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

Thoughts?

It's common knowledge to those in the clinical research industry that when a new ICF is issued, subjects actively participating in a trial should be reconsented to inform them of changes to the study so that they can decide whether or not they would like to continue participating.  Generally the guidance as to whether the subject should be reconsented or not comes from the IRB, although the sponsor will supercede that decision (even though they shouldn't, in my opinion, but that's another story).  This reconsenting process should mirror the initial consent discussion done prior to study entry, and 90% of the time subjects agree to continue their study participation...but what happens if the subject actually refuses to continue and won't sign the new consent?

When considering this, it seems there are three options: 

1) Document the situation and let the patient leave without any early termination assessments because the subject is not a part of the new consent and hasn't agreed to any further study procedures

2) Document the situation, but proceed with early termination assessments if required by the protocol

3) Proceed with the new consent under the provision that the subject will sign consent, then immediately withdraw from the study.

After thinking about this for some time, I believe that option 2 is the best choice.  Here's why:  Some would argue that by declining to sign the revised ICF, the subject is withdrawing consent to participate in the trial, which is true.  Also because there was a new ICF issued, the old consent is no longer valid and the subject is technically not participating under any ICF by the time they are presented with a new consent form.  Thus any procedures done prior to the new consent would be done without the consent of the subject, and a big no-no.  The previous two sentences are where my opinion differs.

By signing the original consent at the start of the study, the subject is agreeing to take part and follow all study procedures, including the early termination assessment.  If a new consent is administered, the subject is still participating under the old consent and no further procedures may be carried out until the new consent is signed.  However an early termination assessment is likely something that was required under the old protocol, and in almost every case, is a critical safety assessment to ensure the subject's health was not compromised over the course of study participation.  For this reason, I would argue that it is acceptable to perform early termination assessments if a subject refuses to sign the new consent (as long as the subject agrees to those assessments) and once that is finished, the subject can be formally considered withdrawn from a trial.  The one caveat to this situation is if the early termination assessment is a procedure that was changed from the start of the study....in that case I would say the sponsor should be contacted to see if the old ET procedure would suffice because the new assessment would contain procedures that the subject did NOT agree to have done (and doing these would be a big no-no). 

As for the other options: choice 1 could be okay, but would likely require additional documentation to show why an ET visit was not done.  Choice 3 would be the worst choice because a consent signature means the subject agrees to participate/complete a study and I feel that having a subject sign the form with the direct intention of discontinuing immediately afterwards violates the meaning of the consent signature itself.  You may disagree with my opinion, and if so, I'd love to hear your reasoning, so shoot me and email or leave me a comment!

Oh, and by the way, the MOST important thing to remember if this situation arises, is to document the whole thing to death.  I cannot overstate the importance of a clear explanation of this type of situation in the event of an audit.

If clinical trials are necessary for new drug development, where are the participants?

PharmaTimes published an interesting article on clinical trial participation (or lack thereof) in Ireland, and while that is across the pond from us I think the ideas are probably universal.  The article polled  the "general public" (actual methods were not discussed) on the perception of clinical trials and the results were interesting.  Basically, people do not participate in clinical trials because they either have: a poor understanding of what "clinical research" its or they are not willing to put themselves at risk by taking an investigational drug with serious or unknown side effects (Of course every drug has a laundry list of potential side effects, some quite serious, in the package insert, but how many patients read that before taking a medication?).  The strange thing is that, in spite of this, people seem to understand the importance of clinical research in developing new or improved treatments for any number of illnesses.  I have certainly experienced this first hand at the clinical research site side of things, and in my opinion the key to changing this trend is public education through a variety of platforms, including physicians (not just those who are clinical investigators).

All practicing physicians should advocate for participation in studies because the majority of the public does not have direct contact with a physician conducting a clinical trial, so what exists is essentially an untapped resource.  This can be as simple as an informational flyer or a discussion in an exam room, but all doctors should understand what clinical research is as well as the importance of enrollment in these medical research studies. 

Another option, which has been discussed at length recently, is social media.  We as a society have only begun to scratch the surface of the far reaching potential of services like facebook, youtube, and twitter.  While pharmaceutical companies struggle with appropriate ways to utilize these services, it should be a no-brainer for investigative sites.  As long as IRB approval of an ad is in hand, sites should be tweeting their new trials, updating their facebook pages (you DO have a company facebook page, DON'T you?) with new studies (as well as useful links about clinical research...think centerwatch.com), and posting ads on youtube.  From there these social media platforms should be posted, updated, and publicized as much as possible to increase visibility.  While this is a relatively new advertising plan (compared to print ads, which are becoming antiquated), social media has already proven in many other industries to be a vital educational and marketing tool whose power should not be overlooked.

Read the Life Science Leader piece on clinical trials, pharma, and social media

Barking up the wrong tree?

There are some things that monitors/auditors always seem to examine and then drop the hammer on a site for if discrepancies are found.  For example monitors will look closely at the expiration date of medical licenses or to see if the appropriate lab reference ranges/certifications are filed.  The thing is that if these are missing/expired, I would wager a considerable amount that the site simply forgot to update them, not that the investigators are working without a valid license or that a lab does not use reference ranges.  In spite of this monitors/auditors will always spend more time going through sections like that in the regulatory binder when, in my opinion, there can be bigger fish to fry.  Here are a few suggestions:

1) Look at the lab reports more closely.  When were they received by the site?  When were they signed by an investigator?  Was this done in a timely manner?  To me, a lab report with abnormalities that is evaluated by an investigator 3 weeks after receipt is a much more significant issue than a medical license that expired last week because patient safety is potentially being compromised.

