Thinking About Site Startup

I've been thinking a lot lately about how important it is to choose the right clinical trial sites for the success of your trial.  Just last week I blogged about the painful process and high costs of closing non-performing or under-performing sites.  I recently told a non-industry friend that it can take upwards of 18 months sometimes to usher a clinical site from selection to initiation.  He responded, "well that make sense since many clinical trials last several years and it takes a while to give the medication to enough patients to test it out thoroughly."  Then I realized he had misunderstood me, I clarified, "Initiation means the doors are open. At initiation, a doctor can start looking for patients.  I am telling you that it can take one year or more sometimes just to get a site open for recruitment to start the trial."  He was floored and responded, "no wonder we're paying so much for our prescriptions..."

I recently went to an ACRP seminar called 'Why Sites Fail in Study Startup'.  The dynamic speaker, Christine Pierre is the President of RxTrials Institute (RxTi) and gave a terrific talk.  If you would like to meet her or discuss this topic further, perhaps you would like to attend the Site Solutions Summit in October.  I haven't booked my travel yet but I am definitely considering going.

Early bird rates are available now!

I am excited to see the next-generatiion startup
tracker product when it is released. 

Then, a few days ago I traveled to downtown San Francisco, CA to visit the offices of goBalto. This innovative company has developed a web-based platform for Clinical Study Startup, Tracker™. The software "enables clinical trials sponsors to collaborate with multiple partners directly from the web in a transparent and regulatory compliant manner".  They invited me to a demo of their next generation product to participate in a user feedback session.  I was really impressed and found them to be extremely forward-thinking.  I am excited to see the product when it is released.

So, all of this has led me to develop a new series for the blog focusing on: Site Startup.  In addition to my work as a Lead CRA, I have been involved in clinical study site startup for a variety of pharmaceutical companies pretty much without interruption for the past 28 months.  Whoa, over 2 years you say?  "Surely, Nadia you must have tremendous experience launching study sites for many clinical trials in that time!"  Yeah, well uh, regrettably, no.  However, in that time I have worked with six disparate clinical operations teams and supported the process of opening a few hundred sites in five different countries (mostly Phase II trial sites).

As a regional monitor at a CRO, I would routinely assist with pre-study site selection visits and administration of feasibility questionnaires but the majority of my work was 85% regional monitoring and site management once sites were open.  Since I have moved to an in-house role, I spend a lot more time in the start-up side of things, buried in spreadsheets, trackers, dashboards, and demands from my boss and the board of directors, so I have gleaned some valuable insights. We'll be stepping through several broad topics of site startup in the coming weeks including:

• What are the typical milestones of site startup?
• What is feasibility? How do sponsors choose which clinical trial sites they work with?
• What is an essential document package and a regulatory submission?
• Informed Consent Form templates
• Site Budgets
• Why do contracts take so long? How are they complicated?
• Developing Investigative Site Patient Recruitment Plans
• IRB submissions
• Calculating Investigational Product needs
• Providing study supplies and source documents
• Ensuring sites are adequately trained and prepared to participate
• What correspondence goes in the Trial Master File?
• Metrics, trackers, reports, and dashboards 
• Gating tasks...bottlenecks
• Lessons learned, where did the process breakdown?
• How to speed up site startup?

What is missing from this list? Do you have other questions or topics that you would like me to cover related to site startup? Please leave me a comment or drop me an email at leadcra-mail@yahoo.com.

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

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