Brand-Name Makers Liable For Generic Injuries
25 CommentsBy Ed Silverman // November 8th, 2008 // 8:34 am
A ruling on Friday by a California appeals court is likely to spark a good many lawsuits against big pharma. The upshot - brand-name drugmakers were put on notice that they can be held liable not only for harm caused by their own meds, but also for injuries caused by a generic drugmaker selling a copycat version.
The First District Court of Appeal in San Francisco reinstated a lawsuit by Elizabeth Conte, who had taken a generic version of Wyeth’s Reglan heartburn med for nearly four years and developed tardive dyskinesia, which causes incurable and involuntary muscle movements. Although she took only generics, Conte accused Wyeth and three generic drugmakers of failing to warn of the risk of long-term use.
In reaching its 3-to-0 decision, the court cited evidence that Conte’s doctor may have relied on product warnings distributed to physicians by Wyeth when he decided to prescribe the generic version. Meanwhile, summary judgement in favor of the generic drugmakers - Teva Pharmaceuticals, Pliva and Purepac Pharmaceuticals - was upheld.
“As the foreseeable risk of physical harm runs to users of both name-brand and generic drugs,” Justice Peter Siggins wrote, “so too runs the duty of care and Wyeth has not persuaded us that consideration of other factors requires a different conclusion…We believe California law supports Conte’s position that Wyeth owes a duty of care to those people it should reasonably foresee are likely to ingest metoclopramide in either the name-brand or generic versions when it is prescribed by their physicians in reliance on Wyeth’s representations.” (Here is the ruling).
Hat tip to Drug and Device Law
PaulGGG
This is nuts!
A generics company that decides to genericize a product and make money from making and selling one should accept the risks that comes with that.
A brand name company has no control over what a generics company does or what else they put into a product besides the main ingredients.
G
Seriously! I should get in on this generic med business - tons of money and no risk.
Deborah B
It would be interesting to hear Justice’s take on this issue….
Just A Thought
ANDAs ANDAs ANDAs
(shakes head)
They must only show bioequivalence to the reference product. To the product for which thorough testing was conducted. The labeling must be nearly identical. Right?
Interesting situation.
Salmon
Just a Thought is correct.
Only the holder of the NDA for the reference labeled product can change the labeling, otherwise each generic company could change it as they see fit.
What really bugs me though is how FDA allows generics that aren’t scored when the innovator and other products are. Every month I never know if I will get something that’s scored or not.
Salmon
Nathan
Actually, I agree with this ruling. Generic manufacturers don’t do the clinical studies - the “big pharma” does. If big-pharma covered up clinical data thereby resulting in inadequate warnings, then they should be liable for harm.
That said, as I’ve said previously, I *only* think that big pharma should be liable when it is PROVEN that information was deliberately covered up. Many of today’s lawsuits (think Levine and HRT) are due to poor JUDGEMENT CALLS about risk - not due to actual fraud or cover-up. Hindsight is always 20/20. Sometimes what appears to be a minor blip on the safety radar turns out to be something major. Sometimes it turns out to be nothing. We can’t always error on the side of caution. If we did so, we would never have any new drugs. As we’ve said many, many times here - ALL drugs have safety problems. It’s very clear in my mind: No coverup - no liability.
PaulGGG
Some of these arguments don’t make sense. It cannot be that only the holder of the original NDA is liable for everyone else.
When generics come out, each has its own label and is responsible for its product. Remember, a label os much more that the underlying clinical studies, it is manufacturing methods, non-active incipients, tablet image (and score), etc.
As someone above said, what a great deal generic companies have, all the upside and none of the risk. In a way this is the absolute best proof and justification for higher brand name prices.
Justice in MI
I’m pretty close to Nathan on this. The ‘rub’ is determining what constitutes a ‘cover-up.’ For example, we have gross instances of suppressing or fudging data - no ambiguity there.
