Who's Going to Rescue the Rescue?

An FDA advisory committee recommended today to lower the maximum single dose of acetaminophen for adults from 1000mg to 650mg. As described in "OvertheCounterToday" this could eliminate the 500mg tablets from pharmacies and grocery stores everywhere (see this link:http://www.overthecountertoday.com/2009/06/fda-panel-supports-lower-acetaminophen-dose-liquid-limits-but-spares-combo-products.html#more) . The same panel also voted in favor of decreasing the maximum daily dose of APAP from 4 grams amid strong concerns of hepatic toxicity. That's all fine and good, but how could this affect clinical research?

Many pain studies currently use acetaminophen as the rescue medication of choice with a maximum daily dose of 4 grams. This is based on simple prescribing information for OTC acetaminophen that instruct people not to take more than 4 grams per day. So what happens if, during the course of a trial, participants cannot take as much acetaminophen for breakthrough pain relief as they could earlier in the study? I would hypothesize this could result in increased subject withdrawals as well as the need to potentially amend protocols and informed consent documents (resulting in additional regulatory costs that are passed down to research sites who will ask to be reimbursed for re-consenting participants). Furthermore I would also wonder what the data analysis effect would be if one protocol was originally written with the current rescue medication dosing instructions and a second protocol for a future trial was written with new regulations. Could pain relief be accurately measured if one set of participants was able to use 4 grams of acetaminophen per day while another set could only use 2.5 grams or 3 grams? I don't know the answer to that (perhaps statisticians can answer that one), but I would think that, at the very least it would complicate matters.

Additionally I suppose that under the supervision of an investigator, acetaminophen doses of 4 grams per day taken in 5oomg tablets could be used in clinical trials, but it may be difficult to encourage good compliance when most participants are completely familiar with being able to take 1000mg 4-6 hours (and likely have not ever had any issues). More likely though, I could see future protocols both decreasing the maximum daily acetaminophen dose to mirror the FDA's decision as well as including more rigorous criteria for including patients without any risk factors for liver damage. Another realistic option is the addition of additional safety testing for hepatic toxicity throughout the protocol in addition to mandatory, detailed work ups if such toxicity occurs during a trial. It is important to note, however, that these changes would ideally be implemented to show that due diligence was taken to protect the safety of research participants, not just to make the FDA happy.

I'm not arguing against any decision to restrict the availability and use of over the counter acetaminophen because often times people don't take the time to really read the information on the back of the bottle. Actually I think in the long run such changes will probably end up benefiting society in the long run more than it hurts manufacturers. However I also think that there may be lasting implications in the clinical trial industry as result of these discussions by the FDA in the past few weeks.

Tweet Tweet

Social networking is everywhere. So much so that the word itself it likely to become one of those overused buzzwords that defines 2009 when we look back on the year in December. However as identified in the blog "Eye on FDA," pharma has been slow to jump on the bandwagon. Only a small portion of pharma/biotech companies have either a Facebook page or Tweet on a regular basis. Because there is so confidentiality in the business, I'm not sold on the importance of such social networking for those companies themselves. They could try and sell their products through such sites, but the products should be sold through therapeutic value (I digress there). On the other hand that same blog brought up an even more interesting point that pharma/biotech companies should be investing in applications for smart phones that help with product compliance (such as daily reminders to take medication or measure blood pressure). I started thinking about that and realized that this could even be applied to clinical research.....

The cost of developing applications is fairly minimal if you have the right people. On the clinical research realm, applications could be developed and downloaded to trial participants that document product dosing compliance, adverse events, and remind them of study specific procedures. This could include reminders to take (or not take) medication prior to a visit, to complete a diary daily, etc. The list of possibilities is really endless, but if developing those apps is not your cup of tea, there are other options....

Sites could use the hottest, now almost ubiquitous social networking sites: Twitter and Facebook. Right now both can be used to inform potential participants about upcoming studies, but how can it be better utilized? Maybe sites could develop individual Twitter or Facebook pages for individual studies. These sites could host drug dosing instructions, tweet or instant message reminders to report AEs, or maybe even inform participants about an upcoming consent change for which they would have to contact the site to get more information. These social networking sites have applications that can be downloaded to smart phones so people get information on the go, and best of all...they are FREE!! All that would be required is for someone at a research site to establish the account, customize it, add study participants, and update it as appropriate.

Keep in mind, however, that because of confidentiality laws sites could not have the subscribers to the site public because full names are listed. Also, study specific information posted may have to be IRB approved, so if you consider this...be aware of IRB regulations. Those two minor (facetious) hurdles aside, clinical research should absolutely find ways to immerse themselves in social networking because the generation of today and tomorrow are/will be linked to the world through smart phones and computers, not newspapers and phones like the past 100 years.

What's with all the Consents?

I've worked on several studies (more the norm than the exception, actually) where a consent has to be revised for some reason during the trial. Most of the time the changes to the consent are minor, nothing that would really impact a participant's decision to continue participating in a trial (change of address, administrative changes, etc). However many IRBs insist on issuing an ENTIRE consent form where the revisions may be buried within the original text of the document, regardless of the actual content of the changes. My question is: If a revision is necessary, why not condense the revision to one or two pages for a trial participant to review instead of going over the entire consent again?

In my opinion a simple, one page description of changes would appeal more to sites and subjects for a number of reasons:

1) Subjects would have less information to digest, and would be more likely to retain such changes if they don't have to be concerned with reviewing study information that they received at the initial visit

2) Sites would be less error prone because of fewer pages to review. Many IRBs require subjects to initial/date each page of a consent indicating their understanding of the material. If the information has not changed, why should a subject have to acknowledge their understanding more than once yearly, especially for studies that are brief in duration? As a general rule, the more pages that require initialling/dating, the greater chance that errors and inconsistencies will occur.

3) Currently enrolled subjects can be updated on pertinent changes during the trial while new participants would have to sign the completely revised consent. This would require two separate documents sent to sites, but I believe we could manage that.

4) It would save paper....we all like to do that, right?

So what would I recommend doing? For starters, once a study has started enrolling participants IRBs could issue two different types of consent revisions: one would be a complete consent form for new enrollees, the other would be a detailed description of changes on one or two pages....enough to inform the subject completely. Oh, and let's not forget that the addendum would have the same requirements for documentation as the complete consent, such as requiring a signature of the person administering the consent and mandating that the subject receives a copy of the new information. In general I think this procedure would drastically improve the information disclosure process from sponsors to participants during an active trial. Keeping study participants consistently informed during a trial is a critical aspect of protecting the best interest of volunteers in clinical trials, so anything to improve that would be a very positive thing.

A New Box is Opening

Although the code of federal regulations, ICH guidelines, and most other regulatory publications are written in stone, clinical research is a malleable industry that has much room for interpretation and discussion. My goal here is to provide my thoughts on current topics within the industry, and perhaps shed some light on some topics that I feel require scrutiny at some level. I'm more than happy to field questions and comments on my ideas because, hey, I'm flexible too and just because I'm stating my opinion doesn't necessarily mean I'm right.

So, with that being said, let the blog begin! Remember: thinking outside the box is old hat, thinking in terms of a new box is what's going to separate you from the field.