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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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October 18, 2012

The Generic Wellbutrin Problem: Whose Fault Is It?

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Posted by Derek

One of the questions I get asked most often, by people outside of the drug industry, is whether generic medications really are the same as the original branded ones. My answer has always been the same: that yes, they are. And that's still my answer, but I'll have to modify it a bit, because we're seeing an exception right now. Update: more exceptions are showing up in the comments section.

Unfortunately, "right now" turns out, in this case, to mean "over the last five years". The problem here is bupropion (brand name Wellbutrin), the well-known antidepressant. A generic version of it came on the market in 2006, and it went through the usual FDA review. For generic drugs, the big question is bioequivalence: do they deliver the same ingredient in the same way as the originally approved drug and formulation? The agency requires generic drug applications to show proof of this for their own version.

For bupropion/Wellbutrin, the case is complicated by the two approved doses, 150mg and 300mg. The higher dose is associated with a risk of seizures, which made the FDA grant a waiver for its testing - they extrapolated from the 150mg data instead. And right about here is where the red flags began to go up. The agency began to receive reports, almost immediately, of trouble with the 300mg generic dose. In many cases, these problems (lack of efficacy and/or increased side effects) resolved when patients switched back to the original branded formulation. That link also shows the pharamacokinetic data comparing the two 150mg dosages (branded and generic), which turned out to have some differences, mostly in the time it took to reach the maximum concentration (the generic came on a bit faster).

At the time, though, as that link shows, the FDA decided that because of the complicated clinical course of depression (and antidepressant therapy) that they couldn't blame the reported problems on a difference between the two 300mg products. A large number of patients were taking each one, and the number of problems reported could have been explained by the usual variations:

The FDA considers the generic form of bupropion XL 300 mg (Teva Pharmaceuticals) bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300 mg. Although there are small differences in the pharmacokinetic profiles of these two formulations, they are not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective. The recurrent nature of (major depression) offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product. The adverse effects (e.g., headache, GI disorder, fatigue and anxiety) reported following a switch were relatively few in number and typical of adverse drug events reported in drug and placebo groups in most clinical trials. . .

But they seem to have changed their minds about this. It appears that reports continued to come in, and were associated most frequently with the generic version marketed by Teva (and produced by Impax Pharmaceuticals). That FDA page I've quoted above is not dated, but appears to come from late 2007 or so. As it turns out, the agency was at that time asking Teva to conduct that missing bioequivalence study with their 300mg product. See Q12 on this page:

FDA continued to review postmarketing reports throughout 2007. In November 2007, taking into consideration reports of lack of efficacy, FDA requested that Impax/Teva conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The study protocol stipulated the enrollment of patients who reported problems after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. Impax/Teva began the study, but terminated it in late 2011, reporting that despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients.

The agency apparently was continuing to receive reports of problems, because they ended up deciding to run their own study, which is an uncommon move. This got underway before Teva officially gave up on their study, which gives one the impression that the FDA did not expect anything useful from them by that point:

In 2010, because of the public health interest in obtaining bioequivalence data, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The FDA-sponsored study enrolled 24 healthy adult volunteers and examined the rate and extent of absorption of the two drug products under fasting conditions. In that study, the results of which became available in August 2012, Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

That FDA-sponsored study is what led to the recent decision to pull the Imapax/Teva 300mg product from the market. Their 150mg dosage is still approved, and doesn't seem to have been associated with any increased reports of trouble (despite the small-but-real PK differences noted above). And it's also worth noting that there are four other generic 300mg bupropion/Wellbutrin products out there, which do not seem to have caused problems.

How big a difference are we talking about here? There are several measurements that are used for measuring blood levels of a drug. You have Cmax, the maximum concentration that is seen at a given dosage, and there's also Tmax, the time at which that maximum concentration occurs. And if you plot blood levels versus time, you also get AUC (area under the curve), which is a measure of the total exposure that a given dose provides. There are a lot of ways these measurements can play out: a very quickly absorbed drug will have an early Tmax and a large Cmax, for example, but that concentration might come back down quickly, too, which could lead to a lower AUC than a formulation of the same drug (at the same nominal dose) that came on more slowly and spread out over a longer time period. To add to the fun, some drugs have efficacy that's more driven by how high their Cmax values can get, while others are more driven by how large the AUCs are. And in the case of bupropion/Wellbutrin, there's an additional complication: some of the drug's efficacy is due to a metabolite, a further compound produced in the liver after dosing, and such metabolites have their own PK profiles, too.

