|
|
|
|
|
|
|
the need to conduct bio-equivalence studies that are necessary if the formulation used is other than marketed. Although the Koseisho may change the guidelines to strengthen the use of placebo comparison, senior investigators who control the protocol content would probably strongly resist such efforts. Where a registered therapy exists, Japanese physicians are not well disposed to placebo studies. Similarly Japanese patients, whose medication is paid for by their health fund, may be prepared to try an investigational product with potential benefits over that currently available, but they are less willing to enter a study where there is a fair chance that they will receive a placebo. However the general attitude is changing with the Koseisho favoring the conduct of Phase III studies to incorporate a placebo. While the demand to demonstrate statistical superiority or equivalence (to be discussed later) would require smaller studies when the new drug is compared to a placebo rather than a comparator drug with a good efficacy rate, such a change would not be without drawbacks for the pharmaceutical company. Studying a new drug against a placebo may align the price against the most expensive drug in that therapeutic category. To increase the ability to obtain a 3% premium, however, it is better to test against that drug and show superior efficacy. Under the current reimbursement system, this 3% advantage may be crucial to the success and survival of the company. |
|
|
|
|
|
|
|
|
The current Japanese guidelines encourage investigators to conduct more scientifically correct studies, including the determination of decision criteria before the commencement of a trial, demonstration of statistical equivalency in the comparative studies (in preference to showing no statistical difference between groups), and the recruitment of more patients from fewer centers [27,28]. The use of more patients from fewer centers is not occurring and will require either the New Drug Subcommittee or the Special Committee to reject all studies failing to enroll at least 10 patients per site. Until this happens the present practice will continue because the investigators do not want to change and the studies are controlled by them according to Japanese GCP. In contrast the Special Committee has begun rejecting files not showing at least equivalency (on a statistical basis) against the comparative drug. However, in private discussions the Koseisho has made it clear that drugs that fail to show statistical equivalency may nevertheless be approved if evaluated usefulness (a Japanese assessment incorporating both efficacy and safety data) is demonstrated. This may be achieved by having a drug with a new mechanism of action or a demonstrated superiority in safety. It is likely that this may be an interim measure to rescue some NDAs during the early days of implementation of the need to demonstrate, at least, statistically based equivalency. |
|
|
|
|
|
|
|
|
Where a test medication is being developed in more than one dosage strength or in more than one presentation, such as tablets and capsules or liquid, patients must be entered on all dosage strengths and formulations. The |
|
|
|
|
|