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.