So in this case, it turns out that the AUC just missed on the low side. The FDA wants the statistical 90% confidence interval to fall between 80 and 125% compared to the original drug, and in this case the 90% CI was 77-96%. The Cmax was definitely lower, too - 90% CI was 65-87% of the branded product. And while the agency doesn't provide numbers for the metabolite, they also state that it missed meeting the standards as well. There are drugs, it should be said, that would still be effective at these levels, but Wellbutrin clearly isn't one of them.

My own take is that the FDA was willing to consider the adverse reports as just the usual noisy clinical situation with an antidepressant until the other generics were approved, at which point it became clear that the problems were clustering around the Impax/Teva product. Here's how the FDA addresses the "Why didn't we find out about this earlier?" question:

Q17. In retrospect, were FDA’s decisions regarding the approval and ongoing monitoring of Budeprion XL 300 mg appropriate?

A17. A less cautious approach in studying the bioequivalence of Budeprion XL 300 mg could have brought the data to light earlier. The FDA-sponsored study was completed only weeks ago, which is a very short time for data from a clinical experiment to be announced to the public.

Bupropion is associated with a risk for seizures, which was the basis of the Agency's cautious approach with regard to the early Budeprion XL bioequivalence studies, in which data were extrapolated from Budeprion XL 150 mg in patients to the projected consequences of exposure to Budeprion 300 mg. In retrospect, it is clear that this extrapolation did not provide the right conclusion regarding bioequivalence of Budeprion XL 300 mg. FDA also has much more knowledge today of the seizure-associated risk of bupropion-containing drugs. The trial design of the sponsor-initiated study of 2007 could have been successful, had it been replaced by the trial design employed in the recent FDA-sponsored study.

Of course, the trial design in the sponsor-initiated study of 2007 was that requested by the FDA. But Teva, for their part, does not appear to have been a ball of fire in getting that study recruited and completed, either. It's quite possible, though, that they couldn't round up enough patients who'd had trouble with the generic switch and were also willing to go back and experience that again in the cause of science. Overall, I think that the FDA is more on the hook here for letting things go on as long as they did, but there's plenty of blame to go around.

Still, I find this post at Forbes to be full of unnecessary hyperventilation. You wouldn't know, from reading it, that the FDA initially waived the requirement for 300mg testing in this case because of the risk of seizures. There's a line in there about how the agency is making patients their guinea pigs by not testing at the higher dose, but you could have scored the same debating points after a 300mg study that harmed its patients, which is what it looked at the time would happen. You also wouldn't know that the other generic 300mg formulations don't seem to have been associated with increased adverse-event reports, either.

And that post makes much of the way that these bioequivalence tests are left up the manufacturers. That they are: but if you want to change that, you're going to have to (1) fund the FDA at a much higher level, and (2) wait longer for generic switches to occur. The generic manufacturers will run these tests at the absolute first possible moment, since they want to get onto the market. The FDA will run them when they get around to it; they don't have the same incentives at all. Their incentives, in fact, oscillate between "Don't approve - there might be trouble" and "Definitely approve - we might be missing out on benefit". The winds of fortune blow the line between those two around all the time.

In this case, I think the FDA should have exercised its court-of-last-resort function earlier and more forcefully. But that's easy for me to say, sitting where I am. I don't have to see the mass of noisy adverse event reports coming in over the transom day after day. If the agency acted immediately and forcefully on every one, we'd have no drugs on the market at all. There's a middle ground, but boy, is it hard to find.

Comments (44) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System


COMMENTS

1. Electrochemist on October 18, 2012 8:50 AM writes...

Derek, I cannot agree with your blanket statement that "generic medications really are the same as the original branded ones." There are plenty of examples to the contrary (see below). The actual truth is that generics are *usually* close enough to the original innovator's drug that patients will do ok taking either.

