Lead CRA Q&A: Consenting Subjects Before IMP is On-site

Anonymous commented in... "Pre-Study Visits and Site Initiation Visits":
Post SIV, can a site share the Informed Consent Form (ICF) with pre-identified subjects prior to Investigational Medicinal Product (IMP) receipt at the site? -November 26, 2010


NadiaBoBadia responds...

Hi and thanks for your question. In one of my previous trials, all of our sites consented and screened subjects prior to receipt of Investigational Product. First shipment was only triggered after a second qualifying screening visit (4 week screening window with up to 40% screen failure rate).

Investigational Medicinal Product can only
be released to a site once all of the required
regulatory paperwork is in place.

In order to consent, our SOP required that the site be authorized for drug shipment, rather than requiring that drug was actually physically on site. In order to authorize drug shipment the site must have 1) completed the SIV 2) received IRB approval for protocol, ICF, Investigator's Brochure (IB), and all PRO instruments 3) Submitted complete regulatory document package to sponsor (1572, signed/dated w/i 1 year CVs for all personnel on 1572, Financial disclosures, Protocol signature page, IB signature page, etc. (some of this package goes to the FDA before the trial is initiated at the site) 4) fully executed contract and budget 5) written activation letter from sponsor. At that point the sites were allowed to begin distributing ICFs for review and signature.

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...from The Lead CRA archives:

• Selecting Qualified Investigators April 2010
• Routine Monitoring Visits March 2008
• Close-Out Visits July 2008

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

CRA Orientation and Training

I have been a Clinical Research Associate (CRA) for three years, but I recently accepted a new CRA position and thought it would be helpful for me to explain the on-boarding process. Whether you are working for a CRO, pharma/biotech, or as a consultant, there is always new hire orientation and training to complete. The CFR and ICH/GCP require drug companies to ensure that the monitors like me are qualified by training and experience. In order to demonstrate our compliance we must document that training. Our expertise is also documented in a signed copy of a CV.  Finally, we typically sign and date a copy of our company furnished Job Description to be saved in the training or employee files that serves as an acknowledgment that we understand what is expected of us in our role as a CRA.

I blogged a few years back about my experience in my last New Hire Orientation but I will elaborate today on what types of Standard Operating Procedures (SOPs) and training courses a CRA might reasonably expect to complete at any company. So the important thing to note is that you repeat some form of this training at any new company whether you have one year experience, five years experience, or twenty years experience.  In fact, even within a company you may find that you repeat these trainings annually or periodically - this protects you and the company because you have a documentation trail demonstrating your qualifications to monitor clinical trials.

Everyone signs off on the required training before they step foot into a clinical site. This protects you as well so be wary of any company that wants you to go out and monitor without proper training and qualification documentation in place - it really can be a risk for you.

Companies typically offer new CRAs administrative training, regulatory/procedural training, and project specific training.  Trainings can be administered via a traditional classroom setting, via webinar/teleconference, over the internet using recorded playback sessions, in person, or on-the-job.  Obviously there are pros and cons to the different formats (opportunity to clarify and ask questions, assess understanding, consistency of training delivery, level of interactivity and engagement, etc. but that is a bit off-topic for this post).  Irregardless of the format, at the end of each training some documentation is typically generated and signed (may even be signed electronically) to detail who led the training, who attended, the topics covered, and the date of the training.  You may be in training for a few days or even a few months.  The formality of a new CRA training program is very company specific but I am going to attempt to generalize the three categories of required training that I have experienced.  This is not exhaustive and certainly these may not all apply to you:

CRA Administrative Training
General: How to Order Office Supplies, Completing Timesheets, Expense Reports, Travel Policy

Information Technology (IT): Accessing the Computer, Intranet and Email Policy, Company Specific Websites or Applications, Using Microsoft Outlook/Lotus Notes, Setting up Voicemail and Email Signatures, Electronic Data Capture (EDC) System

Human Resources (HR): Company Overview, Employee Benefits, Performance Review and Employee Development System, Ethics and Compliance, Insider Training, Conflicts of Interest, Privacy Policy, Dispute Resolution, Harassment/Sensitivity Training, Ergonomics, Workplace Safety