And then there are a range of what Jerry Avorn calls ‘passive-aggressive’ compliance - technically, being in compliance, but going out of one’s way to camoflage red flags in the mode of reporting/counting, hiding internal studies (not requested by FDA), and a range of behaviors outside of FDA’s oversight (attempts to bribe or intimidate researchers; publishing misleading (cherry-picked to death in which risks minimized) journal articles; etc.. In a recent thread, a number of such ‘lesser delinquencies’ (lesser than felony fraud, that is) were listed in the context of Vioxx, anything but the most serious offenses.
And then there is the question of how we learn of such things. If, as the Bush FDA/DOJ has argued, only the FDA can find fraud against itself (following 2001 Buckman decision), there is no discovery and thus most of the kinds of delinquencies noted above would remain unknown. ‘Deliberate cover-up,’ in that context, means proving intent - prosecuting felony fraud. And, for a variety of administrative reasons, this is something FDA/DOJ essentially never do, as we’ve discussed.
So I am essentially with Nathan in principle, but - when translated into practice - I believe restricting liability to proof of deliberate cover-up necessarily requires a broader scope for civil liability than may initially be apparent.
As for the issue of generics…lots of additional complexity. I’ll pass for the moment.
Just A Thought
“Generic manufacturers don’t do the clinical studies - the “big pharma” does.”
Sometimes. And sometimes they change their own products without fully testing them- creating an even more convoluted situation. Tossing the thorough studies of their own product- whether they created the product or acquired it along with another company.
Then the question becomes:
Which set of numbers and what labeling does the generic maker have to follow when the innovator drug has changed?
Anne PME
Most states have automatic generic substitution. If the physician writes the prescription for the brand name drug and a generic is available, the prescription is filled with whatever generic brand the pharmacy has on shelf or available as an add on (needs to be ordered). In the case of new generics, the physician or other prescriber is often unaware of the generic substitution. If there is a problem, it is less likely to be attributed to the generic substitution and more likely to be attributed to disease progression, disease complications or patient noncompliance. While generic drugs have made medical treatment accessible to many people, in hindsight, they also likely further convolute safety reporting and response such as label changes.
I like to think of a package insert as a drug instruction manual. The majority of practicing doctors, first responders and pharmacists that I know do not have law degrees and don’t write or have the time to participate in the writing of legal briefs. That being said, on an increasing basis it seems as though the instruction manual that my doctor (or other prescriber), first responder and/or pharmacist relies on to protect their patients’ and themselves from liability (and litigation) is written in a foreign language called legalese.
A lot of time and attention is focused on the drug label/package insert, but we need to question whether or not these scarce resources would be better spent on tightening a convoluted and dysfunctional health system. In real life, outpatients seldom review the drug label before taking the prescription because they usually do not receive the drug label – the package insert - with their prescription. In most cases, the prescription drug is taken out of the manufacturers packaging and the original packaging with accompanying insert is destroyed. The drug is dispensed in pharmacy packaging and comes with a pharmacy insert. Patients take prescription drugs because they are sick. The majority of patients are not licensed medical professionals or lawyers, so they would probably have a hard time understanding the package insert. Patients (or their caregiver) are more likely to read and rely on the larger print, easier to read and interpret pharmacy insert or on the information given to them by licensed health professional who oversees and/or administers the drug(s). Despite this, the majority of drug labeling cases center on package inserts that are not accessible to many licensed medical professionals or their patients.
NDAs
Great business. No clinical research costs. Grab profits from the big pharma that made all of the investment. Then pass all of the risk back onto them. We should all quit making new drugs and biologics and just go into the generics business. That would be just great for the future health of America, right?
An FDA Reviwer
Justice presents a much more realistic picture of what the true situation is.
Industry has many ways of hiding or obfuscating information. Typically during development they may ask for a meeting with FDA and ask for agreement that they don’t need to study something further. This is usually a tip off that they have something that worries them and they don’t want to look any further and they want FDA agreement. Typically if you look, you find that companies report a severe toxicity within a couple of months that mechanistically might be related to the science that they don’t want to pursue.