2) Check out the vital signs.  Were there a lot of changes from baseline?  Was this even evaluated?  Was an investigator evaluating those measurements for clinical significance?  An important fact that is often overlooked is that measurement of vital signs is a safety assessment that needs to be considered by a medical professional when making study related decisions.  Again, patient safety is at stake here, but some monitors would rather spend time making sure that email correspondence are in chronological order instead of looking at this.

3) Look at the timing of assessments.  Were the labs drawn immediately after vitals?  Were the assessments (vitals, for example) done according to the protocol (5 minutes resting, supine, etc)?  Was this documented?  All of the prior questions need to be considered because they could affect the accuracy/validity of the assessments.  Just because the assessments have been documented doesn't necessarily mean that they were conducted per the protocol requirements.

4) How about the delegation log?  Are the right people doing the right things?  Are sub-investigators delegated the ability to sign crfs?  Who is doing the recruiting?  Appropriate delegation of tasks is a critical aspect of clinical trial conduct and should be underplayed or overlooked.  The FDA will scrutinize that log in more detail than most sites would probably like to imagine.

These are all some suggestions that I think would improve the overall quality of monitoring.  Yes, these tasks take more time, but the potential benefits of completing them far outweigh the inconvenience.

who's responsibility is it?

Women of child bearing potential weren't always allowed to participate in clinical trials of new drugs.  That has only been permitted and encouraged within the last 20 years.  The reasoning for including such women is obvious because it is important that drug evaluations include young women as well as young men.  It is not conceivable that a new medication could be approved without including data from women 18-50 or so. However by allowing women of childbearing potential to be included, the FDA is essentially exposing pregnant women to new drugs with unknown mutagenic or teratogenic effects.

For this reason women of childbearing potential are required to use an effective form on contraception for the duration of participation in a trial (and often for a period of time before and/or after completion as well).  This requirement is explicitly outlined in study specific informed consent document that all participants must sign before participating in a trial.  To me, this should serve as documentation enough that a subject is aware of the unknown risks of a new drug to a fetus, but if a site reports a pregnancy one of the first things asked by the sponsor is: was the subject practicing an approved method of contraception and was she educated on the necessity of it?

I don't think that any investigator would willingly expose a woman wanting to become pregnant to a new drug because two lives could be at risk, but a lot of times the sponsor takes their requests of documentation too far. For example I have heard of studies where the site must contact participants on a regular schedule during the study to ask if they are still using contraception and if they are pregnant.  This to me is overkill.  It should be sufficient for a subject to sign consent (maybe initial a place saying they agree to use adequate contraception, for good measure) and then the site to document the type of birth control used.  Outpatient studies are supposed to be exactly what they say they are and subjects should be permitted a least some bit of freedom during a trial.  What ever happened to trusting a subject when she says that she agrees to use contraception and not get pregnant during a study?

As long as sites go in to the appropriate amount of depth in the informed consent discussion and make females aware of the requirements to participate, then the signature of subjects should be sufficient documentation of the necessity of using birth control during a trial.  That signature is good enough to prove a subject reviewed the trial duration, obligations, drug side effects, and randomization scheme, so why can't it suffice for the need for adequate contraception?

This has the potential to be a really, really good idea...

Every now and then you come across a new development that seems to have potential to change the way clinical trials are conducted.  Today I found another example of this: Consent Solutions.

Here's how it goes:  right now one of the issues in clinical research is the informed consent process is administered by research coordinators with varying degrees of experience and training.  Unfortunately all that technically is required to administer consent is delegation by the principal investigator.  This is where consent solutions comes into play.  Their product is a web-based informed consent discussion that can be tailored to the many individualized needs of not only research sites, but also the participants themselves.  Apparently with this platform, sites (or a sponsor) can submit an informed consent and in return consent solutions produces an integrated, interactive multimedia consent discussion that will ensure consistency across the board.

I think Consent Solutions is a fantastic idea that requires development by a private company because it is likely too technically complex for any one site to build.  I forsee this (if it comes around) to potentially revolutionize the way that clinical trial participants are educated prior to making a decision about jumping on board with a study.  Consent Solutions claims to offer feedback to trial participants in the form of questions to gauge understanding, customization depending on reading level or native language, but most importantly the company standardizes the consent process across sites....something that is clearly absent from clinical trials today.

Just imagine the potential advantage this sort of system: streamlined, consistent consent administration for all sites in a multi-center trial; no qualms from the sponsor/IRB about the quality of consent discussion (presumable, for a site to incorporate Consent Solutions, the finalized product would have to be IRB approved); easy of understanding for subjects; the list goes on and on.  For now though, Consent Solutions seems to be in its relative infancy, but hopefully this idea will catch on and find its niche in clinical research.

Check out Consent Solutions here

Were you there?

How many studies provide the study coordinator with proof of investigator meeting attendance?  With my experience, that number is pretty small even though the investigator meeting often serves as the site initiation visit.  If that is the case, and the sponsor does not provide a list of investigator meeting attendees, then technically there is no documentation of sponsor provided training prior to conduct of the study.  So what's the big deal?

