This Way or That

One problem with auditing and monitoring is that there is too much inconsistency as to how things should be documented.  A prime example is with date formats.  All of the following are ways of documenting the ninth day of September in the year 2009: 

 9/9/09
 Sep 9 2009
 09 Sep 2009

 But which one is correct?  The answer is all of them, but only if every date in the source is in the same format (according to most auditors and monitors).  I actually have been asked by a monitor to correct date formats because they weren't consistent or because the sponsor provided source asked for the date in a different fashion.  I think something can be said for consistency, especially in raw data collection processes such as educating all investigators on one way of performing exams, but why should sites be slapped on the wrist because a coordinator one day decided to write the date in one format and the next day uses a different one?

 I like the variety, I believe it personalizes the original documentation and does not need a special explanation as to why there are differences in the way dates are formatted.  I believe that auditors and monitors should be concentrating on the bigger picture, not scrutinizing the difference between date formats to attempt to identify fraud (As a side note I would bet that if someone really wants to make up data, it probably won't become evident through differing date formats).  Just like with personalized initials on consent forms instead of simple block letters, the freedom to record different date formats is important to preserving the originality of original source documentation in clinical trials.  Unfortunately, this argument would  likely not hold water for most auditors because of the good ole' consistency card that would be played against the site.

The bottom line is that the majority of sites are doing their best to collect quality data for study sponsors, and differences in date formats are a result of individual people putting their individual stamp on a trial while collecting this data.  Until this is acknowledged universally regulatory authorities should consider implementing a standard date format to be used at all levels of clinical trials. While this would remove some individuality of clinical trials, it would at the very least give sites some definite ground rules and hopefully prevent some generally meaningless queries at the hands of a monitor or auditor.

Screen me, please

A site's relationship with clinical trial participants starts at the initial contact.  For most sites this first contact is picking up the phone to either call or receive a call from a potential participant, and I think that in many cases the power of establishing a relationship here is grossly undervalued.

Customer service is a hallmark of any industry that sells goods to a consumer.  Just like any muffler shop, department store, or restaurant a clinical research site relies on "customers" to function and turn a profit.  However if potential subjects are left with a sour taste in their mouth after the initial screening conversation over the phone, then they may not be likely to show up for their visits or, even worse, they may spread word around that the site is incompetent and rude to their patients.  If you called a car repair shop and the voice on the other end was rude, short, and uninformative, how would you be likely to respond?  Would you be likely to take your business there?  I didn't think so.  The same goes for clinical trial recruitment.

That being said, sites should ensure that not only will phone calls be answered and messages returned within a tight time frame (think 1-2 business days), but also that the people performing these calls are friendly, able to empathize with the caller, and knowledgeable about the protocol.  I'm not saying that those who take the calls at the site become best friends with the callers, but establishing a cordial phone relationship is important to helping ensure that enrollment gets off on the right foot.  While research sites are not selling physical goods, we are salesmen in a way and establishing a long term relationship with our participants is the best way to entice return customers.  Establishing this relationship should start with the first contact.

Black and Blue

Is it really a requirement that consent forms are signed with black or blue ink?  I don't see what the big deal if someone wants to use red, pink, green, or any other color to sign the consent form.  Yes the majority of people have either blue or black pens, but what difference does it make when it comes to signing the consent.  I would think that as long as the consent is signed in pen, not pencil or crayon, it would be valid and immune from any monitor or auditor's comments.  My reasoning is twofold:

1) Isn't it easier to distinguish and original signature from a copy if the original is in colored ink?  I have seen it happen too many times where the original consent is given to the participant instead of the copy, likely because it was not easy to tell the difference between the original and the copy (this can happen much more frequently with gel-ink pens, so use ball point if you can...and press hard when you write).  Furthermore if you have a large, quickly enrolling trial with many consents, it is easier to separate originals from copies if the signatures/initials are in colored ink.

2) The consent is designed to reflect the subject's individualized signature, and this can be more accurately displayed if the subject is permitted to use colored ink if that's what he/she has brought to the visit.  I'm not saying that subject's should be given a choice of color, but rather if the subject brought a red pen, let him or her use it to sign the consent.

To me the idea of only using blue or black ink (black ink only is more ridiculous) is not something that should be enforced or documented as a deficiency in clinical trial documentation.  I believe the requirement for those colors is more derived from the days of paper case report forms where lighter colors might not show up 3-part NCR paper.  Those days are over, and if someone wants to use colored ink, that should be perfectly acceptable.  A CRA once told me that he prefers colored ink because it personalizes the documentation and gives a better indication of the original and contemporaneous nature of the documentation, both of which are critical attributes of complete source documentation in clinical trials.

Is it good to recycle?

One common recruitment technique utilized by pretty much every research site is the recycling of research participants, but is this really a good thing?  On the one hand people who have participated in multiple studies are experienced in the conduct of trials, are aware of the time commitments, and most importantly are aware of the their obligations to report medication/health changes.  On the other hand, research naive participants have not been exposed to an investigational product before and may actually have a keener sense of changes to health/behavior that might be cause by a new drug or device.

