My name is Lou Lasagna. I am the Dean Emeritus at Tufts University of
the Sackler School for Graduate Biomedical Studies and for many years
was Director of the Center for the Study of Drug Development, first at
the University of Rochester and then at Tufts University.

My interest in analgesics harks back to a half century ago, when I
became involved in clinical trial design and the search for
non-addictive substitutes for morphine and for new pain relievers that
offered safer and more effective analgesia.

I am here today to present my personal views and have not received
compensation for my time. As a clinical pharmacologist, I have consulted
with many of the major pharmaceutical companies whose products are being
discussed today and tomorrow. Also, some of the research at the Center
for the Study of Drug Development at Tufts University is supported by
unrestricted grants from the pharmaceutical industry.

My goal today is not to draw any conclusions or make specific
suggestions on solutions to the complicated questions before this
Committee, but rather to raise some relevant issues that I believe need
to be part of the deliberations of this Committee. These issues and
principles can be applied to any of the drugs under discussion during
this two-day meeting.

The following three issues are of special concern to me:

1.  Dose-Response versus Benefit to Risk

OTC drugs are by their nature considered safe at recommended dosages and
regimens. It is, or should be, intuitively clear that the minimal
effective dose should be utilized in an OTC setting. Even with "safe"
drugs using excessive amounts of drug or dosages above the ceiling dose
for efficacy can only lead to an unwarranted increase in the risk of
toxicity. The balance of benefit to risk of all OTC drugs is clearly
related to the dose-response for efficacy. In the ideal world, the
ceiling dose for efficacy is well below the toxic levels, allowing a
wide therapeutic window and margin for safety. The question of
dose-response for acetaminophen, as well as other OTC drugs, needs to be
reviewed. The Committee needs to determine for both single-entity and
combination products whether the current dosages and regimens are
justified based on the available data.

2.  Combination Policy

My second point relates to the way OTC combination products are approved
for marketing. Under the FDA Guidelines for analgesics, the combination
policy clearly states that the contribution of each ingredient must be
shown in well-controlled clinical trials. This policy is applied to all
new combination drugs that seek approval under NDAs. In contrast, under
the monograph system, the monographs for analgesics and for
cough/cold/allergy products allow combinations of certain ingredients to
be marketed based solely on historical data of the individual
components. Often there are few or no data from well-controlled clinical
trials to justify the dosage of the analgesic ingredient in the OTC
combination or even whether the analgesic ingredient contributes
meaningfully to the overall efficacy of the combination. The monograph
policy has led to proliferation of a vast array of cough/cold/allergy
products that contain an analgesic. Both acetaminophen and aspirin at
their highest allowable dose are often part of these combination
products. For the newer analgesic drugs, this problem appears under
greater FDA control because of their NDA status requiring clinical
studies to demonstrate efficacy. From a public health perspective, it is
worthwhile to question the optimal dose of the analgesic that should be
in these OTC combination products. Wherever possible, data from
well-controlled clinical trials should drive the decision-making
process. Again, I want to stress that unnecessarily taking an excessive
amount of drug adversely alters the benefit to risk ratio and can
increase the potential for toxicity.

3.  Responsible promotion of products

> My third and last issue is more philosophical. Although there is
> fierce competition among the pharmaceutical companies, they all have a
> responsibility to be honest with the consumer. This honesty and
> forthrightness needs to be reflected not only in the label of the
> products, but also in promotional material in TV and print
> advertisements. The reality is that OTC drugs are neither perfectly
> safe nor are they without drug interactions and this message needs to
>
> be clearly articulated to the consumer. Overstating the safety image
> of any drug can lead to serious adverse events. One only needs to look
> at the overdose statistics from hospital emergency rooms and poison
> control centers to appreciate the importance of this problem. I would
> strongly encourage this Committee to review how OTC drugs are imaged
> to the public and I would encourage all the companies to be
> responsible in the promotion of their products.
>
> I thank the Committee for taking the time to hear my views. I hope
> that these issues resonate in your upcoming deliberations.