chance to get all the doctors and staff together at one venue with the sponsor (usually a fancy hotel or somewhere fun) so that all the details of the study protocol can be reviewed and everyone's questions get answered. Also, because a lot of money is spent at these meetings to woo, wine, and dine the Principal Investigators (PIs), the meeting has the bonus effect of getting everyone psyched up and excited/competitive about enrolling in the study.

For my new study (it is a high cholesterol drug therapy study) I will have 11 sites each of which needs to be visited at least every 4 weeks depending on enrollment. There are 60 PIs total and 4 other CRAs but I am the only one on the West Coast. I am lucky that 7 of my sites are located near one another in LA so I can combine my visits into longer trips and not have to fly so often. I also have 2 sites in Phoenix, a site in Seattle, and a site 1.5 hrs drive East of my house. In any case, this is a heavy site load but luckily it is a straightforward study and the PIs seem to be both experienced and motivated.

An electronic patient diary looks just
like a little PDA and the patient gets
an alarm to remind them it is time
to take their medicine or fill out a
little outcomes summary. This data
gets sent in via the telephone or
loaded into a computer and is used
in the study analysis.

The trial leverages some cool technology such as an electronic data capture system (so CRFs go into the computer in an EDC system rather than on triplicate forms) and the patients all get electronic diaries (little palm pilot devices) so they can capture adverse events and be reminded when it is time to take their medicine, plus the medicine (Investigational Product - IP) comes in blister packs one week at a time, so drug accountability should be a cinch thanks to this clever packaging. This is a proof of concept study so there are 6 different study arms (some patients get placebo, some get the real drug, some get a mix of both...) and only 275 subjects will be enrolled. The subjects take their meds for around 7 weeks. Recruitment is anticipated to end in mid-April so it is a really short enrollment period. The Inclusion exclusion criteria are very tight so a high number of screen failures are expected (up to 800). Luckily, screen failures will not get their own casebooks but just be captured in the Integrated Voice Response System (IVRS) web portal.

In my next post I will tell you more about how to prepare for a CRA interview and what types of questions you can expect to be asked. Then I will post about Routine Monitoring Visits, as promised. Let me know if there are other topics that are of interest to you by emailing me or leaving me a comment here and I will be sure to address them in future posts.

Introduction to Monitoring

I've been out on the road for the past few weeks assisting some other monitors to review patient's medical records and the data that has been collected for the clinical trial. It occurs to me, that it would be beneficial at this point to further describe to you the roles and expectations of a Clinical Research Associate (CRA).

In a pharmaceutical/biotech company, teams of scientists are working to discover new molecules, compounds, and foundations for new drugs. In addition, these same scientists sometimes work to re-formulate current drugs or apply them for new diseases and indications (all of this work is done in animal models before the human clinical trials can begin). It is at this point that monitors such as myself come into play. Once an experiment that involves humans is designed, monitors help the company choose qualified and interested physicians to carry out the study. These 'investigators' are reimbursed for their efforts to conduct the trial and a CRA may also help negotiate the budget and/or contract between the parties involved.

A CRA job is a traveling job. Sometimes we go to glamorous places but more often than not we are monitoring in hard to reach or otherwise obscure locations. 

Objectives when we visit the investigative site (Doctor office, hospital, research center, etc.) include: 1) perform pre-study tasks during a Pre-Study Visit (PSV), 2) kick-off the study with a Site Initiation Visit (SIV), 3) routinely check back with the site regarding subject enrollment, trial conduct, and data collection during one (or typically many!) Interim Site Monitoring Visits (MV), and finally 4) shut down the site after their participation has ended during a Close Out Visit (COV). Before and after each visit, there are a variety of tasks and communications that need to occur in regards to preparing for, scheduling, confirming, and then following up on items from previous visits. Read some of my other blog posts to learn more about Site Initiation Visits, Routine Monitoring Visits, and Close-Out Visits.

Also, between visits, a CRA needs to regularly contact the sites and perform site management activities such as answering questions regarding the study design, encouraging enrollment, sharing tips from other sites, and distributing study drug (Investigational Product, IP), and managing site supplies inventory levels (often you are assigned up to 10 different sites to manage but this really can vary depending on geography, how many patients/doctor sites are participating, how many monitors are on the study, how complex the trial is, and a variety of other factors).

I'll explain more regarding the key tasks at each visit in later articles. There are many Federal and International regulations that apply to human research to ensure that the studies are valid, reliable, and above all, that the rights of the participating subjects are protected and we'll also get into those soon.