NDMA OPPOSES REQUIRING COMPARATIVE STUDIES WITH CURRENT OTCs

NDMA OPPOSES REQUIRING COMPARATIVE STUDIES WITH CURRENT OTCs as the basis for determining the efficacy of a new OTC analgesic, Nonprescription Drug Manufacturers Association Senior VP/Director- Science and Technology William Soller, PhD, said in a Sept. 9 presentation to the FDA subcommittee on analgesics. NDMA believes that the current FDA policy for approving OTC candidates is adequate, Soller said.

Soller described current policy as requiring "a determination of safety and effectiveness in the target population for the switch/de novo OTC candidate in question and not on a comparison of effectiveness with other currently marketed analgesics" as the basis for approval.

Soller acknowledged that "when we look at analgesic efficacy studies you want to insure upside sensitivity. And as you look at the data bases, the currently marketed OTCs are going to be put in there as the standard so you can mark how the new product or OTC candidate" measures up. This "clinical judgment" is "appropriate" for determining whether you have a validated model, he said.

However, Soller pointed out, "once the efficacy has been demonstrated in the model, the regulatory decision is not based on a comparison to other analgesics....There's a nuanced distinction here."

Soller's remarks were in response to a question by NDAC member Marcus Reidenberg, MD, New York Hospital-Cornell Medical Center. "If we're not to use the currently marketed drugs as a working standard for what constitutes clinically significant relief for an OTC analgesic," Reidenberg asked, "then what kind of criteria should we use for the degree of efficacy over placebo to [be able to] say we're getting clinically significant relief at the particular dosage being recommended for OTC sale?"

Reidenberg also raised the issue later in the meeting, noting that if "what's happened in the past continues, if the OTC dose recommended will be lower than the prescription dose, then we're faced with the question not of, 'is the drug effective?' but rather, 'how much better than placebo do we want a particular dose to be?'" Since companies now have "experience with efficacy for the presently marketed analgesics at the present over-the-counter doses," he continued, "it is very hard for me to see how we can have some absolute criteria for efficacy ignoring what the current experience is."

On this basis, Reidenberg said, "it certainly seems that a reasonable criterion for effectiveness of the new dosage form is that it shouldn't be worse than...the presently available OTC drugs at the labeled dosage for the indications."

Juhl noted that the dosage issue leads to a related question "that I think the agency would like us to address as well." If a company has done a "good dose-ranging study and perhaps has a low dose that has good data to support it," he queried, "does the group believe that we should stick to the dogma of 'now go back and try to find a lower dose?'" Juhl noted that such an approach "possibly violates the 'Reidenberg principle,' which says a drug that's going to be switched should fail into the same ball park in terms of efficacy as other drugs."

Subcommittee guest Louis Lasagna, MD, Tufts University Medical School, pointed out that "the challenge here is how do you come up with OTC labeling with regard to individual and total dally dosage? That judgment will have to take into account safety data, pharmacokinetic data and efficacy data and it seems to me that getting some comparative trial data with standard analgesics will help you in coming to that judgment."

Exactly how the performance should "match up" will "have to be determined case by case," Lasagna suggested. "I can imagine, for example, a drug that might not be quite as effective as the things on the market but is unbelievably safe -- you couldn't kill yourself no matter how much you took of it -- and one might well want such a drug on the market."

The "general view" among the members of NDMA's analgesic task group, Soller noted, "is that most companies that are talking about switch are not going to want to come out with something that's less efficacious than something that's already out there as the standard."

Given that view, Soller recommended that "the principle perhaps should be the importance of having a positive control." However, he questioned whether a particular analgesic ingredient should be specified by FDA as a control. Instead, Soller advised "specifying a positive control which would likely be the standard dose of a currently marketed analgesic in that context."

That information "might well be available in the Rx data base," Soller said, "and it might well be developed...in terms of case-by-case as you're looking at safety and doing the benefit/risk in the end. It might be developed from looking at a number of different trials, it might be a pooled analysis...or it might be an actual study." Regardless, he stated, "I think if the general principle is made to carry and then the specific approach is done on a case-by-case basis (because you won't know what the data set is), then I think it is on the right mark."