Some examples:

Drug A - blatent lethal extremely extremely rare side effect (1 in 100,000) observed in 1 in 200 people listed in the overall safety summary with onset within days. Medical reviewer listed the side effect several hundred times in the review but not once in the summary which would be published upon approval. No mention in FDA’s proposed labeling. Second reviewer finds the mention at the last minute when looking for something else. Raises the issue. Drug turned down for not being as efficacious as others. Company starts campaign that FDA overly cautious and nearly 9 months later suggests in the press suing FDA for illegal nonapproval. Reviewer who had raised the safety issue is by now on the verge of being fired so as to remove obstacle. This was first review for the Medical Reviewer who came from major pharma company. Medical reviewer promoted within 2 months of completing the review. Evidence of insider trading when safety and efficacy signals caught. Medical officer then made supervisor over all review discipline on pilot project showing how to review drugs quicker and allowing communication with sponsors during the review (previously not allowed).

Drug B - Reviewer ordered not to review early human studies and is forced to agree in writing. At last minute when writing background history on the development, reviewer takes a quick look at the very early studies and in abstract finds a mention of lethal side effect in earlier studies so takes a look. Finds multiple cases of different lethal side effects one of which the sponsor indicates are dose and time related. Sponsor indicates that the safe dose is limited to 1/5 of the proposed marketed dose.

Drug C - Safety summary lists multiple cases of suicide in drug and active control groups that largely only occur in first 2 - 3 weeks. None in placebo group. Sponsor tries to hide by normalizing to time on drug (up to a year) with none on placebo more than 3 weeks, and combining with another disease where there are equal numbers of suicides in the placebo and drug groups. It makes it look like more suicides on placebo. Medical reviewer parrots company line. 2nd reviewer realizes problem and reports it and is eliminated.

Drug D - Non-phase III reviewer when looking at safety summary at last minute prior to completing review finds suspicious deaths listed in the safety summary, (~ 100 pages in front of NDA) that match a mechanism indicated by pharmacology and symptoms seen in single dose drug interaction (phase I) studies. Brings it to management’s attention. Senior Management (above division director) wants a list of all suspicious cases and exactly where found in submission, the primary medical reviewer (who is also the safety reviewer which is highly unusual) is then used to dismiss each case. While compliling list of SAEs for upper management reviewer finds 2 suspicious deaths listed under other studies (e.g. still in progress or indications not being requested in initial NDA submission). These cases including evidence that sponsor saw a change in lab values indicating a lethal side effect that is known to occur frequently with some drugs in the class and rarely with others. Lab values are flagged by computer for investigator to contact sponsor. Instead of following protocol and discontinuing drug patient (or even following labeling for similar drugs) patient is allowed to remain on drug and in study without adequate monitoring. Since it occurred in Europe the patient has to be unblinded and a safety committee has to look into it. Safety committee by contract is not allowed to recommend stopping development or the study. Unblinding is not allowed by US law without special permission so request is made to FDA for unblinding of safety signals but is not told the reason. Patient does not come in for following appointment and upon followup is found to have died. The following day and several times over the next 2 weeks the company is contacts the FDA for permission for unblinding the study. Neither death is reported to the IND as required by law. Several years later sponsor decides not to include this study and indication for the original approval so only includes mention that patient died under other studies in progress which may or may not eventually be submitted. Medical reviewer intentionally does not review even the safety summary for these other studies.

These cases do not necessarily mean that the drugs should not be approved, however the cases need to be fully vetted, i.e. full data obtained, discussed internally, a true risk benefit analysis performed, and needs presentation at the required AC presentation for NMEs, (unless division director find way to cancel due to no concerns). Instead simply raising issues results in severe retaliation and labeling that simply indicates that some of these toxicities have been seen with other drugs in the class and thus suggests it’s simply a hypothetical consideration.

* With cigarettes it can come down to people making irresponsible and bad choices.
* With pharmaceuticals the consumer is much more a victim- being told he needs this or that by someone else who is depending on accurate information to make the call on someones behalf.

There is hope.

I agree with Justice.

The question becomes whether upholding Levine also entails requring a specific change in labeling about use (of phenergan) relative to what FDA reviewed and approved.

My guess, again, is that the Court will view Levine as much more like Riegel than this tobacco case, upholding preemption but within the narrow conditions of FDA specifically having reviewed the relevant risk and there being no evidence of fraud or significant negligence in the approval or compliance process.

These narrow conditions arguably do not apply to much of pharma litigation. And so the argument will likely continue for some time.

It is hard to imagine these issues applied to tobacco in a relevant way. So the issue of drugs seems to me likely to be viewed differently. There is, of course, also the Riegel decision and Justice Breyer’s now famous comment that did not suggest he would join the other “liberals” on the Court. I doubt Kennedy would either, particularly in a narrowly defined version of preemption if Wyeth prevails.

May I be wrong.