They are all sharks, every single one of them

The growing competitiveness of clinical research is mind boggling to me. I understand that in pharmaceutical development, maybe more so than in other industries, time really is money. Countless reports have been done identifying how much money a year of development costs, how much money regulatory delays cost, and most importantly for us: how much money enrollment delays cost.
Unfortunately for sites it seems that most of the time lines are based on prompt, efficient enrollment at the site level in clinical trials. This means that sponsors are increasingly pushy to meet deadlines and it raises the stress level at the site significantly. Sites can no longer afford to take their time searching for the "perfect" subject, getting start up documents in to the IRB and sponsor, entering data with no mistakes, and recruiting when it is convenient for themselves. Sponsors can and will pull the plug on a site if enrollment is not proceeding as planned and they will strongly consider not using that site for future studies for that very reason. For this reason, the types of sites where clinical research originated (places where doctors were just plain interested in research) are being pushed out of the business by large scale, research factories.
Now on many levels this is not a bad thing because such research only sites are designed to very quickly carry out trials while at the same time maintaining high standards of quality research. Most small practices do not have the time or training resources to both do good research as well as meet the pressured time lines of the sponsor, so I would anticipate most, if all studies going to big research sites in the future. This doesn't have anything to do with the quality of the work, it's just that they can't keep up with all the demands.
There are two problems with this scenario. The first is that the FDA likes diversity in clinical trials, but large research sites are typically based in larger metropolitan areas and they will be recruiting from the same population for all studies. As more and more trials over the years are given to those sites the diversity decreases greatly. The other issue is that every site knows that in order to come out in the black, they need to enroll as many subjects as fast as they can. This puts much pressure on the site staff to work long hours meeting sometimes unrealistic time lines. Unfortunately this can be a recipe for disaster with inaccurate safety reporting, sloppy data entry, and worst of all: weakened subject relationships. So much of clinical trial success is based on good rapport with trial participants and in my mind, the last thing we want is to come across as telemarketers pushing cattle through a processing plant.
Unfortunately I can't foresee a simple solution to the problem because sponsors need their numbers and sites need their payments, so I suppose they will have to keep dancing around each other until something changes.

in other news, check this story out about H1N1 vaccines for everyone!
http://www.biohealthinvestor.com/2009/07/fighting-swine-flu-the-wal-mart-way-wmt-azn-gsk-novn-sny.html

Having a look at AE reporting

Adverse event reporting seems easy enough: document a diagnosis (ideal, but not always the case...obviously), get a start date/time, get an end date/time, and ask your friendly investigator to assess it for causality. He or she may not ask questions about the adverse event and simply make an assessment as to whether or not it may be related to study product. Let's stop right there. What is the problem with this?

Most adverse event logs only list the information that is required by the case report form, and very little else. This is a problem because unless you are going to hold the investigator's hand while he is assessing the adverse events, there is very little that is presented to him which might allow him to make an informed clinical judgement about the causality of a particular adverse event. Granted this may not seem like a big deal at the site level, but if this situation is occurring at most sites, then the whole process is flawed to the point where inaccurate safety information is being gathered.

I believe there is a simple resolution to this issue that would not take up the valuable time of the coordinator while allowing the investigator to assess adverse events accurately. An adverse event log could be very easily amended to include the following information along with is required by the CRF:

-last dose of study medication (if applicable)

-whether or not the AE was listed in the investigator brochure/informed consent (simple yes/no) as a known risk

-whether or not the AE is of "special interest" to the sponsor

-any other study specific information that may of use: is there a titration period? is the AE intermittent? persistent? any other events that may have caused it?

This sort of information made readily available to investigators would greatly increase the accuracy of adverse event reporting across the board. I could think of one hypothetical example to drive home the point looking at adverse events in a vaccine trial:

Subject is vaccinated on day 0. On day 20 the subject reports itching at the injection site after being bitten by a mosquito. The bite becomes inflamed and the subject reports itching and pain in the injection site (say, left shoulder) to the study coordinator who documents the two adverse events on a common AE log and leaves it for the investigator to assess. Without knowing the last vaccination date or any other historical information, injection site pain/itching would seem like a dead ringer to be absolutely related to the vaccine. Thus the investigator chooses that option and moves onward, leaving the sponsor with inaccurate data that could have been rectified by simply providing more information to the investigator.

I realize that many adverse event logs are convenient because they allow for collection of multiple events in limited space, but I believe it's time to re-examine the way that AEs are evaluated by providing the investigators with information that is completely necessary for an appropriate clinical judgement of causality.

coordinators aren't going to like this at all.