Just a few examples of generics that are not equivalent to the original:

(1) Catalog of issues with generic Anti-epilepsy drugs: European Journal of Paediatric Neurology; Volume 13, Issue 2, March 2009, Pages 87–92

(2) Peritonitis caused by generic vancomycin: Am J Kidney Dis. 1991 Jan;17(1):76-9.

(3) Different impurities in generic Cipro compared to the branded medicine: Journal of pharmaceutical and biomedical analysis 2007;44(3):743-54.

Generic drug companies are in the supply chain management business, not medical research. They make cheap products that are "close enough" to the originals to be approvable under an ANDA, usually through a network of off-shore manufacturing partners and loosely regulated commodity-type suppliers.

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2. overthetop on October 18, 2012 9:02 AM writes...

I agree with #1. Your blanket statement that "generic medications really are the same as the original branded ones" is not correct. The active ingredient is the same, but the formulation is rarely the same.

I've sat in a number of internal talks at my company where generics were compared with our branded product, and the differences were often incredible (and often times scary). Sometimes you wouldn't even know that you were dealing with the same active ingredient.

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3. NoDrugsNoJobs on October 18, 2012 9:08 AM writes...

I am missing something. It seems you are saying that the fda was concerned about testing the 300 mg dose in clinical bioequivalence studies due to the fear of seizures in those studies. So instead of testing, they were granted a waiver to go to the public at large with the same dose they were afraid to validate clinically?

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4. Anonymous on October 18, 2012 9:17 AM writes...

When considering switching to a generic for my family I worry about differences in excipients and possible allergic reactions, and manufacturing QC. For whatever reason, my wife did not tolerate her thyroid meds when switched to a generic, so she went back to branded despite the higher out of pocket expense. I also tend to trust that the branded drugs have better manufacturing QC due to a higher level of FDA scrutiny IMO.

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5. Derek Lowe on October 18, 2012 9:18 AM writes...

#3: the 300mg dose was already approved, and had been on the market for years. The FDA believed (at first) that the data to be gained by having Teva test that higher dosage for bioequivalence was not worth the risk of seizures in the test group. The PK of the (branded) 300mg dose was predictable from the 150mg dose, and they made the same assumption here.

But I know what you're saying - that it was apparently OK to go into the general patient population, but not OK to run a specific trial. That's because, I think, that the trial would have been in normal volunteers, not patients seeking an antidepressant. In the end, that's the trial the FDA ended up running for themselves, but only when it looked like it was worthwhile, which it didn't, at first.

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6. Anon on October 18, 2012 9:39 AM writes...

@ 2. overthetop
Can you elaborate on this a bit more? What tests were the generics not comparable? How do you think they passed under the FDA's nose?

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7. PPedroso on October 18, 2012 10:01 AM writes...

I am sorry for all the posters but Derek is correct. Generics when proven to be Bioequivalent to the Branded product will have the same in vivo behavior than the Brand Product.
Actually, show me a Brand molecule that during its development did not have a Bioequivalence study to prove that the marketed formulation was a "generic" of the trial's formulation?

The case with Bupropion is a different one, since the usual procedure was not followed due to the specificities of the product. The guidelines state that the waiver can only be performed from the higher dosage to the lower dosage, basically the higher dosage should be used for the bioequivalence study and not the other way around because, if there are differences, they will be easily noted for the highest approved dose. Additionally, the waiver can only be performed if the some requisites are fullfilled.
Therefore, in this case the guideline recommends that the 300 mg dose should be the one chosen. However, since Bioequivalence studies have to be performed in healthy subjects (to have a standard not biased by diseases sample) and in this case there were some safety concerns in using the higher dose, FDA allowed for the use of a lower dose, the 150 mg. My opinion is that the 300 mg should have been used in patients instead of 150 mg in healthy subjects. Additionally, FDA could have decided to not grant authorization for the 300 mg strenght.

As for the arguments about the metabolites, the parent compound is the most sensible to detect differences between the formulations and should be the Bioequivalence main criterium while the metabolites, if any should serve as supportive data.

Regarding the examples given by #1, the epileptics are a special case in the generic world since they are what is called "narrow therapeutic range" drugs and the Bioequivalence interval (80-125%) may need to be tighten.
The other examples are probably related to excipients problems more than the actual quality of the generic in terms of therapeutic equivalency to the Brand product.

