Investigational Product Accountability

Clinical trials are conducted for new investigational products and also to explore additional endpoints/indications for marketed products or combinations.  The medication dispensed in the clinical trial is governed by country/local requirements and strict regulations dictating that it must be tracked and accounted for throughout conduct of the trial.  There are also regulations regarding how the medication is packaged in order to protect the safety and welfare of the subjects and also to maintain the integrity of the trial.  The guidances and guidelines (ICH GCP Guidelines 4.6) spell out recommendations for labeling, packaging, transport and storage.  Suffice it to say, the investigator is on the hook (although he may delegate some of this responsibility to a pharmacist or another person qualified by skills and experience) for confirming receipt of the investigational product (IP), storing/dispensing it properly, and ensuring subjects are compliant with the specified regimen.

The gold standard in clinical trial design is the blinded placebo controlled trial; in these studies the subject and/or the investigator doesn’t know which treatment is being given and that helps maintain objectivity and reduce bias when assessing safety and efficacy. Reference the FDA website for information on various types of trial designs. In order to maintain the blind in the study, the sponsor will deploy a system to disguise the active treatment and the comparator (achieved through manufacturing, opaque packaging, etc.) but also allow identification of the product(s) in the event of an emergency.  Many trials use an electronic randomization system with controlled access so that drug can be assigned according to a pre-determined stratification (to balance inventory across multiple study sites) and also to provide a record of any blind breaks.  Alternatively, trials may use sealed paper randomization envelopes and/or unblinded monitors.

The investigator needs to maintain records of shipment receipt and records of accountability for the disposition of the investigational product throughout the trial. Investigation product may be provided to the investigator in the form of blister packs, sealed bottles, syringes, inhalers, or some other delivery system.  The investigational product will have storage specifications in accordance to the instructions from the sponsor and applicable regulatory requirements.  If the investigational product is temperature controlled, it may be shipped to the study site with digital data loggers that monitor and record the temperature during shipping. The investigator will also need to demonstrate that the temperature has been recorded and maintained according to specifications since the time of receipt (using a paper log, digital device, or some other documentation).

Once the investigational product is at the site, as monitors we can review expiration dates and inspect the product regularly and document the inspection in our reports.  We need to check that everything that was supposed to be used is not present (counting the used IP and reconciling our counts against the tracking documentation), and also that everything that is supposed to be intact has not been used.  We can also physically check that blinding envelopes plus unused investigational product foils and seals are intact and have not been tampered with.  We will review the temperature logs to record and report any temperature excursions.  We will also verify that there is restricted access to the investigational product; controlled with double lock and key.  Finally, we can review the schedule of planned activities at the site and ensure there is adequate supply of investigational product to support continued research efforts.  We will record any deviations or discrepancies and report to the study team and retrain the study personnel as appropriate.

This red tamper-evident tape reveals the word "opened" if you lift and replace it.

Repeating the accountability exercise at every visit can be a time consuming process. If it isn’t stated in your study monitoring plan, ask your Project Lead if interim return/destruction of the used/expired investigational product is permitted.  This is certainly advantageous to waiting until the end of a long study and then trying to reconcile all the paperwork and re-count everything.  As an alternative, you may choose to box up the used investigational product and seal the box with tamper evident tape (at all seams) or just put the tamper-evident tape completely around the investigational product packaging itself and leave it in the controlled secure IP storage area to verify again at the next visit (though this will likely take more tape and it is actually kind of expensive. Also consider initialing across the tape or signing your name so any tampering will be additionally evident).  With your study team’s permission, this may be sufficient to avoid recounting all the investigational product at every single future visit, hopefully they will provide permission for you just to review that the taped up IP is still present and unaltered.

Occasionally drug will be transferred between investigational sites.  This creates a flurry of documentation and if you are asked to participate in a drug transfer you will receive plenty of training from your study team so I will just move on now.


At the conclusion or termination of the trial or in the event of a recall, the investigational product (and the blinding envelopes or supplies if applicable) will be returned or destroyed as specified by the sponsor although sometimes it may be donated to a hospital, pharmacy, or doctor. Per ICH E6 8.4.2 there are requirements for documentation of investigational product(s) destruction.  Any drug or packing that was not returned by the study subject will be documented on the accountability log and it is recommended that there also be documentation in the source documents of counseling the subject on the requirement to adhere to all protocol procedures and instructions.  Documentation regarding the receipt, disposition during conduct, and return/destruction are to be kept on file in the Site Master File and the Trial Master File (your study team, SOPs, or monitoring plan will inform you which file gets the original documents and which gets the copies).  OK, a lot of material here, please let me know if there is anything you want me to clarify or expand further on.