As I was reading over some CFRs today (that is my life, unfortunately), I came across something of interest in the financial disclosure section (21 CFR part 54, for those of you who are interested). It mentions that financial disclosure is required for any investigator who contributes or evaluates data in a clinical trial. Now that could be loosely interpreted to be any physician (or health care provider) investigator listed on the 1572, but if one thinks about it...coordinators often play a vital role in contributing study data. Take for example hypertension or weight loss trials. Study coordinators will take blood pressure or weight according to a "standardized" system established by the study sponsor. The sponsor is doing its part by standardizing both the collection method as well as the training, but how is the sponsor ensuring that the coordinators providing this essential data are not financial invested in the results? I know it's not a terribly likely scenario, but it is worth considering, especially since there is so much information available for public use today.

A louche coordinator with a hidden financial stake in a study result could very easily "modify" results to help push data that will benefit him/her in the long run. Oh, and let's not forget that according to 21 CFR part 54, financial disclosure also applies to the spouses/dependent children of those investigators providing it. That nugget of information only complicates matters. Given that this situation is probably not going to happen, I think that requiring financial disclosure by coordinators would be an effective mechanism to ensury validity of data collected by coordinators because we all know that the coordinator plays a much larger role in clinical trials than I think the FDA would like to admit.

So how would all this go down? I would consider adding coordinators universally to the 1572 for all studies where coordinator assessments are part of the primary or secondary endpoints of the trial as described in the protocol. I think this would provide sufficient protection for the sponsor that their trial is being conducted appropriately with no financial influences at any level. Additionally box 6 of the 1572 asks for the names of all subinvestigators assisting the principal investigator in the conduct of the trial. You could say that subinvestigators are only licensed health care providers, but one could very easily interpret this to mean that coordinators are investigators for some studies and they are indeed assiting the PI, so they should be listed on the 1572. Granted this would created additional headaches for sites such as the need to acquire FDF part Bs at the end of studies and that might be difficult if coordinators leave the site, but I think the overall benefit to the site/sponsor would far outweigh those minor annoyances.

I'm not terribly optimistic that this trend would catch on because there doesn't seem to be much formal guidance on who signs FDFs other than the loose language in 21 CFR part 54, but with the FDA's apparent trend toward more regulatory enforcement (as well as the growing public microscope on clinical trial results), it might not be a bad idea to consider it.

By the way, check out EyeonFDA today. Good piece on healthcare reform.

Waste Not?

The longer I spend in the clinical trials industry, the more I am baffled by the amount of waste in the field. Unfortunately I am not just talking about wasted dollars for studies that never get off the ground or studies that never enroll at various sites. The physical waste produced by the industry is absolutely ridiculous and there really seems to be very little being done to rectify it.

Exhibit A: Lab reports. Why are lab reports still faxed (and sometimes mailed in addition) to sites? Some labs have recently developed the capacity to have sites log on to secure sites to retrieve lab reports, which can then be downloaded and printed at the site. One may say that this still uses paper, but in this scenario there is no cover page to the lab reports. Just think about how much paper would be saved by simply eliminating the cover page along with any summary pages at the end of the report. For large research sites, this would be a crazy amount of paper per year.

Exhibit B: Lab Kits. Most sponsors send lab kits in small boxes that are often discarded after the actual phlebotomy materials are used. The lab samples themselves are then sent in entirely different shipment boxes that usually do not use the original packaging. Add in the myriad kits that must be destroyed when they are either unused or expire over the course of the study and you end up with a nimiety of waste. While community recycling campaigns are more prevalent then ever before, I would wager that most sites could care less what happens to the unused kits, just so long as they are out of the way. I could see a couple possible solutions. The first would be to streamline the entire process: 1 kit for 1 shipper or multiple shippers for a large batch of lab draw supplies. The main downside to this second suggestion is that it would put a lot of responsibility on the site to make sure that the proper supplies are used at each visit....one of the primary reasons that lab kits are packaged individually currently.

Exhibit C: Emails/Paper Diaries/Questionnaires. Sites are required to keep copies of all correspondence between the sponsor/CRO/vendor and themselves. What would be so difficult about saving all emails, burning them to a CD and filing them with the regulatory documents at the end of the study? Or even burning them prior to monitoring visits for the CRA to review periodically? I think either scenario would save countless amounts of paper and help push the industry towards a more paperless functionality. Along the same vein, there is no reason why paper diaries and questionnaires should continue to exist. Most people have computers or are at least familiar with using a computer/PDA, so sponsors should be willing to pay the extra fee for electronic data capture systems. I would think the overall savings in capturing information electronically and in real-time would easily trump paper documentation in a short period of time.

There are countless more examples of situations in clinical research where wastefulness still exists in a society where recycling and reducing usage is strongly encouraged (I would love to have more suggestions and ideas). Unfortunately I don't see this trend changing unless there is significant pressure from not only the sites, but also the sponsors. I am thinking of starting an initiative to promote less wasteful practices not only at the site level, but also from the sponsors...please let me know if you are interested in participating!

Swine Flu?