They don’t provide us will all the data, and even refuse it on requests and then after approval little by little basic scientific information that might point to problems may trickle out in very specialized scientific publications. At the same time progressive labeling and other changes are submitted. (Get approval for a supplemental indication with young women who are likely to get pregnant. Have higher risk in combination with other drugs. Get labeling changes that point to drug interactions but indicate the problem is in lack of efficacy so need to increase dosage and ignore the induction of a toxic metabolite. Then slowly release information that points to birth defects.) I can go on.
I expect these things from drug companies and it’s my job to try to pick up on them as best I can. If they would be honest with me in the first place and we could work together on appropriate labeling then I would be more predisposed to preemption.
What really bothers me though is the gymnastics FDA management takes to help drug companies hide things. If you start asking for information because a company doesn’t provide it management overrules it.
We used to be able to keep old review jackets near our offices so that when we worked on other drugs in the same class we could look things up and find class effects.
So they removed all our shelving, and set up a special centralized repository and it’s difficult to even get access. (Yes new submission are all electronic, but many drug classes have been worked on since the 60’s or earlier.)
If you do find a problem and ask for information from a company, FDA management steps in and deny your request, or they may just not forward it at all.
They may assign it to a different reviewer or they may schedule discussions with the company when you’re on vacation or may simply prohibit you from attending.
For cardiac toxicity they’ve set up a totally separate group to evaluate thorough ECG studies (thorough QT). This was under Bob Powell (former VP at Glaxo/Pharmacia/Pfizer). They are a supposed to be a consult group. Heaven forbid anyone should question what they did (even when it’s clear the company didn’t include half the data that includes all the highest exposures in the dataset).
You can also be ordered not to review studies in an NDA that are under your discipline or be told to only look at the summaries that companies write, and we all know that these summaries are totally honest.
Guidances are a really big problem. Many times the drafts come out after a reviewer has raised a safety issue and the company is fighting you. So instead they work with FDA management to issue a draft guidance almost immediately that limits the extent of what is needed to what the company wants for that drug. As a draft it’s not final and so reviewers can’t discuss the flaws in it outside as it’s still in the dilberative process. But companies are free to follow it as it’s our ‘best thinking’. Then when the drug comes in for approval all of a sudden the guidance is finalized and if you don’t follow it (except with management permission to go outside of it) you can be reported and get in trouble for insubordination. I really hope that under a new commissioner that every guidance gets a thorough reexamination with opportunities for input from the senior review staff, as new reviewers simply follow them blindly and don’t realize the history.
After generics are approved post marketing AEs are still generally reported to the originator and not the generic company. However I think we give too little consideration to reports of problems with generic switches. Another problem is that the approval is based on estimates of average differences and don’t account for individual variability. Most times this isn’t a problem but if it is, all a company has to do is study more and more people to decrease the confidence interval. Perhaps we should limit the size of the studies so that you can’t game the system this way.
I know many good people at drug companies and they used to let FDA catch things that they couldn’t convince their own management was a problem. With the way FDA management steps in now that’s gone.
An FDA Reviwer
Before I get comments. I would like to say that I know that this is about labeling and generics and who should be liable.
Anne PME makes many good points also. Personally I think that even if medical professionals did take the time to study the labeling in depth. They still wouldn’t fully understand the implications. That’s why I included the example about developmental effects. Another one is a drug for a minor condition where the labeling says you should consider not giving it during pregnancy but structurally it looks and awful lot like thalidomide.
Largely however what goes into labeling is a function of the innovator and the FDA. Hopefully a new commissioner will try to do something, but I wonder who will be left at FDA to tell him/her where all the problems are hidden and how will that new commissioner know who to trust. That leaves being able to hold companies responsible, and allowing a jury to shift through the nuances.
Pharma Newbie
Just to chime in, the genric is not the same as the branded, who is to say the bioequivalence is what causes the difference. It’s seems to me it’s hard to issue fault if they are not the same agent.