Well, the FDA recently released revised guidance documents for investigator oversight of a clinical trial.  The documents basically re-affirm that the investigator is ultimately responsible for conduct of a study at his/her site, but I (and the FDA as well, in my opinion) believe that an investigator cannot properly oversee a study without initial guidance from the sponsor.  Usually this guidance comes from the investigator meeting or an on-site SIV, but unlike the SIV a list of attendees is not usually provided to the site following an investigator meeting.  This could very easily be a significant finding in the event of an audit, especially with the FDA's emphasis on proper oversight of a trial at a site.  Just like with everything else in research, if it isn't documented, then it didn't happen.

So what can study coordinators do to make sure this initial training documentation is in place?  Here are some suggestions:

-Ask the sponsor (project manager, monitor, whoever) for a copy of the investigator meeting attendance roster.  They have to keep it for their purposes in the event of an audit, so they should have it.

-Keep all pre-study documentation of investigator meeting documentation such as travel itineraries, meeting agendas, and contact with your CRA/project manager.  The meeting agenda is equally important in proving that site was adequately trained on appropriate trial issues.

-Hold on to any investigator meeting documentation received at the meeting.  A good example of this is a binder with powerpoint slides from presentations that is almost universal at meetings.

All three of the above suggestions can go a long way in making sure that the research site has the necessary documentation of sponsor provided training before the study starts.  It would be a travesty for an investigator to get dinged during an audit because the sponsor neglected to provide this information to a site.

One size fits all

One size fits all.  Not good if you're looking for clothes, but good if you're talking about electronic data capture systems.  EDC is great because it has the potential to streamline the data collection process, bringing data collection about as close to real-time as is possible right now.  However there are many different EDC systems out there today and while many are private systems like PhaseForward or Medidata, some are sponsor designed/utilized (such as GSK's RDE system or QDS's data capture system).  Competition is good to a certain degree because it no doubt keeps costs down for sponsors, but it really can create headaches for sites.  There are too many passwords, too many guidelines, and too many different ways to access the various EDC systems.  If only there was one system utilized by the whole industry that every site could use for every study, allowing for seamless transitioning from one protocol to another once logged into the master system.  Impossible?  I don't think so.  Just consider the following scenario:

-As the market becomes ultra-competitive and bidding wars ensue, EDC systems start to cannibalize each other, leaving the small companies to be swallowed by up the more powerful ones (notice I didn't say the "best" ones)

-The market narrows, leaving only a handful of viable data entry platforms and sponsors align themselves with one company over another.

-Gradually as the industry continues to have large numbers of mergers/aquisitions, some platforms are eliminated from the market by virtue of company buyouts until one EDC system remains

Every research site by this time will be familiar with this one EDC system and will be completely familiar with the system, allowing for less stressful data entry procedures, database locks, and investigator signature procedures.  Each EDC user will have one global username/password to enter a system and from there he/she will have specific passwords for each study within the system, thereby maintaining compliance with CFR part 11.  Furthermore investigators would only need to remember one set of passwords and only one username for every study on which he/she is working.

Sounds nice, doesn't it? I know that this situation is a long way away and a bit far fetched, but a guy can dream can't he?

Fast forward to post marketing studies

A few months ago, the FDA happily reported that most post marketing studies are conducted/completed within reasonable time frames.  Move ahead to today when the Government Accountability Office made public its results on the FDA's history with using data from post-marketing studies to actively review a product's effectiveness over time.  So what did the GAO's study show: a kind of nothing for the FDA.

Apparently the FDA has not ever pulled a drug from the market because of a lack of effectiveness information provided by the manufacturer.  The article says that even when the sponsor provides the post-marketing data up 10 years late, the FDA takes no action to punish the sponsor for the delay in data reporting.  Even worse, the FDA has also never removed a drug's marketing approval when real data that prolongs the life of terminal patients does not exist.  Some time ago the FDA instituted a policy where new drugs could be approved based on lab based data, not actual patient survival times.  This was implemented to speed the drug development process and get more novel therapies to market for life-threatening conditions.  Where did this go wrong?

The idea is good, I agree that for some life-threatening illnesses the standard timeline for new treatments is simply too long and involved to be of benefit to patients.  Along the same lines manufacturers are less likely to pour millions of dollars into a development program that may or may not work without some help from the government authorities.  The problem, however, lies with the FDA's enforcement of its own policies.  There is no excuse for granting permission to market a drug and letting the data sit unattended for years.  The FDA should be following up with developers on a regular basis for status checks on post-marketing studies or even encouraging more comparativeness trials to be conducted to better identify the best treatments for patients.  To me, the evaluation of drug absolutely should not end at the approval of a marketing application (and while I'm sure the FDA agrees with this philosophy, you wouldn't necessarily know this looking at the report published by the GAO).

How can this be rectified?  Well for starters the FDA needs to put some teeth in its requests for post-marketing data.  If a sponsor does not get data to the FDA in a timely manner, hit them with a fine, a warning letter, or even better a temporary marketing suspension.  You could say that the FDA would be depriving patients of needed medications, but it would really be on the sponsor to ensure that the required post-marketing safety/effectiveness data is reported expeditiously so the approval remains valid.  As the top pharmaceutical regulatory authority in the United States, you would think the FDA would have a better handle on all types of data being developed/presented and not have the sort of almost lackluster enforcement of post-marketing trials actually seems to exist.