Even though these investigational products have been evaluated to the point where metabolization rates are known and subjects are prohibited from participating in a study at least 30 days following previous study completion, I feel that any participation within the past 6 months or so could be grounds for disqualification from a trial.  This is for a couple reasons.  The first is that these drugs are still under development.  Even though researchers know a lot about their metabolism, it would make sense to me to wait much longer than necessary before allowing participation in another clinical trial just to err on the side of caution.  Imagine the situation if a subject finished one trial, waited 30 days, and then jumped on board with another trial, only to develop some nasty adverse event.  Seems obvious that the first investigational drug didn't cause the reaction because of the length of time between trials, but how can we be sure?...I mean the drug is still being researched and even if we're talking about a Phase IV trial, scientists are still learning about the drug.  Better to wait extra long than risk it, in my opinion.

The second reason is logistical.  If a study prohibits those people from participating in a previous trial only within the past month, participants would be more likely to jump from trial to trial in search of a better treatment or money.  I have seen it before where a subject is enrolled in a trial and loses interest (could be because he/she finds about a different study in which she might be interested) in the study before completion.  The subject discontinues prematurely, only to jump over to another trial at the conclusion of that 30 day period.  If the minimum wait time was a mandatory 6 months after receiving an investigational product, people might think twice about discontinuing for that reason or, hopefully, signing consent for the study in the first place.  Some studies actually do use more stringent rules for determining the eligibility of previous research participants, but that certainly isn't the norm because a lengthy wait time hinders enrollment to a certain degree (and of course if enrollment is slowed by even 1 subject, money is wasted).

I believe the entire industry would benefit from tighter restrictions on participation in multiple clinical trials, but unfortunately the number of people willing to participate in any study needs to grow considerably before this would even be considered.

Out of Control

This supply situation is getting out of control.  One would think that in today's economy sponsors would be more mindful of how their resources are allocated to save time and money.  Apparently, that has been completely overlooked as far as supplying the sites with variety laboratory things.  For example sites are often issued lab specific shipping boxes, bags, and gel packs (to function as a coolant in warm environments or serve as a temperature buffer in temperate climates).  However most sites never use all of these supplies and are left with a ridiculous surplus that the labs will not accept as a returned item.  Because research sites vary greatly in terms of storage space, many of these surplus items are simply discarded and, likely, rarely recycled.  This is a travesty and waste of resources, both human and environmental.  How can this be fixed?  Let me propose a few options:

-Prior to study initiation, the lab contacts the site and inquires on the site's current inventory of shipping boxes, basic phlebotomy supplies, gel packs, etc.  If the supply is sufficient, the lab will refrain from sending supplies to the site until the site actually runs low and asks for them.

-At the conclusion of a study, the lab offers a research site the option to return unused supplies such as unopened lab kits, boxes, etc.  These could be recycled to other studies or destroyed if they are expired.

-Central laboratories should perhaps consider one standard shipping box instead of lab specific boxes, pre-labeled with the lab's information.  The only information really necessary on the box is the appropriate IATA transport stickers/notifiers and a study specific airbill.  Such continuity would likely decrease the amount of shipping waste by eliminating the need for a "special" shipping box just because one lab requires it.

I don't know why this issue hasn't been addressed yet, but it seems like that each lab doesn't know that a research site is likely working with that lab on multiple studies.  It's not really a novel concept considering that many commercial sites are conducting multiple studies at the same time, but it's about time that the people in charge of the labs take initiative to reduce this unnecessary expenditure of resources.

who's minding the shop?

If I were examining a site, I would key in on their policy for dealing with abnormal lab values.  Specifically, what happens when panic values are called in by the central lab?  Typically when a value is reported that is outside of 2 or 3 times the upper limit of normal, the lab will contact the site via phone and/or fax.  The problem is that most labs do not ask to speak with anyone working on the study, they are content with a fax sent over or even being put into voicemail.  That is fine for some scenarios because a panic value may not actually be of clinical significance.  However, what happens when the participant's safety is actually at risk?  Why should that participant's health be balancing on a sheet of paper sitting on a fax machine or a message stuck in voicemail?

I would envision a process where the person answering the phones takes note of the panic value and immediately notify the lead coordinator on the study or someone who is involved with the trial (a clinical manager would be ideal in this situation as they could triage the value to the appropriate party).  In this scenario phone calls from the lab about abnormal results would be resolved promptly and there would be no question about the response time to such alerts.  In my mind, if sites can be cited for not documenting the evaluation of labs expeditiously, then sites can also be cited for not responding to alert values quickly enough or not having a plan to promptly take care of such situations.  

On the other hand, central labs should take more responsibility for ensuring that alert values are resolved quickly.  They should have policies where phone calls should be taken and acknowledged by a person involved with the trial in some way.  Similarly a fax alert should not suffice because faxes can sit on the machine for hours without being checked.  

It's probably worth noting, however, that the clinical investigator is ultimately responsible for the safety of his/her trial participants, so if messages about lab values are left on a coordinator's voicemail for days, the investigator is the one at fault for not responding to them and taking action quickly.  