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8. Cytirps on October 18, 2012 10:05 AM writes...

FDA should change the generic drug approval process to make sure the generic drug demonstrate similar human pharmacokinetics. My experience is that whenever the physiological effect is highly dependent on absorption rate, branded drugs perform much better than generic drugs.

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9. PPedroso on October 18, 2012 10:09 AM writes...

@8
The generic drug proves similar human pharmacokinetics to the brand drug in the Bioequivalence study. Those trials are mandatory for FDA and EMA.

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10. CMCguy on October 18, 2012 10:13 AM writes...

It may be semantics as I have always considered generics as the "same" but that does not mean "identical". As commented above this is mostly related to precise formulation/excipients and manufacturing sources (QA/GMP not QC) and in majority of the differences are without consequence. Unfortunately the rare cases where the variations do matter, such as ones cited above, are found in complicated indications or more complex formulations and thus difficult to detect till "Phase IV" studies of a generic (essentially introduction of any new drug can show unexpected AEs upon wider exposure).

Often time Pharma gets beaten up for having "Formulation Patents" that extend protection period and in some cases can indeed be an artificial benefit but this illustrates how critical that area can be for success of development and commercialization and when I see a more complex Patented formulation I take as sign that particular formulation probably plays import role either is ability to deliver or control dosages. Process chemists can feel heavy pressure to advance programs quickly but in general there is even less time and efforts provided to Formulators so any "non-simple" compounding can be a flag.

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11. David Maris on October 18, 2012 10:17 AM writes...

1 - not hyperventilating - please tell that to the untold number of children and adults that have worried about their loved ones wondering why their disease was getting worse, when it was the drug that was not working, that we are being to alarmist. How many people committed suicide or attempted it bc their drug did not work - those people and their loved ones deserve answers.

2 - the FDA had more than five years and numerous complaints - they not only ignored it, but affirmed that that it was safe when they did not tell the whole story about the waiver at the time. This is not like some batch failure - they had been warned about this for more than five years.

3 - explain the trial results being known in August and the public only hearing about this in October. I predict the FDA negotiated with the mfg on what to do (the tail wagging the dog)

4 - first do no harm - the FDA, when unsure given the need to do their own tests, should have at least warned doctors and patients about this controversy so they could be on the lookout for changes when put on the generic. With other generics ont he market and the brand too, the public would have had many options

5 - the risk of seizures is low enough that both Teva and the FDA got IRB buy-in - it did not need a waiver.

Lastly, I would bet if and when people decide to dig on this, they will find people at the FDA that knew of the problem and were shot down when they raised it - and those at the mfg that knowingly did not do the trial. I never said the FDA should do all the trials - but it is moronic when there are problems to ask a mfg to do the studies (esp with no deadline, no penalty, etc...).

Generics are not identical. The regs say they are not and when you have clear evidence in this case, you want to count this one as the rare and odd exception, when pharmacists and others are saying they have evidence that this is an uncommon, but not singularly isolated incident. They are close enough to probably not matter for most drugs and most people is the best way to put it in my opinion.

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12. PP on October 18, 2012 10:23 AM writes...

@David Maris,

I am not saying that this is a rarity. I am saying that the BE study was not conducted so there was no way to confirm that the two 300 mg formulations were equivalent.

Additionaly, I have just noticed that this is an extended release formulation, and what I stated above applies to immediate release formulations. In this case, the guidelines are more strict and the 300 mg could never be considered bioequivalent without in vivo testing.

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13. wcw on October 18, 2012 10:27 AM writes...

As a little tiny anecdote, I can share that my wife refuses to fill one of her migraine prescriptions with Reddy's generic. The brand name and competing generics are fine.

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14. luysii on October 18, 2012 10:28 AM writes...

#1 Electrochemist

(1) Catalog of issues with generic Anti-epilepsy drugs: European Journal of Paediatric Neurology; Volume 13, Issue 2, March 2009, Pages 87–92

Sad to see the problem with generic anticonvulsants is still ongoing. I had to write a lot of letters back in the 80s and 90s to Medicaid explaining why generics just wouldn't do (one for each patient).

Also, as I recall, there were a lot of problems with generic L-DOPA and CarbiDopa

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15. Ronald Pottol on October 18, 2012 10:37 AM writes...