I'll post the actual GAO report when it becomes available, but until then here's a brief article on the findings

Time is of the essence

How long should it take for a coordinator to complete a study visit?  A loaded question for sure, because the answer depends on the number of tasks and procedures to be completed. For example a screening visit may easily take 2+ hours because of all the initial paperwork, while a follow vaccine visit may be only 20-30 minutes because it only may require a blood draw and brief physical exam.  A significant issue among managers and coordinators is how to maximize the coordinator's time so that down time is maximized to ensure that as many participants can be seen as possible during the day.

For some coordinators, study visits will be conducted one step at a time with no overlap.  This is not the right way to take advantage of the way a clinical trial visit is set up.  Coordinators should be aware of the procedures required at each visit and set up the visit to allow for the most of use a minimal amount of time.  Clinical research study visits often have significant down time built into the protocols.  For example subjects are often required to be resting for at least 5-10 minutes prior to taking vital signs.  Instead of just leaving the patient by his/herself, a coordinator should be copying a consent, reviewing medical records, preparing a lab kit, or entering demographic info in an ECG machine.  This will allow for productive use of that 5-10 minutes  because as small a period of time as it is, a coordinator's day is busy and 5-10 minutes can go a long way.  Here's a few more examples of utilizing down time appropriately:

-Reviewing a new participant's intake form while consent is being read, so any questions/concerns can be identified ahead of time
-Filling out source headers while a subject is completing questionnaires
-Taking temperature/scheduling an appointment while the subject is applying pressure to the site of a blood draw
-Presenting the participant's information/demographics to an investigator (prior to a physical) while questionnaires are being completed or a urine sample is being given

Proactive utilization of time of a critical aspect of a coordinator's job and learning how to do this is part of the maturation of an inexperienced coordinator into an efficient, vital member of a clinical research team.

Information please.

I don't think enough information is provided to sites regarding the proper collection and processing of laboratory samples in clinical trials.  For those of you not familiar with the central laboratory process, let me give a brief overview: 

1) site receives bulk supplies, lab kits, lab manual, etc at start up

2) site is supposed to review lab manual for guidance on sample collection/processing

3) material is reviewed with site by CRA at site initiation

4) patient visits start

Unfortunately, that is the extent of most study specific lab education.  For some of you, this may seem sufficient because you have processed thousands of labs and it is like second nature, but can you tell me why samples must be stored at -20 degrees Celsius for 4 hours, then moving to -70 degrees C for long term storage?  Or why you shouldn't leave a tourniquet on too long when drawing blood?   Or how about why you shouldn't let urine samples and blood samples sit unprocessed for longer than an hour? If you can answer those questions, good for you, but I would wager that the majority of commercial sites only follow the rules without an understanding of why they are written as they are.

I believe that sponsors would receive much higher quality lab data (which is crucial, I might add, to almost every study in the form of either safety or pharmacokinetic data) if sites were completely educated on not only how to process lab speciments, but also why.  Knowing that leaving samples unprocessed for too long can give erroneously low glucose values for a metabolic panel or even bacteria growth in a urine sample, might encourage a site to adhere more closely to lab manual guidelines (It's the real world, and we all are guilty of letting samples sit for 5 hours in the lab before processing).  The same goes for processing PK samples.  If sponsors provided reasoning behind the lab manual's guidelines, sites would be much more likely to follow those rules instead of occasionally bending them (and potentially compromising data) because it doesn't seem to make any difference to a coordinator who processes tons of lab samples day in and day out.

The major drawback to this that I could see is a lot of repetition in education of proper processing, but just like GCP I think that too much education is far better than too little.

Learning from others

I took a little time today to review some more older warning letters sent to clinical investigators following FDA inspections.  Here's one I came up with that I thought could be worth discussing.

There are numerous violations identified by the FDA inspector in this warning letter, but the two observations I wanted to talk about were:

1) A discrepancy between sources and CRFs.  This goes to show that you cannot take FDA inspections lightly.  There were several situations identified by the inspector where source documentation at the site did not match what was reported in the Case Report Forms.  Yes a monitor should have caught this prior to the inspection, but the site is ultimately responsible for the data.  Furthermore a site may argue that mistakes happen and the data may have gotten somehow transposed, but even small differences between the source and CRF could have significant implications for the data in a trial.  Morale of the story: take your time and be diligent when transcribing data from source to CRF.

  P.S. The FDA inspector also noted that corrections were made after a subject completed a trial without explanation.  It does look suspicious and I can completely agree with the inspector on questioning the legitimacy of the data in that situation.

2) Not properly consenting subjects.  Their were several violations of this genre reported, but one that I would like to point out is as follows: 

 "In a letter dated March 1, 2006, the IRB informed your site that they had approved informed consent form version 021706 which included modifications that were made to the risks section. The IRB’s letter further stated that current and new subjects were to sign the revised informed consent form. There was no documentation found during the FDA inspection to show that your site re-consented Subject #0004, who was still enrolled into the study at the time, with the revised informed consent form to inform them of the possible additional risks the subject may experience."


   This says that the site received notification from the IRB of a amended informed consent and that all currently enrolled subjects (as well as new ones) should sign the amended consent to inform them of newly identified risks of study participation.  For some reason this re-consenting did not happen (whether it was accidental or not is not the point here), and the investigator is the one who takes the heat because the participant was never made aware of new risks that could have affected his/her willingness to continue participating in the trial.  Again, mistakes do happen but the FDA will not take them lightly if the safety of subjects are at stake (if at all).  Morale of this story: take whatever measures are necessary to ensure that the recommendations of the IRB are followed with regards to the consent of subjects participating in clinical trials.




