Friday, October 25, 2013

Replies to Inquiries to FDA on Good Clinical Practice

Good Clinical Practice (GCP) is the law of conducting the clinical trials. Sometimes, interpreting the law is challenging, the same is true in interpreting the GCP and other regulatory guidelines. FDA has set up an Office of Good Clinical Practice and provided  Good Clinical Practice Contacts for helping interpreting the GCP and answering the GCP related questions.

Recently, I just found that the FDA has an email address for questions and answers regarding GCP questions. The original questions along with FDA's responses are posted on the web. While FDA's responses may not directly address the original questions being asked, Replies to Inquiries to FDA on Good Clinical Practice is still a great resource.

Monday, October 21, 2013

Monitoring the double-blind study: unblinded pharmacist, unblinded monitor, and drug kit

In many clinical trials with biological products, the investigational products usually need to be reconstituted before the use. If the study is a double-blind study, the reconstitution of the investigational products can not be performed by the investigator in order for the investigator to remain blinded to the treatment assignment.

There are two ways to tackle this issue.

1. Using a third party (unblinded pharmacist).

With this option, the unblinded pharmacist at the investigational site will be the only person who knows the treatment assignment. The unblinded pharmacist will obtain the randomization number and treatment assignment information from the randomization envelope (manual process) or from IRT (interactive response technology including IVR or IWR) system. The unblinded pharmacist will then prepare and reconstitute the study drug, and then give to the investigator for administration.

The unblinded pharmacist must not communicate with the investigator about the subject treatment assignment.

The unblinded pharmacist must maintain the records for drug accountability for auditing and inspections.

With this option, the study team will need to include an unblinded CRA (clinical research associate) for the purpose of checking the drug accountability. In other words, there should be separate roles for two type of clinical monitors:
  • Blinded Monitor: A monitor designated to perform site monitoring activities except for pharmacy, drug accountability, and reconciliation of the blinded investigational products.
  • Unblinded Monitor: A monitor designated to perform the site monitoring activities for pharmacy, drug accountability, and reconciliation of the blinded investigational products.

 Some of the references for this approach:

2. Using the blinded drug kit for the investigational product  

With this approach, in addition to the randomization schedule (containing the  randomization number and the treatment assignment), additional list of drug kit numbers (and the linked batch or lot number corresponding to the investigational products) will be generated. Through the packaging, the label for the investigational product kit will contain only the kit number. Investigators can dispense or administer the investigational products to the patients based on the kit number without knowing the actual contents and the treatment assignments.

There is no need to have separate roles for site monitoring (ie, unblinded monitor and blinded monitor). The same monitor can cover the study activities and the pharmacy/drug accountability.

This approach can also be used for pills (non-biological products). It is especially useful when the investigational products are dispensed to the patients for their self-administration.  

A couple of examples for using this approach are listed below:
“Randomization was to be blocked by study site, based on a SAS-generated code. Treatment assignment was made through a call to a centralized interactive voice response system for a drug kit number. Subjects were considered randomized upon verbal assignment of kit number.”
“Patients were randomly assigned to 1 of 3 groups of GXR treatment (2, 3, or 4 mg/day) or placebo, in a 1:1:1:1 ratio. Matching GXR and placebo tablets were provided to patients in the form of weekly prepackaged individual study drug kits, identical in appearance, according to the randomization schedule. Every morning during the double-blind treatment period, patients took a total of 4 tablets, without regard to meals. Patients who completed the screening and washout periods were assigned to the treatment group of the next available drug kit in ascending order of the drug kit number (or randomization number), which was recorded on the case report form.”

Friday, October 11, 2013

Science or Just for Fun? - Correlation between Chocolate Consumption and Winning Nobel Prize

 The New England Journal of Medicine is a very prestigious medical journal with very high impact factor. I am surprised to read an article by Dr Messerli to claim that the chocolate consumption is correlated to winning the Nobel Laureates. See “Chocolate Consumption, Cognitive Function,and Nobel Laureates” at NEJM 367;16 1562-1564.

I hope that the paper was published just for fun, not for serious discussion of the science.

Nothing is wrong about the statistical calculation. The p-value for correlation coefficient is indeed statistically significant. However, this superficial correlation ignores many confounding factors behind this correlation. I guess that it will be embarrassing to find out that even though there is a correlation between the chocolate consumption on national level and the number of Nobel Laureates, the Novel Laureates are those who consumed little or no chocolate.

In my first college lesson about the correlation, the teacher told me that before calculating the correlation coefficient, make sure that we were comparing two things that are related. If we try to claim there is a correlation between the growth of a tree and a growth of a baby, we will certainly be able to establish the correlation, but so what?

An excerpt from J. A. Paulos,Beyond Numeracy gives some examples that the wrong correlations are assumed.

“Children with bigger feet spell better. In areas of the South those counties with higher divorce rates generally have lower death rates. Nations that add fluoride to their water have a higher cancer rate than those that don't. Should we be stretching our children's feet? Are more hedonist articles in Penthouse and Cosmopolitan on the way? Is fluoridation a plot?
The odd results above are easily explained in this way. Children with bigger feet spell better because they're older, their greater age bringing about bigger feet and, not quite so certainly, better spelling. Age is a factor in the next example as well since those couples who are older are less likely to divorce and more likely to die than are those from counties with younger demographic profiles. And those nations that add fluoride to their water are generally wealthier and more health-conscious, and thus a greater percentage of their citizens live long enough to develop cancer, which is, to a large extent, a disease of old age.”

Unfortunately, nowadays, many articles in medical journals consciously or unconsciously presents the correlations between two things without further considering the confounding factors or the basis for the correlations. This is why we often see that a conclusion from one study is later totally reversed by the results from the another study.

Fields Arranged by Purity - A Cartoon

See the explanation for this cartoon, please visit: