you got a password?

A sponsor recently presented some site audit findings at an investigator meeting and I think two of them are definitely worth repeating:

1) The site has a number of personnel that were granted IVRS/EDC access, but never changed the initial passwords or accessed the system at least once.  So what's the big deal?  Well when user accounts are generated an initial password is created, which is sent either by email or fax and must be changed (by the person whose account it is) to something unique.  The sponsor is likely arguing that if an account is never fully activated or deactivated after the initial access information is sent, then that log on information could easily be abused by someone who is not supposed to have permission to access study specific files or databases.  The take home messages here are that if you have multiple users for a number of EDC/IVRS accounts, make sure that those individuals log in at least once when access is granted and if someone leaves the site (or study), contact the system administrator to have their account deactivated.
   Seems easy enough, but I imagine there are lots of situations where this situation exists at research sites.

2) Eligibility reviews.  The same sponsor noted that they are looking out for an assessment of continuing study eligibility by a qualified investigator at every visit up to (and including) randomization.  This includes washout visits, run-in visits, and screening visits.  Such a request is there to demonstrate that the site is continually monitoring subjects for eligibility and that inappropriately qualified personnel are not making decisions concerning subject eligibility.  While it may seem like more of a hassle than its worth, the eligibility assessment prior to baseline can be as simple as a statement signed by an investigator that a subject "meets all study criteria at this time."  Once that's done, you're in the clear (but of course, make sure the investigator is actually assessing eligibility...no blind signatures, please!)

Linked Up

EDC provider OmniComm has announced that it has finalized plans to link its TrialMaster EDC with an electronic medical records platform: MS HealthVault.  This plan would allow for those patients or providers using this medical records system to seamlessly upload their records to the EDC system. Sites using paper records are currently stuck in a perpetual battle with ensuring that the information they report about trial participants is accurate and up to date.  Such a connection between electronic records and EDC would eliminate the need for tedious data entry for medical history and allow for the inclusion of more detailed participant history into the trial database.  I imagine there could be all sorts of interesting trends that could be gleaned from the merger of EDC and patient records, likely going above and beyond what is possible today.

The one thing that this merger of EDC and EMR would need to recognize is that patient confidentiality has to be maintained.  There has to be some sort of mechanism to remove confidential patient identifiers from the records before transfer into the EDC system while at the same time allowing for identification of patient in the trial database (by date of birth, initials, etc).  Check out this link for more information: OmniComm

Also, in an unrelated note, I think it's worth mentioning the importance of organization for clinical trial sites.  If a site is audited one of the worst things that can happen is to have files in a state of disarray.  This will frustrate the auditor (amongst other things), and cause he/she to start looking more closely for problems.  Yes, the auditor is there to perform a detailed review of the study files, but it's in the site's best interest to make the auditor's job as easy as possible.  One of the best ways to do this is having everything in order because uniformity, clear labeling, and precise filing can do wonders for a site.  More to come on this later...

Spread the Word

The FDA has taken what I believe to be an important step to increase public awareness of what exactly the agency does by creating a section of their website called "FDA Basics."  The idea behind this website is that most people don't really know what all the FDA does and how the FDA does its job.  It looks like a work in progress, but it does have a section on "drugs," which contains some information about the drug approval process as well as enrolling in clinical trials. 

Research sites should take advantage of this resource and use it to not only inform site staff of the FDA's functions, but also present it to potential trial participants as a free educational public outreach tool.  Clinical trial sites are always struggling to find better ways to inform the public on research studies.  Often the problem is not getting word out via advertising, but rather actually educating people on how and why clinical trials work.  It's important to remember that a critical part of informed consent is the actual "informed" part, which may be detailed in descriptions about a study but could be lacking on a description of the "big picture" of clinical research.  That's where this new website from the FDA can help: it has the potential to offer information direct to participants straight from the top regulatory authority in this country.  I think that the site could stand to have more detailed clinical trial background information, but it's certainly a step in the right direction.

Feel free to share the site on your websites or in your conversations with staff and potential participants:

http://www.fda.gov/AboutFDA/Basics

return of the paper CRF?

Everyone has heard about the recession and the economy affecting almost every industry out there.  In clinical research the recession has tightened R&D budgets and made new trials harder and harder for sites to come by.  In line with this trend, sponsors are always looking for new ways to cut costs such as limiting CRA travel and taking lower bidders for study vendors.  But how about the technological revolution in clinical research?  Is its growth going to be stunted by the recession?