  Notice I did not say that the sponsor has power over the administration of the consent....more on that later...
   
   

Rescue Me

How many of you have heard sponsors say that accountability of rescue medication is not required because the study endpoints, data, etc are not concerned with that information?  If you haven't consider yourself lucky because I believe that anybody who tells you that is not correct and is potentially hanging a site out to dry with that advice.

Rescue medication, if dispensed by the site pharmacy, is technically investigational  product and subject to the same rules and accountability logs as the actual study medication.  For example, if a sponsor for a GERD study provides Gelusil or Tums as the rescue medication to be dispensed by the site, then the site is responsible for ensuring that subjects are dosing properly and not causing themselves harm by overusing the medication.  So what's the big deal, you ask?

Well, these medications/products are being dispensed as part of a government regulated clinical research trial and the subject is receiving the medication free of charge from the site.  Basically this means that the product should be considered and evaluated under the same umbrella as the actual investigational product being examined in the trial.  Taking 50 Tums that are expired and have been stored on a hot windowsill at the coordinator's desk with no regards to temperature monitoring could be as risky for trial participants as unmonitored study drug.  Okay, so maybe that was an over-exaggeration, but the bottom line is that any medication provided by the site for ANY use in an clinical trial is regarded as investigational product, no matter what your sponsor says.

So, to make a long story short and to potentially avoid ssues down the line, (I'm sorry if this leads to more work) consider the following:

ALWAYS keep a master accountability log of ANY medication leaving/returning to the site, even if the sponsor says you do not have to do so.  Thank me later if you get audited.

Monitor compliance with the rescue medication at each visit, even if not required by the protocol.  Diligence in this regard is important even if it takes up more of your time

Thoroughly educate the subject on the use of the rescue medication, even if it is something with which they are familiar.  Think Acetaminophen for example: most people know you can get extra strength over the counter, but how many are aware of the maximum dosing guidelines (4 grams by the way, at this time but subject to change based on FDA recommendations)?

These suggestions will serve the site's purposes better if they are followed, and sponsors can learn from it too because if they are providing sites with rescue medication, then they should very well be treating it just like an actual study medication...no ifs, ands, or buts.

Now Hear This

As discussed at length on EyeonFDA blog, there will be a public hearing on the use of social media and its use in the pharma/biotech industry.  This FDA hearing will take place on November 12 and 13, and really has been a long time coming.  Social media has been a sort of unregulated medium for all sorts of things in the pharma world, from advertising to clinical trial recruitment to DTC (direct to consumer) publications.  It seems that the FDA has been slow to react to the viral potential of social media, issuing a warning letter here and there when it comes across a piece of marketing that it finds obtrusive or provides nebulous information to consumers about a product.  Just like with other forms of marketing, unregulated social media has the potential to take advantage of an uneducated public, which is especially dangerous when speaking of pharmaceuticals  There should be some sort of formal documentation from regulatory authorities about how social media can and should be used by the pharma/biotech industry for various purposes.

I don't think that the use of social media by pharma should be banned because Twitter, Facebook, and blogging can be very effective ways of properly informing the public about a topic/product or even inviting public opinion in an informal fashion.  There are lots of companies that use the above mentioned social media platforms to keep consumers up to date with the company and its products.  However pharma has a bad reputation of using media in less than completely ethical fashions to benefit itself, so we cannot rely on the industry to regulate itself.  Hopefully this hearing next month will elicit some good, solid recommendations (maybe even a formal guidance document) from the FDA on what can and can't be done with social media because like it or not, social media is here to stay.

For some light reading, check this link to the official FDA release

Medical Records?

There are quite a few opinions out there on whether or not clinical research sites should request medical records for research participants that are not patients of the research facility.  Some people argue that without medical records there is no way to complete assess an individual's eligibility for a trial and there are absolutely no exceptions to this.  On the other hand some sites may argue that medical records are not necessary unless specific documentation about a condition (ie arthritis, cancer, MS) is required.  These sites may say that most records contain lots of extraneous information that is not clinically relevant to the trial, but must be documented in such a way that it greatly waters down the quality of the data from the site.  Not to mention that it leaves plenty for an overzealous monitor to scrutinize for possible study entry violations. 

So who is right?  The FDA does not explicitly require that copies of medical records be obtained for clinical trial participants, but good clinical practice would strongly advise that attempts to request records are made prior to enrolling a subject in a trial.  The federal regulations do mention that a clinical investigator needs to collect a complete and accurate case history of a subject and that this history does include past/current medical conditions, but those rules do not indicate how this history should be acquired.  In my opinion a site is more than welcome to use a medical history interview in the clinic to acquire a case history, but there should absolutely be some sort of documentation signed off by an investigator that the interview was deemed to be accurate/complete if this practice is utilized.  However I think that if copies of medical records can be obtained, that is always preferable to ensure total collection of a case history and to protect the site in the event of an audit (even if it does open doors to much more work by site staff in recording extra medical conditions, having an investigator review those records, and fighting with monitors over questionable findings).    