I've heard generic Ritalin is often not as good as the original as well.

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16. PP on October 18, 2012 10:44 AM writes...

I have read the NDA for Wellbutrin XL (available at FDA website) and one of the main studies used for the approval of the brand drug extended release formulation was a bioequivalence study of the 300 mg immediate release formulation with the 100 mg immediate release formulation (TID) of Wellbutrin IR in healthy subjects.

I do not understand why for the generic version of the Wellbutrin XL a Bioequivalence study with the 300 mg was not required (either in healthy subjects or patients)!

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17. Chemjobber on October 18, 2012 11:03 AM writes...

Are the specific issues in this case (or any other cases) known? Is it all just formulation-related, and that the pills aren't releasing nearly as well?

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18. processchemist on October 18, 2012 11:29 AM writes...

@PPedroso

Of course, the regulatory process both in the USA and in Europa reuquire the so called "bio batches" to prove bioequivalence. But I have to agree with 1 and 2: the evidence says that regulators
1) Don't have the power to control all the manufacturers with a registered DMF
2) Can be easily framed; the classical case is to have a DMF opened with a western supplier for the API (or with a regularly inspected one), then source the cheapest acceptable product no matter from what kind of supplier.

The force driving these habits are not only greed or need for better looking balance sheets. In a context when insurance companies and national health systems want to cut more and more the costs for pharmaceuticals, these are simply obvious consequencences.

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19. Nekekami on October 18, 2012 11:32 AM writes...

OK, so I'm not a biologist or chemist, so I might have confused some terms etc, or think they mean different things, though they are the same, but...

Trusting brand names from the same vendor isn't a guarantee either. GSK claimed immunological equivalence(not the same thing as bioequivalence if I understand correctly) between two of their flu vaccines, Pandemrix and Arepanrix. Pandemrix was used heavily here in northern europe against the swine flu, and has been conclusively linked to an increase in narcolepsy among children and youths/young adults in the countries where Pandemrix was used(In Sweden, the rate among those who took the vaccine is 4 per 100k, as composed to 1 per 100k among the non-vaccinated), while in Canada, where Arepanrix was used, no such increase has been noted so far.

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20. partial agonist on October 18, 2012 11:41 AM writes...

There are enough variables in play that one can anticipate that a branded/generic difference will arise that, while usually inconsequential, may be an issue if you are up near the maximum tolerated therapeutic dose.

Just a slight change in the pill coating, for example, can make all the difference. Use a different dye, different sweetener, whatever, and you might get that 20% difference in average dissolution rate that makes all the difference.

My wife hates getting generics but I often think it's because the packaging is usually worse. If the drug is something in a blister pack, for example, the branded ones always seem to be less of a pain to get out than are the generics.

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21. Electrochemist on October 18, 2012 11:47 AM writes...

There are well-documented differences in the impurity profiles between some generic and branded drugs.

These are not minor differences in the ratios of excipients between different formulations; they are different chemical species (usually process-related impurities). Depending on the monograph, the total impurities may only need to be controlled below a particular threshold; thus, the specific impurities may be quite different when comparing drug products from different manufacturers.

In the citation on Cipro that I listed above (comment #1), the authors used (19)F and (1)H NMR to determine the different impurities in the generic vs branded drugs, and could tell the manufacturer from the NMR spectra. Another example showing the same thing via HPLC for generic vs. innovator Fluoxetine HCl: Chromatographia, 1997, 46, 511-523.

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22. PPedroso on October 18, 2012 11:53 AM writes...

@21

what about the impurity profiles of different batches of brand drugs manufactured in different factories?

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23. DrSnowboard on October 18, 2012 11:55 AM writes...

Given that the placebo effect is so strong, does a similar effect apply to patients given a branded vs a generic?

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24. PPedroso on October 18, 2012 12:02 PM writes...

@23

for the Bioequivalence studies since the main and only variable are plasmatic concentrations of the drug there is no placebo effect to account for. It has not been proved that the mind can affect the concentration of a given drug in the blood.

In the market I think it may have some effect if the person taking the drug is against generics.

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25. Electrochemist on October 18, 2012 12:13 PM writes...