The main example I'm thinking of is with case report forms.  I'm thinking that some sponsors may forgo the expenses of electronic data capture such as bidding for services (those RDE companies cannot be cheap at all) in favor of more traditional paper case report forms.  Yes electronic data capture is faster, more efficient, and cleaner (no illegible handwriting), but paper case report forms are likely cheaper to implement for smaller studies even if the data takes longer to process.  I may be wrong about this, but I think it's a situation that sites should consider because most studies at this point are using some form of electronic data entry.  However I should mention that even if paper CRFs return (at least for the short term), it won't be long before they are totally obsolete.  The emergence of the entirely paperless source document is just around the corner and if you want to talk about a real game changer, that will certainly be it.

In the meantime, if you start seeing more paper CRFs come your way don't say I didn't warn you!

Pharma Audible

Fierce Biotech and the Wall Street Journal reported today on the evolution of Research & Development at Eli Lilly.  In a nutshell the pharma giant is changing the way it gets from novel molecule to blockbuster drug by outsourcing more and more of its R&D operations to CROs instead of running them in house.  On the surface, it makes sense that most huge pharma/biotech companies cannot reasonably do everything at once without tearing themselves apart, but this trend (which is mirrored by companies like Sanofi, GSK, and Pfizer) also has implications for clinical research sites.

For example with Lilly's growing investment in CROs for R&D, it is exceeding important to maintain strong relationships with CROs as they will provide valuable feedback to the study sponsor about the quality of work coming out of research sites.  If a site is a high enroller, collects clean data, has few deviations, and is generally pleasurable with which to work, then that site would likely receive a favorable recommendation from the CRO to the sponsor.  Present studies beget future studies, and the best way to ensure this continues (and that we all stay in business) is to provide high quality work with high quality customer service.  I believe that Lilly's movement towards more collaboration with CROs is a sign of the changing times, and sites must work harder than ever to ensure that a good reputation precedes them when being considered for new studies.  A good reminder of this fact comes straight from the Code of Federal Regulations that basically says if a sponsor elects to delegate certain clinical trial responsibilities to a contract research organization, then that organization assumes the role of the sponsor....keep that in mind when working with CROs...they have essentially the same authority as the sponsor itself!

Oh, and here's a few reminders about good customer service:

-Be prompt in returning voicemails and emails (every "customer" is important!)
-Act/Dress appropriately when working directly with sponsor/CRO representatives
-Respond to requests in a timely manner...this includes queries/data entry (few things please a sponsor more than fast/accurate CRF transcription)
-Be organized! (this took me a long time to figure out, but I'm glad I did!)
-Be confident, but not cocky...know your stuff, but don't flaunt it.

Keep your Guard Up

Two years ago Quintiles launched iGuard, a personalized medication monitoring service for patients that doubles as a clinical trial recruitment tool.  The multinational CRO has reported (as reported by PharmaTimes) that the service has over 2 million enrollees (Quintiles claims this is more than Twitter got  in its first two years...a strange claim that to me is meaningless...like comparing apples and oranges...but that's another story) and that iGuard is even helping to reshape the clinical trial enrollment landscape. 

The method by which this is allegedly happening is that patients are emailed information about a clinical trial and they either opt-in or they don't.  Simple enough, but the other way that this service seems to be assisting trial recruitment is through patient feedback on new advertising schemes, compliance promoting measures, and retention tools.  Doesn't that sound weird that the largest CRO in the world is making a big deal out of this when involving potential trial participants in the clinical trial process seems obvious?  It has long been a concern of mine when central recruiting services present advertising and retention items to sites that clearly aren't effective, yet they are required by the sponsor to be utilized (some recruiting services, in my opinion, use more smoke and mirrors than actual results when selling their product to sponsors...but again, that's another story). 

This system put together by Quintiles is a better example of how trial recruitment and retention should be researched and developed.  After all, the participants are the ones that we are trying to bring in, so why not ask them what would catch their eye or what would encourage them to remain in a trial?  Unfortunately because iGuard is managed by Quintiles, the results of such research remains the property of CRO and will likely not be disclosed to anybody who asks about it.  Research sites, though, can take this plan and come up with some ideas of their own to get potential participants involved in the recruitment process.  Here's a few ideas off the top of my head:

-Send out a poll included in an email newsletter asking about what recruitment ideas work best

-Have participants fill out a survey asking: why they participate?  why they remain in the study?  what would make them more likely to complete a trial rather than drop out?  less likely?