Approval of a generic version of a proprietary drug by the FDA requires demonstration of “chemical equivalence” (similar quantities and availability of the active ingredient in proprietary and generic formulations), and “bioequivalence” (defined by absorption parameters generally falling between 80% and 125% of those obtained with the proprietary agent under the same testing conditions) (2) The use of the –20%/+25% rule is based on a regulatory decision that for most drugs that difference in concentration of the active ingredient in blood will not be clinically significant.
Justice in MI
FDA reviewer writes: “I wonder who will be left at FDA to tell him/her where all the problems are hidden and how will that new commissioner know who to trust. That leaves [?] being able to hold companies responsible, and allowing a jury to shift through the nuances.”
Of course, the obvious answer is your colleagues. So the question becomes - what sort of circumstances would make this legal and not suicidal thing to do?
Perhaps I misunderstood, but I had gathered at one point that reliable members of Congress have played a relevant role as recipients of critical information. Certainly, they have in the past - viz., Rezulin.
Justice in MI
Also wanted to thank FDA reviewer for detailed comments.
I was especially struck by the ending: “I know many good people at drug companies and they used to let FDA catch things that they couldn’t convince their own management was a problem. With the way FDA management steps in now that’s gone.”
The situation parallels some of what we’ve also seen in the context of potential litigation, in which that threat was useful to “moderates” in companies to help reign in the “cowboys.”
As DDL makes clear, the preemptors’ core mission of seeing “prescription drug litigation vanishing from the face of the earth” [their words] has not changed.
An FDA Reviwer
Justice,
Congress is so busy with so many major things. That they only have time to listen to really major things like actual numbers of suicides on antidepressants that has been sent in a table. They don’t have the time to deal with all the specifics. They need to rely on the next commissioner to fix things.
Harassment can force out nearly anyone who raises a question about general science, guidances, procedures, or why management wouldn’t listen to review staff (Von Eschenbach we want to listen to you so talk to me) especially since raising a question identifies the person as a potential troublemaker, or someone who will help change things back. Nearly everyone of those individuals don’t have specific big safety issues to whistleblow on like Vioxx, or suicides and antidepressants. With the experienced reviewers who would speak up gone. Some of the people remaining who were part of the problem will jump on the new bandwagon and may even be intentionally placed there to minimize changes away from industry. (There’s been a lot of talk about succession planning at FDA over the last 1 - 2 years).
During the past 10 - 15 years sychophants and people from industry have been brought in and rapidly promoted into critical positions. This is especially true of those who control the evaluation of the science and approvals. That doesn’t mean that there would be sufficient PROVABLE grounds to remove those individuals. However, the depth of the takeover has been so complete and has occurred over such a long period that it permeates every level. Including the new reviewers who have been hired from the industry layoffs. Thus a new administration will have a virtually impossible task to change things back as the changes are so deep. This is a problem especially if Pharma is planning on submitting a lot of dangerous drugs in a short period of time during the end of the current and during the beginning of the next admin, and getting them through before changes can be made or problems realized. Based on published FDA IND data I believe this is the case.
What we really need is the whistleblower protection act. Unfortunately a single senator (likely Kyle) is holding it up. Sunshine is the best disinfectant and allowing reviewers to speak publicly e.g. via a book that includes numerous examples and shows exactly how the FDA takeover has been orchestrated and the subtle problems still around that need to be addressed. (e.g. guidances allowing valuating metabolites that are only 10% or greater than parent drug - what is 10%. I can jump over an anthill, I can’t jump over 10% of mount everest.
Also it doesn’t matter what the law says. It says you can’t retaliate against someone who reports a crime, but if it’s not vigorously enforced and the people punished then no one’s going to come forward in the future. It isn’t a matter of vindictiveness, it’s really a matter of what is best in the long run as a whole.
In addition, there are those who go along whole heartedly simply to get ahead even if they really don’t understand the big picture and what’s really going on. Vs. those who won’t help fight and go along simply because they’re afraid. No one should be excessively penalized, but some consequence is definitely needed for the first group.
