A New Box

you got a password?

2010-02-10T20:26:00.000-05:00

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

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

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

Linked Up

2010-01-26T22:31:00.000-05:00

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

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

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

Spread the Word

2010-01-19T12:54:00.000-05:00

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

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

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

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

return of the paper CRF?

2010-01-12T22:37:00.000-05:00

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

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

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

Pharma Audible

2010-01-05T22:00:00.000-05:00

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

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

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

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

Keep your Guard Up

2009-12-30T10:45:00.000-05:00

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

2009-12-26T14:48:00.000-05:00

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

2009-12-12T17:25:00.000-05:00

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?

2009-12-07T11:16:00.000-05:00

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?

2009-12-02T17:29:00.000-05:00

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?

2009-11-21T21:57:00.000-05:00

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?

2009-11-14T16:13:00.000-05:00

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...

2009-11-09T22:06:00.000-05:00

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?

2009-11-07T19:34:00.000-05:00

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

2009-11-02T14:17:00.000-05:00

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

2009-10-26T23:08:00.000-04:00

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

2009-10-22T22:03:00.000-04:00

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.

2009-10-19T22:11:00.000-04:00

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

2009-10-15T22:36:00.000-04:00

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

2009-10-13T23:30:00.000-04:00

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

2009-10-11T22:05:00.000-04:00

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?

2009-10-07T17:48:00.000-04:00

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.

2009-10-05T13:59:00.000-04:00

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

2009-09-30T20:43:00.000-04:00

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

2009-09-28T21:13:00.001-04:00

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.