I guess the take home message here is that while the clinical investigator is ultimately responsible for the eligibility of research participants, there is no substitute for outside, objective information that verifies a subject's case history.  Most clinical research staff (investigator's included) are truly trying to do a good job with honest data collection and documentation, but there are those out there who will leave out exclusionary conditions or medications just to see a person enrolled in a trial (remember, this is one reason that audits occur). With all the discussion lately about the FDA tightening the reins on clinical research, it's more important than ever for research sites to ensure that GCP is followed tightly and medical records are an excellent way to prove this.

Noted.

I find that one significant gray area in clinical research is the use of the Note to File.  There are numerous situations that may or may not require the use of an explanatory Note to File, depending on who and when you ask.  Generally the Note to File should be reserved for situations where something has occurred over the course of the study that cannot be explained sufficiently using the documentation already present in the chart (or file/crf/etc...).  The point of the Note to File is to provided clarification so that an auditor or outside reviewer can understand a situation, see what was done to correct it, and move onward with few or no questions.  The problems with Notes to File, however, that I see are twofold:

1) Notes to File (and one of my pet peeves is incorrect pronunciation of the plural...it's Notes to File, not Not to Files.  Welcome to middle school grammar) are often written poorly with too little or too much information. 

2) Charts will have either too many or too few Notes to File to explain situations in the trial.

 Notes to File should ideally be concise, well written grammatically, and informative.  They should not be filled with flowery language and should not go into great detail explaining something that an auditor would already know.  For example auditors should understand the protocol, so one should not describe protocol procedures related to a note to file in great detail because the note will become too wordy and likely confusing to the reader.  Ideally, a Note to File will identify what the problem is, how it was fixed, and what was done to prevent it from occurring in the future.  Anything that goes outside of this is a furbelow.


Secondly one should exercise good judgement when creating Notes to File.  Too many of them will raise a red flag to an auditor that there were many mistakes in a study, too few will not adequately address mistakes or issues with the data/study files/etc. A good rule of thumb is to write a Note to File when a situation arises that cannot be explained by a progress note (ex. regulatory binder issue) or when a mistake occurs that has implications for the entire study (ex. consent error or dosing error) if not corrected. 

It is confusing for inexperienced coordinators to decide what merits a Note to File, but it is important to learn so make sure you ask an experienced staff member if you have questions.  Remember  that even though a Note to File is useful for explaining sticky situations,  it is also an indication of a discrepancy or mistake in a trial and should not be used liberally. 


 



 

  

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.

Let's Talk Diaries

With vaccine season bearing down on us, maybe we should discuss diaries briefly. No, I'm not talking about the diaries that talk about our day and other things like that, I'm talking about the diaries used in clinical trials that collect a nimiety of information reported by the research participant. As any coordinator who has worked with subject completed diaries knows, they can and often are a huge headache. This comes from several things, including: poor layout/format for the subject to follow on their own, inadequate education on the part of the site, failure to capture necessary information in the trial, and lack of proper review of completed diaries returned to site after completion. Two of these items fall back on the sponsor, and two of the them fall upon the site staff.

Since it's virtually impossible to have all sponsors agree on one format for a clinical trial diary, the layout of the diary is unlikely to change across the board for some time. I think eventually paper diaries will be obsolete and electronic diaries that provide data in real time will take over. This also could include diaries done over the phone, but I personally find that they last too long and trial volunteers get tired of "for yes, press 1; for no, press 2. If you are satisfied with your answer, press 1; if you want to change your answer, press 2" for 15 questions. Electronic diaries are faster, allow for a variety of variable inputs such as medication names for adverse events or unsolicited information that you cannot capture on a phone diary, do not waste paper (yea!), and they allow for direct data transfer into the study database.

That being said, until we reach that day when e-diaries are ubiquitous, remember these tips about paper diaries:

-Make sure that your trial participants understand not only how to properly complete the diary, but why it must be completed that way. For example, if a post-vaccination diary asks for a rating of injection site pain, then it asks for muscle aches; the subject should know that those are actually two different types of reactions. A positive response on both can mean different things to the sponsor than a positive response on one or the other.

-Fill out all diary headers (subject number, dates, contact info) ahead of time. You'll thank me later.

- Educate the volunteers thoroughly, but do not lead them. Many diaries will ask for information that may include or exclude a participant from a study, so be sure that the subject knows what each question is actually asking. Do not leave anything open to interpretation, that can lead to subjects being inappropriately lost from participating.

-When a diary is returned review it in detail with the subject. At that time the participant should make corrections and clarify any missing/questionable information recorded in the diary. It is much, much more difficult to clean up any discrepancies after the fact. As a side note, you can try educating volunteers on the "right way" to correct errors (line through, initial, and date. repeat as necessary), but if it takes new coordinators months to burn that into their brains you may not see promising results with study participants trained for less than an hour. I would just say you are better off with reviewing/correcting diaries as they are returned.

I hope you enjoy the tips, and let's all be ready to celebrate when everything goes electronic!

Goldmine for Recruitment?

A recent article in FierceBiotech IT detailed the emergence of a new patient recruiting service co-developed by Pfizer and Private Access. Allegedly this service will allow potential trial participants to log on to a website (presumably) and upload their health information to be made available to participating clinical investigators and physicians. Participants could also then restrict the amount of information available as well as to whom the information is provided (good for the patient in terms of privacy). Where this behooves the researcher is that an investigator would be able to only see the information of those who either seem to meet a study's criteria initially or are interested in a particular trial. But let's dig a little deeper, shall we?