A little warning letter discussion

I was browsing FDA warning letters (which for those of you who don't know, are indeed available for public viewing) and I came across one from July 2009 that had some interesting topics worth mentioning.  You can read for yourself at this link: 7/27/2009

Basically this looks like a standard warning letter addressed to a clinical investigator.  However most warning letters that I read usually have more to deal with inadequate supervision of a clinical investigation, failure to obtained informed consent, improper conduct of a trial, or a failure to maintain accurate accountability of investigational product (examples of the last two in this letter).  What makes this one unique is the apparent concentration on the accuracy of the data collected.  The inspector points out several instances where site personnel changed/altered dates or times of diagnostic tests in the source document, but not the CRF.  Granted there could have been a legitimate reason for these corrections, but the warning letter does not assume that.  All that is mentioned is that there was no "supporting documentation" for these changes.  There are several of these instances noted in the warning letter, many of them could be suspicious in nature, but I feel that correcting source documents without a documented reason for the change is something that occurs ALL the time in the world of clinical research.

To me it is almost unreasonable to ask that each correction be accompanied by a reason for the correction or change in the data because of the unnecessarily tedious nature of this request.  Honest transcription errors occur from time to time and I think audits should look at the big picture rather than zeroing on one particular situation.  It's possible that maybe the coordinator just had a bad day with subject 002 or maybe there were shady practices with the entire study, but we can't really assume either way.  The only way to truly document every single change effectively is using electronic records, where changes to data are required to have a reason for the change (much like electronic case report forms).  With this sort of documentation, any auditor could look at the electronic paper trail and see not only why corrections were made, but also when they were made and who made them.  This would allow for clean documentation and remove the question marks that arise when corrections to source data are made well after the initial entry date and by a different site representative.  Until that day, unfortunately, if sites really want to be diligent in their pursuit of perfection they should either: not make mistakes, or be prepared to accompany every correction with a brief reason as to why it was edited (and why the correction was made later on down the road).

Another thing to mention: I have a problem with the finding in the warning letter that "CRF page 54 for Subject #002 incorrectly identifies the subject number as #001." That really seems like nickel and diming the investigator.  A monitor easily could have missed that mislabeling of the CRF page, but in the grand scheme of things, why should that be identified on a warning letter?  Data management would catch this mistake anyway, and it is highly unlikely that transposing a subject number on a CRF would be detrimental to patient safety and/or data integrity.

Do you really know what you're doing?

My experience with central advertising companies is that they don't always seem to be worth the money that I'm sure the sponsor is paying for their services. Often times an advertising company will present itself as the guaranteed solution to slow enrollment, but most of the time that promise does not pan out. If it does work I would wager that it is because the study actually is not that difficult to enroll and the sponsor could save significant resources by leaving enrollment in the hands of the sites.

From a site's perspective the idea of central recruitment is extremely convenient: ads are run by a company, calls from the ads go to a call center, calls are screened for eligibility, those that qualify are sent to site via fax/email/whatever. However, the call center may not actually be accurately screening those callers because they do not have an intimate knowledge of the study, only a checklist with sponsor designed questions. Furthermore those call center employees do not have the ability to start establishing a relationship between the site and the potential trial subject that a site based recruiter or coordinator does (that initial recruitment relationship is vital to the success of not only recruitment for one study, but also the site's rapport within the community). I think that if people hear the ads they are going to call in regardless of who places them, so the responsibility really falls on the person receiving and screening the calls to make sure that no potentially eligible participant is left out of the mix. Unfortunately because of the rigidity of call center phone screening scripts, that is not the case.

Companies that generate and place ads are a step in the right direction because calls go directly to the site, but they still are lacking and in some cases a waste of the sponsor's money. Again as indicated above, if a study is difficult to enroll advertising will not make a difference, no matter who implements the advertising plan. There needs to be more discussion with the sites as to what works in an area, what the demographic is, and what times the site is available to handle calls because advertising companies will often go off on their own with what they believe is the best way to advertise in a region (even if they are located elsewhere and don't have a good idea about demographics). The study sponsors pay good money for these services, wouldn't you think there would be more of an effort to really tailor the advertising to a specific site or region?

So what is the solution? For starters if a site wants to recruit on its own, the sponsor should give the site the resources to do so. Most sites with active recruitment departments are good at what they do and will be able to garner more phone calls if they are free to advertise as they choose. Sponsors should not assume that there is one recruitment method that will work for all sites.

Next sponsors should really do their homework in pre-study visits (Don't just take the site's word for it that they have X number of potential people in their database. Ask for a physical lists of potential participants, get a pre-screening log started well in advance of the visit, ask for enrollment numbers on previous studies, discuss the study at length with the PI).

Finally the importance of physician referrals should not ever be understated. It is absolutely critical that the investigator is conscience of the study and its need for participants. Sites and sponsors alike would agree that the best type of recruitment is when a physician investigator asks his patient if he/she is interested in a trial. The best recruiter in the world can never replace a good personal referral by an investigator.