Regulatory Procedural Training
Regulatory: 21 CFR 312 & 812; 21 CFR Parts 11, 50, 54 & 56; ICH/GCP; Good Documentation Practices; HIPAA/Confidentiality

SOPs: Informed Consent Process, Investigator Site Selection, Pre-Study Selection Visit (PSV), Site Initiation Visit (SIV), Routine/Interim Monitoring Visit (MV), Close Out Visit (COV), Source Document Verification, Record Keeping and Retention, Electronic Signatures, Fraud and Misconduct, Protocol Deviations, Audits, Inspections by Regulatory Authorities

Project Specific Training (may overlap SOP and general training)
Writing a Monitoring Report
Monitoring Plan
Trial Master File Maintenance
Completing Site Contact Records
Case Report Form (CRF) Completion Instructions
Integrated Voice Response System (IVRS)
Using Diaries, PDAs, or other Patient Reported Outcomes (PRO) Instruments
Protocol Training
IRB & Regulatory Submissions
Study Budget
Investigational Product Handling and Accountability
Randomization and Unblinding
Study Supply Management
Serious Adverse Event (SAE) Reporting

I hope this overview was helpful. I am happy to expand on any of this - just comment or email to let me know if you have follow-up questions.

Efficiency Tips: Spend less time on Monitoring Visit Reports

As a monitor, you may visit several different study sites in a single week and possibly for different protocols. I often find when I get home from a trip like that it is hard to write my report and keep the details of the different sites straight. One thing I have done to successfully overcome that is to draft my report before I even do the visit. On most studies, your Lead will provide you with a template report that you will need to complete following each visit type. You might also use an electronic system to create your reports but luckily, mine are usually just MS Word templates. Every report is guaranteed to have a header section that includes the MD name, facility name and address, visit type, visit date, date of last visit, and list of attendees. You probably know all of this information before you step foot on the site so just fill it in before you go.

Things I am unsure about I highlight in yellow so I remember to return to them later. Unless this is your first visit to the site, chances are there is a previous report completed by either you or another CRA that has items that probably need to be carried over to your current report. You will want to refer to your company's SOPs and your project-specific monitoring plan to know which items get carried forward. On some of my recent reports, this has included Enrollment data (I can usually get the current number of Screened, Screen Failed, Enrolled, Early Term, and Completed subjects from the IVRS system before I even show up for the visit), summaries of Protocol Deviations to date (they stay on the report until the IRB acknowledges receipt of the deviation), SAEs that are not resolved, Regulatory Documents that need to be collected, and pending Action Items or those that have been resolved since the last report date.

Drafting your report before the visit has the added benefit of helping you write your confirmation letter and get a grasp on what activities need to take place during the visit. You will be organized before you get there and more likely to monitor efficiently if you know exactly what is outstanding.

While you are at the site, avoid keeping notes on notebook paper; just write pending items directly into the Action Items or other applicable section of your report. If the items you notes are resolved by the time you leave you may decide to dump them from your report (depending on how much detail your company/sponsor is looking for) and if not, mark them pending and submit them as part of your draft.

When I am at the airport waiting for my flight to board, I can usually knock off a draft report in about 20-30 minutes. Then when I have internet access, I just submit it and forget it (or at least until I get a revisions request)! What efficiency tips work for you?

Not getting any work done in the airport terminal?
Your company may reimburse you for airport lounge
access or you can typically get a discount pass through
loyalty to an airline or credit card offers.  In the lounge
you can be productive, enjoy snacks and beverages,
access the internet and a business center plus plug
in all of your devices.  

Pre-Study Visits and Site Initiation Visits

Depending on the company you work for and the Standard Operating Procedures (SOPs), you may be required to complete an in-person Pre-Study Visit (PSV) before an investigator is initiated to join a clinical trial. In some cases, you may even be able to perform this via telephone, web-conference, or it might be waived altogether (say, for example, an investigator your firm has collaborated with in the past 18 mos or so).

The objectives of a pre-study visit are to review the adequacy of the site, the training and experience of the study staff, the access to the right patient population, and the site's interest in the study. If the site isn't motivated or if they are already participating in studies that would compete for the patient pool, they may not be a good recruiter. It is expensive to start up a site, monitor them, and supply them with all the study materials and training. Ideally, you would only open sites that would perform well but in reality, there are always 'dud' sites in every study (Read my related post on Selecting Qualified Investigators). This is typically a 2-4 hour visit. After your visit, you will likely need to complete a report template or assessment and send a follow-up letter to thank the site for hosting you and inform them whether or not they have been chosen to participate in the study.