The article goes on to say that most people don't participate in clinical trials because they either aren't aware the studies are going on or they can't find one for which they may be eligible. I agree with this statement. There are clinical trial search engines available today like centerwatch.com, clinicaltrials.gov, and clinicalconnection.com; but not enough people know about them to make them wildly successful. THAT is what Pfizer and Private Access need to take into account when developing this program.

I think the first step is to get the word out to clinicians who are not participating in trials to encourage their patients to sign up for this service or using Pfizer's vast financial resources to run marketing campaigns to get the ball rolling. Part B of the first step is to ensure patients that this information is indeed confidential because the whole idea of being able to access your protected health information from any computer and your PHI sitting out there in the clouds is a bit intimidating to most. The second step would be to prove that this service actually does what is supposed to do. It would have to be successful in hitting underrepresented populations of study participants, which is another problem with clinical trial recruitment as it stands today. The final step is showing that even though the service is developed by Pfizer, the service would not benefit Pfizer any more than it would benefit any other pharmaceutical developer. People generally have a bad taste in their mouths about profiteering in the world of Big Pharma and although Pfizer could potentially benefit greatly from this service, they would be better suited to open it up to any investigator participating in any trial.

Generally I think this product is a step in the right direction if implemented properly, and the ball lies in the court of the developer to make it happen.

Here's the article from FierceBiotech IT, FYI: (http://www.fiercebiotech.com/press-releases/pfizer-and-private-access-announce-plans-develop-online-community-accelerate-clinic-0)

Are We Gonna Hurry this Along or What?

There are multiple companies working to develop a H1N1 flu vaccine in time for mass vaccinations this fall and the media is doing a good job of publicizing the necessary clinical trials (well, at least for large academic research centers...the private sites who are probably doing a larger volume of the trials seem to be left out in the wilderness to do their own advertising) needed to complete the development process. However there is one thing worth mentioning that needs to be addressed before we get too far along into the Northern Hemisphere flu season:

What is the FDA doing, exactly? The FDA is trusted with the not so desirable task of regulating the medication/vaccine/device industry in the United States and they must walk a delicate line between a rapid development process and ensuring the safety of the millions of people who may receive a product once approved. The issue is that like many other government agencies, there is significant red tape and there seems to be no real timeline that the FDA follows when working with drug developers. Ordinarily the only people a regulatory delay significantly affects is the developer, but this an entirely different situation. The media makes a big deal out of the implications of a deadly, virulent pandemic on not only the health care system, but also the economy, so one would think that there would be a real sense of urgency from the FDA to get this vaccine (as well as any new treatment for the illness, more efficient diagnostic tools, etc). Unfortunately, I don't get the impression that this is the case. There are situations where a study is ready to start and just before the anticipated start date...the FDA says "stop, we need to talk about changing a few things." What is wrong with this picture? The FDA technically has up to 30 days upon receipt of a prospective protocol to advise for any changes, and they often use as much of that time as possible. According to the regulations the agency can take their time, but should they in this situation?

What I think would make sense is for the FDA to have a 1 business day turnaround time for any H1N1 related protocol. Even if they do request changes, it at least would give the sponsor enough time to implement them without disrupting the enrollment or time lines of the study (hopefully). To the sponsor, although we may not want to admit it, time is money and while it is a great thing to develop the next pandemic vaccine, there are millions (if not billions) of dollars to be had from a successfully developed vaccine. For the rest of us, the longer that we have to wait for clinical trials to start, the more likely it is that we will have a significant pandemic problem starting any day now.

You could argue that the H1N1 crisis is not the only thing on the FDA's plate, but there are few other situations with the potential explosiveness of this one. FDA needs to step up to the plate and quicken their processes before this swine flu gets out of hand.

Delegate or Die Part II

So let's get back to the delegation log discussion. Here are a few more tips on avoiding delegation log issues:

-Every investigator on the 1572 should sign the delegation log, even if an investigator does not perform any trial related activities. Once again, make sure that investigators are appropriately trained and have corresponding training documentation...an untrained investigator evaluating study participants is almost as bad as having an investigator not on the 1572 seeing them.

-Make every effort to have investigators print their own name, sign their own name, and sign their own initials on the delegation log. One purpose of the document is to prove the authenticity of signatures/initials on study documents, this cannot be accomplished by someone else signing the name of an individual on the delegation log.

-If your site uses dedicated recruiters, don't forget to have them sign the log as well. Recruitment is a part of the study enrollment process, so anyone assisting with it should be included on the delegation log

-Keep the log up to date with end dates of study staff. It's difficult to remember when someone started/stopped a study long after the fact, keeping up with it as it occurs is best practice. In addition no one should want to look forward to having to explain why someone had a start date on the delegation log listed after he or she had already performed study assessments. Likewise for ending participation a trial before the last assessment was completed.

Finally, don't be alarmed when the sponsor keeps the original delegation log at the end of the trial....it's supposed to be that way! There are other nuances with this fine document, but if you stick to these rules you'll have fewer items to correct and fewer notes to file to write explaining discrepancies. Enjoy!

Delegate or die! (okay, maybe not)

In a perfect world the principal investigator would perform all his own research, enter his own data, and record all adverse events that occur in a trial. News Flash! That doesn't really happen!