-Interview willing participants on their entire trial experience, from recruitment to completion

-Be visible in the community.  No one can argue against the importance of branding in advertising, so get out there and make a name for yourself.

I got the right temperature

Over the past couple weeks, there have been 3 notable incidents involving publicly available (and administered) vaccine efficacy being compromised.  In two separate events MedImmune and Sanofi Pasteur recalled hundreds of thousands of H1N1 vaccine because of lower than expected antigen levels while in Ohio, a clinic had to inform over 2000 people that the H1N1 vaccine they received could have been frozen, thus potentially destroying the effectiveness of the shot to protect against swine flu.  While these occurences are likely unrelated, they still represent a serious issue in the vaccine supply chain.  The manufacturers all work as quickly as they can to produce a quality product that will protect patients from influenza, but sometimes things go wrong and in this case they went wrong at the worst possible time.

The Ohio incident could happen in any clinic, but what is bothersome to me is that the vaccination site claims that the vaccine was received in good order and was stored properly, thus indicating that the vaccine was either not packaged properly (eg with too much coolant) or was stored improperly at the distribution center.  The other problems with low antigen levels are a strictly a sponsor problem, but they still shouldn't happen, especially when the public expects a quality vaccine to be produced that is not only safe, but also does what it is supposed to do.  How do clinical trials factor into this?  Well, as anyone involved in trials knows, sites and sponsors spend a large amount of time ensuring that the investigational product is shipped, stored, and administered properly.  This includes strict temperature monitoring requirements in storage and shipping with the potential for significant consequences from sponsors and regulatory agencies if these requirements are not met.  Temperature excursions can even compromise a site's ability to conduct vaccine trials because of the fast paced enrollment requirements of many studies (the mantra for many vaccine studies is: you snooze, you lose.).  Sponsors must also adhere to strict temperature monitoring requirements because the FDA would likely not look favorably upon any submitted data that did not contain sound storage/shipping documentation (don't forget that ICH GCP guidelines and FDA regulations require this).  The same goes for efficacy testing of investigational products, but that does not affect the sites to the same degree as temperature monitoring.

My message here is twofold:

1) Just because sponsors have an approved product, does not mean that a product should be shipped/stored/evaluated with any less diligence than in a clinical trial.  Yes, the FDA won't pull a product off the shelves because of a temperature deviation (maybe a big fine for some egregious error), but public safety is still on the line.  Please note that I'm not saying this happened with the recent issues, but it is a possibility

2) Research sites should look at these events and learn from them.  Take the time to review practices for receiving, storing, and dispensing investigational products so that all federal and sponsor guidelines are met.  Temperature monitoring is a really big deal, and it should never be overlooked or undervalued as somehow less important aspect of clinical trial conduct

The CROs can get it too

Sometimes it seems that whatever research sites do, there is always the threat of regulatory agencies coming down hard on investigators.  Don't do this a certain way or the FDA will get you.  Make sure you document this like so, or else an auditor will cite you.  After hearing this repeatedly a research site must wonder if the bullseye is always squarely on the investigator.  If you think I have good news about that, you're right..sort of.  First of all, the responsibility to properly conduct a research trial does lie first and foremost with the investigator, but the FDA also has its eyes on the sponsor and those who contract with the sponsor to conduct the research.

This fact was brought to light last week when the FDA issued a potent warning letter to ICON, citing their inability to properly monitor a research study.  Granted, the findings were likely issued to the corresponding investigators, but the number of citations was a reflection of the lack of a sound monitoring plan.  This warning letter was surprising to me because the types of errors noted are not nitpicky, rather they are surprising violations of a variety of FDA regulations and GCP.  I was shocked at the different findings noted by the FDA and even more surprised that the errors were not picked up during routine monitoring during the trial.  Obvious drug dosing inconsistencies, discrepancies between the source and CRF, lack of drug accountability; the list goes on and on, but the point I'm making here is that even though monitors will always remind investigators of the importance of following FDA regulations and GCP, the monitors are also held accountable for their work (or lack thereof, when applicable).   

So, research sites, read the warning letter and realize the burden of clinical research isn't squarely on your shoulders.  Remember too though, that patient safety is your responsibility and if you ever question the quality of monitoring efforts, you can discuss this with the study sponsor.  Both parties have a vested interest in quality study monitoring, and the FDA will take no sides when reviewing study data.

Read the monitoring letter in its entirety here