At an Investigator Meeting there may be
presentations and break out sessions
to answer questions and train study
staff with the skills required to properly
execute the protocol.

The initiation of a site can sometimes occur at an Investigator Meeting (IM) where all the potential investigators are brought together in (a typically quite fancy) hotel or other conference arena to receive group training on the new study. More often, however, this will actually take place - on-site. This is usually a 4-8 hour visit and you may be accompanied by a Project Leader, Medical Monitor, or even Data Management personnel just depending on the desire of the sponsor. Before your visit, you will coordinate a convenient time for the study site and confirm your visit with a letter informing them when you will arrive and what the objectives of the visit will be. It is important to physically be at the site so, as a monitor, you can visit the labs, pharmacies, and other areas where the research will be conducted to ensure they are adequate. For example, both labs and pharmacies should have restricted access and the site should know where it will store the Investigational Medicine/Product (IP) and this location should be locked. If the site will be storing blood or tissue samples, you will inspect their freezers and ensure that they maintain adequate temperature logs and have standardized sample handling protocols and training.

During your initiation visit you will probably spend a great deal of time training or reviewing the study protocol design and answering questions from the site personnel. You will also want the Principal Investigator (PI) to be available for specific parts of your presentation. Specifically, you will need to discuss the Investigator's Responsibilities as related to the regulations to ensure there is agreement and understanding (The investigator may choose to delegate some of his/her responsibilities but ultimately, they will be responsible for all actions and conduct of the study. Specific study related activities can only be delegated to those who posses adequate training and experience -- a secretary cannot perform a Physical Exam, etc.); You will explain publication policies and documentation responsibilities; You will inform the PI that you will need timely access to subject's records and the acceptable time frame for completing patient data case report forms (CRFs) and answering queries regarding the data). Document everything that is discussed so you can add it to your report and if there are any questions that are unresolved at the end of your visit, you can include resolution for those in your follow-up letter after the visit.

Email me if you have more specific questions. Now that our study is underway, next time I will discuss how and why we complete routine monitoring visits throughout the study conduct period.



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

• Selecting Qualified Investigators April 2010
• Routine Monitoring Visits March 2008
• Close-Out Visits July 2008

Staying Flexible and Creating my CV

Working at home isn't all bad but I
have to stay focused and shoo off
distractions like my little yorkie, George.

I have been kicked back at home in my bunny slippers pouring through the SOPs and online training courses for my new CRA gig. As of orientation, I was assigned to one study but now I have been picked up for 2 different ones (luckily in lieu of the first rather than in addition!). One of the first tasks every new CRA at a CRO must complete is entering your Curriculum Vitae (CV) into the corporate database. CV is fancy biotech jargon for résumé (Wikipedia tells me that CV is Latin meaning "course of life" and résumé is French meaning "summary"). Basically, you want to chronicle all of your past relevant work experience but more importantly, you must complete an inventory of all of your relevant skills and therapeutic experience. I had to indicate which Phases of clinical trials I have experience in, what types of studies I have worked on, and quantify everything...3 months? 6 months? 1 year? The other fun part of the CV was the summary section where you write a little paragraph about yourself in the third person.

BIOGRAPHY
Nadia BoBadia, BS is a CRA II responsible for monitoring clinical studies with various indications. Before joining the company, Ms. BoBadia was employed as an in-house CRA I at a specialty cardiovascular biotech company, where she managed site budgets/negotiation,forecasts/accruals, and processing/disputing invoices, along with monitoring 3 Phase I cardiovascular and pulmonary trials. She traveled internationally to support FDA audit inspection preparation visits and NDA triggered activities for 2 large Phase III studies. For two years Ms. BoBadia was employed at a CRO and an Electronic Data Capture (EDC) company performing data management functions including designing CRFs and clinical study databases for a variety of therapeutic areas. Prior to that she was employed at one of the top 3 pharmaceutical companies and a large biotech performing commercial product and field sales personnel support for pulmonary and CNS indications. She has additional experience as a project assistant on a Phase III Ophthalmology study. She joined the company in 2007 as a CRA II.