The FDA does realize that the PI cannot do everything so it allows for delegation of certain tasks to individuals who have been trained to do that task and are qualified to do so. Unfortunately there is not too much out there to guide investigators as to what extent this delegation can occur. Consequently, what could be seen as improper delegation in eyes of one individual could be seen as completely acceptable to another, and neither could matter if an FDA inspector feels differently! There are certain guidelines that the FDA mentions such as who can perform physical exams (unless stated otherwise by a sponsor, it would go by what qualifications are acceptable from state to state), but generally delegation of tasks is left to up to the PI.

In many situations, the coordinator will complete the delegation log and the PI will sign off on each individual participating in the trial as proof that he is indeed passing on/sharing responsibility with him or her. That being said, here's a few reminders to help avoid problems with the delegation log (as well as a potential 483) in the event of an audit:

-Make sure you have clarification from the sponsor, in writing as always, as to who exactly can perform the following: physical exams, ECG assessments, Lab assessments, AE assessments, special study evaluations like neurological exams. Improper delegation of these tasks can be a huge headache if it has to be resolved after participants have already entered a trial (I'd be happy to elaborate...just let me know if you want more of this!)

-The PI really should be the only one who signs off on the Case Report Forms (CRFs) as accurate representations of data collected during a trial. Sub-investigators do not sign the back of the 1572 and should not be delegated the responsibility of signing CRFs.

-Specialized tasks require people with specialized training. Is there a certain type of diagnostic assessment like an echocardiogram or a sleep study? If so, the person running those assessments should have documentation of appropriate training and should definitely sign the delegation log.

-Make sure that everyone who has not received sponsor provided training on the trial (ie: didn't attend the site initiation visit) has documentation of training in place before the delegation log is completed. This training should note the training involved, who was providing it, who received it, and most importantly, that the PI verified it. Just like improper the improper delegation described above, delegation of tasks without training is another huge headache that is very easily avoided with due diligence.

In the interest of suspense and writer's cramp, that is part I of delegation log tips....more to follow soon!

Report this?

Even though most IRBs only require deviations that affect subject safety or data integrity to be reported, many sponsors/CROs/CRAs still ask that sites report all deviations to the IRB. Why is that? I've heard some sponsors say that they would prefer all deviations to be reported to err on the side of caution and I've also heard some sponsors claim that they want to take the decision making process away from the PI. Those reasons are fair enough because the sponsor really is the one with the financial/corporate assets at stake in a trial and limiting the choices of investigators with regard to deviation reporting (investigators are not typically jumping up and down to send issues to the IRB) can have positive effects for study conduct.

On the other hand IRBs are there to protect the integrity of the study and the safety of the research participants. Many IRBs have numerous protocols to review and if they are overburdened with deviations or problems that don't affect subject safety or data integrity, they may not be able to properly do their job. I can't tell you the number of instances where the site has only submitted a deviation to the IRB because of a sponsor request only to receive an acknowledge back from the IRB indicating that it was received, but not reviewed because it did not meet their reporting requirements. The time and effort needed to send those acknowledgements could be better spent dealing with actual issues that meet those IRB reporting requirements. In addition IRBs function as separate entities from the sponsor, so they technically have their own agenda when reviewing study related issues, documents, etc. By asking sites to report every issue/deviation that emerges, the sponsor can disrupt the essential functions of the IRB.

Also it's worth nothing that along these same lines, the FDA issued guidance earlier this year regarding reporting of adverse events to IRBs as well (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf) Adverse event reporting is not something that occurs as frequently as unexpected problem/deviation reporting at the average research site. However, I would suggest that the FDA should issue guidance (guidances are not set in stone, and they are not actual "regulations"...remember that) on deviation reporting to IRBs in addition to the adverse event reporting AND that sponsors should work to help investigators report adverse events to the IRB instead of just concentrating on the problems in the trial. I think that such action would allow IRBs to do their job more effectively as well as cut down on the amount of unnecessary documentation on the site's end over the course of a trial.

A Coordinator's Quick Guide to Avoiding Queries

Query resolution is a pain. How much time and energy is spent on the sponsor as well as the site's side taking care of queries throughout the study? I couldn't even take a guess, but I would wager it is a significant account. Certain types of queries will always happen, but a coordinator can and should be more proactive to limit the number of avoidable queries.

For the coordinator:

Take a detailed medical history, and remember the following:

- Each surgical procedure MUST have a corresponding diagnosis/reason. For example, do not leave a cholecystectomy without a corresponding indication for the surgery. It may seem insignificant, but as it stands right now data management could easily query the unattached surgical procedure.

- Make sure that medical history entries supersede or match medication start dates. It would not make much sense for a medication for high cholesterol to be reported as starting 5 years before the reported start date of the high cholesterol (unless of course the medication was given prophylactically, but that is a somewhat rare occurrence)

- For female subjects: their child bearing potential status should be documented in the medical history. This includes hysterectomies, a start date for menopause, bilateral tubal ligation, etc.

- Adverse events should list a diagnosis, not symptoms. Try to make life easier on yourself by grouping symptoms into one diagnosis, if possible. The classic example is grouping cough, sinus congestion, and sore throat as an upper respiratory infection.

- Don't be passive. If you have a question about a particular data entry field, ask your monitor. If you disagree with a query, let data management know. This takes time, and it may be fruitless, but it just may save you the time and effort of redoing many data points because of a misunderstanding of the completion guidelines.

-Read the CRF completion guidelines. They are written and sent to the sites for a reason. That reason is not take up space in the regulatory binder, so have a gander at them...you just might learn something!