@22. PPedroso

Minor differences only compared to generics vs. innovators. What's worse, there are lots of examples of generics that don't even meet the compendial specification acceptance criteria.

I posted another set of examples that should appear as soon as Derek validates the links I included.

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26. cynical1 on October 18, 2012 12:31 PM writes...

Ok, the post says that there was problems with the generic that were "lack of efficacy and/or increased side effects". The post also says that there was a lower Cmax and AUC from the generic drug vs. the branded.

Ummmm........ why would you expect increased side effects from lower exposure of the API? Unless, that little detail about the metabolite levels being different but no detail as to how. See, there's the rub if you ask me. I can rationalize lack of efficacy but not increased side effects unless they're due to the metabolites. But that opens a huge can of worms. That would mean that all of our generic companies would have to not only show bioequivalence of the API but also the metabolites. Or are they already required to do that? My understanding is that they are not but I could be mistaken.

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27. processchemist on October 18, 2012 12:55 PM writes...

@26

Lack of efficacy can be a serious issue. Lasix 500 mg is a "life saver" pill for people suffering of chronic respiratory/cardiac/circulatory disorders. What if a generic 500 mg has lower AUC and Cmax? It doesn't work no more as a life saver. That's all.

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28. exGlaxoid on October 18, 2012 12:55 PM writes...

I used to not be concerned with generics, but the problem that I see is that they do not seem to be checked once they get one batch tested for the FDA, they don't ever seem to be tested again by anyone.

As stated above, they can source the compound from a reliable, but pricey supplier, then later swap suppliers for a cheaper source (eg, the Chinese Melamine company) and the chance of being caught are nearly zero.

Since many drug stores have multiple sources of generics, and there is no good tracking mechanism for who got what, it is very hard to tell which people got which lot of a drug. I have had some generics where the pill look poorly produced, crumbly or non-homogeneous inside. That is the hallmark of poor QC or poor manufacturing.

Having worked with people who worked for generic companies and hearing a few stories, I would not be surprised to learn that a growing number of generics are not to spec. or substandard. This goes along with the number of chemical reagents I have received which were also not to spec or substandard, most from China or other low cost sources.

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29. emjeff on October 18, 2012 12:59 PM writes...

Pk guy and former FDAer here. Where the FDA went wrong here is "waiving up" - in other words, they required BE at 150 mg, but "waived " the requirement for 300 mg. Thi is unusual - the usual procedure is to waive down.Had they followed the usual procedure, this would have been uncovered immediately. The issue about seaizures is silly; these are single dose studies conducted in healthy young men with MD's and RN's on -site.

As to why it took so long, God alone knows. The FDA is very biased toward generic drugs, and they seem to be loathe to take action on complaints about generics. One thing is for sure - they will try to leverage this to expand their powers and create more rules, when what really needs to happen is for someone in the Agency to be held accountable for this.

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30. PPedroso on October 18, 2012 1:14 PM writes...

@26

The recommendation, at least in Europe, is to always use parent compound. Only in exceptional cases, metabolite data is allowed.

The assumption is that once absorption is done (as long as it is in the same rate and extent) the active molecule will be available for metabolization in both generic and brand formulations.

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31. Clinical pharmacologist on October 18, 2012 1:34 PM writes...

In the case of wellbutrin, the contribution of the many active metabolites to the therapeutic effect should not be underestimated. The rate of production of these active metabolites will be driven by the absorption of the parent and may vary widely depending on where in the 80-125% bioequivalence range the parent concentrations lie.

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32. peej on October 18, 2012 7:29 PM writes...

I'm confused... I thought generic drugs DID NOT undergo human pharmacokinetic testing to get approval.... it's a dissolution test only.

Has this changed?

That being said...as a pharmacist, I've seen lots of quality control issues with generics - shattered tablets, powdery residue, etc.

But as a general rule they seem to work fairly well for most patients if you go by clinical testing - BP, cholesterol levels, etc. Not much change when you switch to generics.

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33. Processator on October 18, 2012 9:11 PM writes...

The answer is absolutely not.

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34. alig on October 19, 2012 7:52 AM writes...

@peej
Only BCS class 1 drugs (very soluble & permeable) can get away with the dissolution test only. Others must do BE study.

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