So it's well known that clinical trials of H1N1 Flu (Swine flu as it was formerly known) vaccines have already begun with more to start in the next few months. That is excellent news and it looks like that with the wide variety of vaccine producing companies fighting for a piece of this potential cash cow, there will hopefully be no shortage of vaccine when it comes time to mass produce the shot. As per the usual, I have a couple questions....

1) How can the regulatory approval process be expedited so much that the clinical trials will essentially be ongoing when the vaccine is expected to still be delivered to the general population? I know that for most of the trials, the manufacturing process is very similar/identical to typical seasonal vaccines, but this is still a new strain of virus that we're dealing with here. How can we know that the vaccine will confer enough immunity to protect the population or how can it be ensured that the vaccine is actually safe (see 1976 Swine Flu fiasco)? After all the primary purpose of the clinical trials is to prove and/or verify the safety of pharmaceuticals in human participants. I don't think there is a real solution for this situation other than to put our trust in the scientists charged with developing the H1N1 vaccine because if the standard approval process is applied to this situation, then by the time a successful vaccine is approved for use, the need for it will be long gone.

2) What's going to happen to those participants in the H1N1 trials if vaccination is either mandated by the government or offered in mass quantities? Some of these studies will presumably have a placebo arm, so one cannot argue at all for protecting the scientific integrity of the trial when the health of the population is at stake. If the H1N1 vaccine does become available in mass quantities as expected, then participants of clinical trials will definitely be interested in knowing not only which treatment they received, but also if the actual vaccine would be available to those who received a placebo. One thought is that the short term safety/immunogenicity analysis might be complete by the time large numbers of shots are available (as long as the trial was started in late summer), so it may not impact the trial that much if unblinding occurred in the fall. The other is that a trial may have a safety valve built into it where if the safety and antibody tests are successful after the first dose is completed, then everyone on a placebo would return for the actual study vaccine prior to the end of the trial. If those tests were not successful, then everyone in the trial would receive an approved vaccine from the general public stockpile as a precaution.

This is certainly an interesting situation that is unfolding, but hopefully the powers that be in the realm of clinical research have had the forethought enough to consider all the options for successfully developing a H1N1 jab while at the same time keeping the general health of the participants at the forefront. Additionally I think the public perception of the vaccine development process will hinge on how these trials are handled. It is definitely a unique opportunity for manufacturers to demonstrate that clinical trials can be beneficial to both the participants themselves as well as future populations.

Independence Day

Happy Fourth of July! Since we are celebrating our nation's birthday today, I thought it might be nice to reflect on one of the often overlooked aspects of clinical research: the general freedom of research sites to conduct business as they like.

The rules and regulations that all research personnel, from sponsor to manufacturers to research site staff, have to follow are written in such a manner that permits flexibility in site research procedures. This flexibility allows a research site to develop its own operating procedures on all aspects of a trial provided that the site is still adhering to the ubiquitous language of the Code of Federal Regulations and ICH guidelines. One principle of quality assurance in the industry is that originality must be maintained in the research process, so I believe the regulations are written in such a way to permit a bit of creative license on the part of the sites to have unique operating procedures. Sites can, and should, take advantage of this fact so that they can say that not only is their site different from other sites, but also that they have their own procedures to ensure that GCP is being observed, staff is trained regularly, protocol visits are done accordingly, etc. The list of aspects of a research site's functioning that can be personalized is really limitless and every effort should be made to distance sites from other sites' practices in addition to sponsor "mandated" procedures.

I cannot tell you how many times I have been given sponsor provided source documentation to "has" to be used in a study, or forms/training documentation that "have" to be implemented during the conduct of a trial. I realize that a lot of such provided items are there to prevent a site from missing key data points, ensuring that site's document critical study procedures, or even ensure that site staff training is documented adequately during a trial. However if source documents are supposed to be original documentation, and every site is using the same ones, then how is that original? Another important fact that gets lost in the start up process is that sponsor provided source documents may only be designed to capture study endpoints. Just because they are given to you by the sponsor doesn't mean that the documents adhere to your site's SOPs or that you would be protected in the event of an audit. The reasoning for this is simple: source documents are supposed to be the original documentation of a study visit procedures at a site, so they need to be able to paint a complete picture of how the study was conducted. This requires a very detailed set of document, and frankly, most sponsor provided source documents do not provide that amount of detail. This won't make many coordinators happy, but I really think that sponsors should not provide source documents to sites for the reasons described above. Naturally if there are detailed questionnaires to be completed, that's another story because there are many assessments that are not consistently used or available in standard clinical practice.

The take home message here to sites is that you should do everything you can to ensure that you conduct studies according to your own procedures (while still following federal guidelines, of course). This includes reviewing sponsor source documents to make sure that you are covered and modifying those documents, if not, to meet your standards. It's also worth noting that before you do that, you need to consult the sponsor first and let them know the reasoning for the changes. So, go forth and celebrate your Independence!

As a patriotic side note, I would highly recommend reading "1776" by David McCullough, it's an excellent look into the happenings of that famous year in the USA.