For anyone who’s reading my comments. I don’t post things that I learned via information in submissions. Rather I also read on my own time for myself and I also talk to people in companies who suggest certain scientific areas for me to look into. So in a number of cases I happened to connect dots based on public information, this also helps me in my review work.
As for suicide. I believe I’ve already committed professional suicide and I really don’t know what I’ll be doing for the rest of my working career.
Quibbler
I find it odd that thereare so many comments about the generic companies not being held accountable.
“Meanwhile, summary judgement against the generic drugmakers - Teva Pharmaceuticals, Pliva and Purepac Pharmaceuticals - was upheld.”
That’s pretty unambiguous, isn’t it? The generics had already lost. This just means thet Wyeth is liable too.
Or am I missing something?
Ed Silverman
Hi Quibbler,
My mistake. The summary judgements in favor of the generic makers was upheld. I have just corrected that in the post. My sincere apologies.
Ed
Really?
Actually, from a policy perspective, the court rendered a horrible decision. Product liability law is designed to police the maker of a product. Wyeth never made the product that allegedly caused the damage. Instead, a company that COPIED the product has managed to spread liability onto Wyeth.
This decision reduces the incentive for generic manufacturers to carefully pick the products that they commercialize, because they can expect that some (or potentially all) of the liability can be transferred to the original manufacturer of the product.
Conversely, this decision reduces the incentives for innovators to develop and commercialize new medicinces, because they will be saddled with additional liabilities at a point in the product life cycle when they cannot possibly recover costs associated with such liablities.
I’m guessing that the judges that rendered that decision really didn’t pay much attention in law school to their product liability law lecturers. One can only hope that their decision gets overturned on appeal.
Nathan
Those are very good points… Maybe I’ll rethink my opinion here…
Moreover, I’m unclear on whether the generics are ALSO liable or not. From Ed’s and Quibler’s post, it appears that ONLY Wyeth is liable — not the generics. They got off scott-free. Is that right?
Ed Silverman
Hi Nathan,
Yes, that’s correct. And you can see that in the conclusion at the end of the ruling, which is worth reading.
Cheers
ed
Just A Thought
If you do not like this decision then your argument should be with how generic drugs are approved.
Cmax, AUCo, Tmax, T-1/2.
Simple studies that compare dissolution. Nothing of the potential a drug has as it builds in the system. No big cast of test participants. Probably no post-marketing commitment. It is why I’ve been complaining about ANDAs for so long.
What’s good for the goose should be good for the gosling too though. The big companies shouldn’t get away with such little testing when they make changes to their formulas either. Not if you want the public to be safe.
“Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.”
http://www.fda.gov/cder/Regulatory/applications/ANDA.htm
What does that do to the more complete testing that gained the NDA approval? Why bother with such scrutiny if they can be reformulated and approved with simple bioequivalency studies later? Give a few people a pill and draw their blood a few times. Makes perfect sense.
(eye roll)
So yep, I do agree with this ruling. If the big companies couldn’t be equally careless I would have a different opinion on the matter. No one should get to have it both ways. Keep your standards high and the copycats will have to keep theirs high too.
Just A Thought
BTW, that CDER page was updated on October 25, 2007. How long has is been that a branded drugs have been allowed get past reformulation this way?
Nathan
Derek Lowe has a nice post on this controversy. Here’s an excerpt: (link below)
“Because they are cheap, generics typically drive the pioneer manufacturer’s drug off the market (or into a very small market share) within a few years, if not sooner. Generic drugs will stay cheap under Conte. But imposing liability in perpetuity upon pioneer manufacturers for products they no longer sell or get any profit from means that the pioneer manufacturers (being for-profit entities) have to recoup that liability expense somewhere. There’s only one place it can come from. That’s as an add-on to the costs of new drugs that still enjoy patent protection.”
http://pipeline.corante.com/archives/2008/11/17/liable_for_generics_you_are_now.php