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

• Routine Monitoring Visits March 2008
• Close-Out Visits July 2008

Employment Reference

One of my colleagues and close friends recently lost her CRA position due to a large round of layoffs at our former employer. I was aghast that she was let go and I felt terrible for the sponsor since we had worked on the same trial here in California; the former team of six was now reduced to just one. The sponsor tried to hire her directly but the CRO refused to allow her access to the clinical trial management system and replaced her with a Junior CRA located on the East coast. I comforted my friend and offered myself as a resource in her job search. I think her work is of the highest caliber and given the opportunity to work with her again, would do so instantly. She has been a great mentor and is truly a talented and dedicated CRA. I contacted all of my trusted recruiters, referred her to my current company, and provided resume and interview advice. Not too long after, a hiring manager contacted me to discuss my friend’s background and experience. I was prepared for the call and gave an excellent reference (if I do say so myself).


Here are the employment reference questions the hiring manager asked me about the person I was referring:

• Describe the employee’s technical and industry skills.
• Is the employee good at resolving problems?
• How does the employee adapt to using new tools/systems?
• Does the employee demonstrate compliance to regulations?
• Have you observed the employee struggle with time and expense reporting policy?
• Describe the employee’s site communication style.
• How does the employee interact with peers?
• What do you think of the employee’s written expression?
• Do you have anything else to add?

So who should you provide as references? The company you are applying for may want to speak with specific people, but typically they will be happy to chat with a supervisor, a peer, and a personal reference. Supervisor doesn’t actually have to mean your current boss (especially if you are trying to keep your job search confidential or you don’t trust your current boss to promote you well enough). You should provide someone with supervisory responsibility for your work. This could be a line manager, dotted line supervisor, or even a project manager who maybe didn’t directly supervise you but was very familiar with your day-to-day performance and responsibilities. Secondly, I like to provide a peer who is at the same level or slightly higher than me in the organization and who has observed my work in the field. For the third reference, I like to pick someone from a different functional group in the organization or a strong personal reference. For example, I might ask someone from legal, accounting, or data management that I have worked closely with or maybe someone from a professional organization like ACRP or someone who I have volunteered for or with outside of the industry to serve as a reference.


How do you ensure your references are prepared? Ask them if they are comfortable being your reference. Pick someone who is responsive and willing because if the hiring manager can’t get in touch with your references, this could interrupt the offer process (trust me, I know from first hand experience). Then, meet them for coffee or schedule a telephone call or short meeting to help them prepare. Provide them a copy of your resume, a copy of the job description you are applying to, and a list of skills and past successes you want them to highlight. Explain to them why you are applying for the chosen position and what special strengths and relevant experience you think you offer. Request that they write up and post a recommendation of your work for LinkedIn or do a practice run with you so you know you are comfortable with what they are saying. Ask your reference to let you know if they are contacted and get feedback on how it went. Genuinely thank your reference afterwards with a hand written note, a meal out, or a small gift or giftcard.


I am happy to report that my friend has been snatched up by a wonderful company; talented people don’t last long in the marketplace. She is enjoying her new assignment and especially pleased about her 15% raise, did I mention she is a great negotiator? Being laid off can be extremely rattling, but if the quality of your work stands on its own, remain positive, reach out to your network, prepare sufficiently for your job search, help your references prepare, and trust that things will work out.

And the Clinical Researcher winners are...

Last Fall I wrote about the Inaugural US Clinical Researcher Competition offered by PharmaTimes and sponsored by several notable pharmaceutical companies and CROs.  The competition is a peer reviewed challenge to recognize excellent performance in clinical research.  They are specifically filtering for the ideal mix of core clinical expertise and interpersonal communication skills that are vital for successful collaboration in clinical trials.

There were categories for CRAs, Project Managers, and Study Coordinators.  Challengers were nominated to participate by their colleagues.  The first phase of the competition was a 40 item online questionnaire that focused on ICH/GCP.  Successful candidates were then invited to write a role-specific essay which was anonymized and reviewed by a panel of judges. The judges narrowed their selections in March to five to eight finalists across America for each category.  The finalists traveled to Philadelphia yesterday for the final presentation to the judges and the subsequent awards ceremony.