So this electronic CV is what the sponsors (pharmaceutical and biotech companies that have contracted with my service company to run part or all of their studies) use to decide whether or not you are appropriately trained to work on their studies. So even though I have a job, it is like I am constantly interviewing in order to be able to do my job (get billable hours/activities). I know in time my skills inventory will be so impressive that sponsors will be delighted to pick me up for their studies so that is definitely satisfying.

Half of the folks from my training class are already out traveling and monitoring but I have to finish my study specific training (reading the protocol, monitoring plan, sponsor SOPs, etc.) and receive my site assignments. Right now I am projected to start traveling the week of Dec 2nd so I am just enjoying the downtime while it lasts. I have been enrolling in benefits, setting up my home office, playing with my new printer/fax/scanner, ordering office supplies, and generally keeping myself busy.

New Hire Orientation

I have been at new hire orientation all week. We started at 8:30a on Monday with HR. They reviewed new employee stuff including company history, benefits, and general company information. I was greeted at lunch by two long-time employees who took me out for a nice meal and told me more about the company culture and their studies. Most of the CRAs at training already knew what their assignments would be but I didn't even know who my manager was at this point.

After lunch, IT came in to deliver rollerbags and laptops. My laptop is more like a workstation (but it is tiny, light, and so cute!) because I have no administrator access and can't even change the system time or download a thing. Sites like YouTube are blocked but luckily Blogger works! Unfortunately we use Lotus Notes so that will take some getting used to. In my previous CRA position I was addicted to my MS Outlook calendar and contact functions. I have a PDA phone by Motorola so I would sync this constantly and it will be hard to go without. Lotus is 21 CFR Part 11 compliant and my CRO has chosen it because of its database capabilities. Every study gets a repository where essential trials documents and forms are stored and this is all shared through Lotus. This is better than a share drive because the repository can be 'replicated' which is a fancy term for saying I can view it even if I can't get on the VPN. For homework I had to read the employee manual.

I talked a few of the CRAs into joining me for dinner so it was a fun and relaxing evening. The next morning we reported for CRA II training. There were 6 of us in the class and we are all Regional associates (4 from the East Coast and a gal from Phoenix). CRA training lasted only about 3 hours and was just a quick review of ICH/GCP and a 'how-to' for source document review. After lunch we learned how to track our time. The system we use is not terribly complicated and I finally found out what study I would be working on and since it is only one at this point, reporting my time won't be so difficult. As CRAs, we are expected to be 85% billable. That means I need to be traveling or doing client work most of the time. I have to 'bill' these items to the sponsor by accurately completing my timesheet. This is easier said than done; I have been telling people it requires a bachelor’s degree because each 15 minute increment has to be coded to the specific task you are completing so it can get complicated. For homework we had to mock up a sample timesheet. Luckily completing your timesheet is billable because it takes a while!

All the new CRAs are asked to take part in a bull-ride
challenge.  If you can last 30 seconds you advance
to the next day of training.  Just kidding!

The third and final day of training was a hands on demo of how to complete an expense report. Again, this is no easy task. It is made easier by the fact that I was issued a Corporate Amex. I will put all charges on my Amex (except where it isn't accepted) and keep my hotels under $150/day and meals around $50/day unless I have written manager approval to go over (which will be required depending on what cities my sites are in). There is no preferred airline but I will be using National car rental and usually Hilton hotels as they are the preferred vendors. A large CRO can have 'preferred vendors' because they require traveling employees to use Amex. In this way, they can run queries to see how many nights employees stay in hotels and things to negotiate special preferred rates. I will have $30/mth for a cell phone stipend, my broadband and phone line will be reimbursable including installation. I have been given a $1600 stipend to furnish my home office. Lucky for us, charges to the Amex pre-populate into the expense report so that helps. Corporate pays the card directly as long as I submit the expense report within 14 days of the trip. Airfare will always be non-refundable so I can submit the expense report the moment it hits the Amex and do not need to wait for the trip to actually occur first.

It was a busy 3 days but a lot of fun, too and I may never again venture to corporate headquarters so it was a nice opportunity to get a glimpse of how the home office runs. I will hopefully have project specific training soon and meet my line manager (at least over the phone anyway). Now I am busy reading SOPs and doing on-line training for the next few days.