Congratulations to all the finalists and a special thanks to all of the sponsors, supporters, and the PharmaTimes competition organizers.  Please follow these links to learn more about the candidates and the winners.  In particular, the bronze award winner in the New CRA/Site Manager category seems especially familiar to me:

Category Winners:
http://www.usclinicalresearcher.com/Gallery2010.aspx

Category Finalists:
http://www.usclinicalresearcher.com/Gallery.aspx

http://www.prnewswire.com/news-releases/chiltern-wins-award-at-the-inaugural-us-pharma-awards-ceremony-92509264.html

http://www.kendle.com/Clinical_researcher_awards.php

Lead CRA Q&A: Dealing with Poor Performance Feedback

Anonymous said..

I understand the productivity loss, time, costs, etc of choosing an inadequate site; however, what are the ramifications against a CRA who chooses a site that turns into a "dud" site? -APRIL 7, 2010 2:00 PM

NadiaBoBadia responds...


Wow, this is a challenging question.  I only choose great sites that end up as top enrollers and execute the protocol flawlessly so I am completely unqualified to answer - ha!  In all seriousness, I think that in any job or task where you can demonstrate that you performed methodically, deliberately, and intelligently the study team would be hard pressed to fault you in your efforts.  If you build a strong reputation for yourself through quality work and your team trusts you, the backlash from these types of issues will likely be minimized but you still may find yourself "on the hook" for a poor performing site.  During my site selection efforts I keep a log of my activities and communications so I can reflect back on the process 1) to look for potential efficiencies for next time 2) to serve as a training tool for Junior CRAs that I mentor and 3) to demonstrate/remind myself/others that I was diligent and thorough in my original efforts (my colleagues and I lovingly refer to this type of documentation trail as CYA).

If I am called to task on poor performance, I will have some documentation to defend my actions, explain my thinking at the time (hindsight is 20/20), and deflect some of the backlash.  This is a delicate line because you want to explain the history behind errors but you need to be careful not to dwell and beat yourself up too much.  You have to move forward and get recruitment back on track - be proactive and start brainstorming solutions.  Just like we tell our study sites, you acknowledge the issue, you create a plan to avoid the issue in the future (obtain guidance and re-training as appropriate), and you implement that revised process.  So you picked a "dud" site, coach them, encourage them, and try to salvage things if at all possible.  How cool would it be if you worked hard enough and your problem site transformed into a model site?  If all else fails, the study team may elect to close the site and focus efforts into better performers but I hope you have been tracking your site correspondence and have been a good site manager and partner (and can prove it with documentation).


Only an unreasonable employer expects you to perform perfectly at all times.  The best we can train for is to develop a toolkit of monitoring skills and a clin ops intuition for making the best decisions.  At the end of the day, we are human and fallible and need to be able to accept our failures when they do happen (and they will happen, this can be a challenging job).  That said, someone does sometimes need to take a fall and as a CRA you may be grilled or disciplined by the study team.  You may receive poor performance feedback at a review or have an uncomfortable conversation with your supervisor or study team.  In my career,  I have known CRAs who were yanked off of trials or "sacrificed" for political reasons not necessarily performance reasons.  I've witnessed CRAs be unfairly scrutinized or singled out in meeting/telecons for site performance issues that were more or less out of their control.


Having your work or ideas criticized can be humbling and may not be warranted, but it is bound to happen at some point.  I hope for every CRA that negative feedback is always delivered respectfully and constructively.  When your work does not meet your employer's expectations, limit the excuses, graciously accept that feedback, and improve. A mistake can be devastating or it can be a development opportunity.  In other words, you can't undo errors, but you absolutely have complete control over how you react and recover from a mistake.  I keep track of my successes at work in an email folder called 'Praise'.  For example, if I get a note from a peer or a higher up complimenting my work, I file it away for later.  Reviewing the items in the 'Praise' folder is a great pick-me-up when I've had a challenging day or even to share with my supervisor when we are reflecting back on my overall performance at review time.  I've veered a bit off topic but I hope my thoughts on dealing with poor performance feedback are helpful and have addressed your question.


Reader questions may have been edited for spelling or grammar, for reasons of anonymity, truncated, or edited in other ways although the main content remains unchanged.



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

• Meeting with a Principal Investigator August 2011
• Work/Life Balance June 2009
• Routine Monitoring Visits March 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