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US generics under scrutiny

US Food and Drug Administration puts generic equivalence under scrutiny
Magnifying glass drugs

Reports in October 2010 that the US Food and Drug Administration (FDA) was considering tighter standards of equivalence for generic versions of some brand-name drugs made uncomfortable reading for an industry supplying 75 per cent by volume of all prescriptions dispensed in the US.

The agency has since confirmed that it continues to examine the available bioequivalence data for narrow therapeutic index (NTI) and, more specifically, 'critical dose' (CD) generics. It is also considering a list of NTI/CD products, in line with recommendations made at a meeting of its Advisory Committee for Pharmaceutical Science and Clinical Pharmacology in April 2010.

Whether these actions will lead to more rigorous bioequivalence standards remains to be seen. Dr Keith Webber, acting director of the FDA's Office of Generic Drugs (OGD), said: "What we're looking at is evaluating the bioequivalence data we have in hand for the NTI drugs and, if it's justified, then setting up standards that would be appropriate for those drugs based on verifiable pharmacokinetic characteristics." 

He added that there were also "other options that we could consider, for example, scaling the bioequivalence standard so that it's not 'one size fits all', but takes into account some of these other concerns about criticality of dosing or the variability of the reference listed drug."

The agency insisted that any change would have little or no impact on the bulk of generic drugs sold in the US. For manufacturers, though, the threat is not so much onerous and costly regulatory requirements as a ripple effect on public and political perceptions of generic fidelity.

Doubts about the therapeutic equivalence of NTI generics have been around for some time. These perceptions have led to 'carve-out' legislation in some US states that excludes whole categories of drugs, such as anti-epileptics and immunosuppressives, from generic substitution provisions. According to the FDA, 13 states list specific NTI drugs regarded as non-substitutable.

The Generic Pharmaceutical Association (GPhA) puts legislative pressure for carve-outs down to brand manufacturer lobbying. Any FDA acknowledgement of an equivalence problem, whether real or perceived, will inevitably help legitimise those efforts. 

Shawn Brown, the GPhA's vice president of state government affairs, said: "When you are advocating in the states and talking with legislators who may be hearing about this issue for the first time, and you're using FDA's statements to support your arguments … if there's any question about that, it really makes my job difficult." 

The issue came under the spotlight in the Budeprion XL Marketing and Sales Litigation case, which questioned assumptions of federal pre-emption in product liability actions involving generic equivalence. In that case the contention was that, by using matrix rather than membrane-release technology for their version of the once-daily antidepressant Wellbutrin XL, generic partners Impax Laboratories and Teva Pharmaceuticals had changed the product's therapeutic profile.

The FDA conducted its own equivalence review of Budeprion XL (bupropion), in response to post-marketing reports from patients who 'experienced an undesirable effect' after switching from Wellbutrin XL 300mg to the generic.

Publishing its findings in April 2008, the agency concluded: '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.'

Dr Barbara Davit, deputy director of OGD's division of bioequivalence, pointed out that the sensitivity about NTI drugs such as some anti-epileptics or anticoagulants related to a "very narrow effective plasma concentration range," below which "the drugs may not be efficacious, above which there are life-threatening toxicities."

A generic is regarded as bioequivalent if the 90 per cent confidence interval falls between 80 per cent and 125 per cent

Therapeutic equivalence
The FDA essentially treats therapeutic equivalence as a composite of pharmaceutical equivalence and bioequivalence. A margin of variance in bioequivalence is permitted, although there is some confusion among practitioners about exactly how wide that margin can be. The FDA's approval procedure involves calculating a 90 per cent confidence interval for the ratio between the average pharmacokinetic values of the generic and the reference product.

A generic is regarded as bioequivalent if the 90 per cent confidence interval falls between 80 per cent and 125 per cent for the mean ratios of the area under the plasma concentration-time curve (AUC, used to measure extent of drug absorption) and the maximum plasma concentration (Cmax, measuring rate of absorption).

As the FDA stresses, though, this does not mean actual blood levels of generic drugs can vary by -20 per cent to +25 per cent from the originators.

In September 2009 Davit and colleagues published a retrospective analysis of bioequivalence data from 2,070 single-dose studies of orally administered generic drugs approved by the FDA between 1996 and 2007 in The Annals of Pharmacotherapy.

They found that the average differences in Cmax and AUC measures between generic and innovator drugs were 4.35 per cent and 3.56 per cent, respectively. Moreover, in nearly 98 per cent of the bioequivalence studies the difference in AUC between generic and innovator products was less than 10 per cent. This data was presented at the FDA's advisory committee meeting in April as evidence that current standards are robust, Davit observes. As an FDA briefing document points out, though, critical-dose drugs made up only a small percentage of the drugs approved during the review period.

The US bioequivalence criteria are similar to those applied in Europe, albeit with a little less leeway in the 90 per cent confidence limits for the AUC and Cmax measurements in most cases, Webber noted.  

All the same, the final guideline issued by the European Medicines Agency in August 2010 suggested that 'in specific cases of products with a narrow therapeutic index, the acceptance interval [for bioequivalence] may need to be tightened' on a case-by-case basis – as a general rule, to 90-111 per cent.

The FDA does not have any immediate timetable for drawing up a list of NTI/critical dose products and, as Davit observed: "there are really very few products that are considered classic narrow therapeutic index drugs."

The legal ramifications of 2010's ruling in the Budeprion XL Marketing and Sales Litigation case also remain. Judge Berle Schiller denied a motion to dismiss a class action lawsuit over alleged discrepancies between Wellbutrin XL and generic versions manufactured by Impax and distributed by Global Pharmaceuticals or Teva Pharmaceuticals.

Impax and Teva argued that the plaintiffs' claims (the failure to warn patients about material differences that compromised the generic versions' antidepressant effects) were pre-empted as the FDA had established the generics' bioequivalence before approving them.

This also tied the companies to the originator product labelling. Generic manufacturers said they had little or no leeway to change labelling without prior approval or direction from the FDA, although the courts have been divided on the issue.

Judge Schiller, citing the landmark Wyeth v Levine ruling in particular, said the pre-emption argument "flies in the face of the Supreme Court's clear pronouncement that 'it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times'."

We certainly need to be compliant with any legal rulings, but right now our main focus is on the scientific aspects of the [patient] reports

If this shifts the onus for labelling changes explicitly on to generic manufacturers, it also carries the implication that FDA's bioequivalence standards for NTI or other potentially problematic drugs may not translate into therapeutic equivalence.

Keith Webber was sanguine: "I don't think it's a significant issue for us regarding NTI drugs right now. We certainly need to be compliant with any legal rulings, but right now our main focus is on the scientific aspects of the [patient] reports and the potential for inequivalence."

For Gordon Johnston, the GPhA's vice president of regulatory affairs, the Budeprion XL ruling may not have had a direct bearing on NTIs, but he stated: "I believe that was one of the events that caused FDA to pause and say, are there other criteria we should be considering along with the normal bioequivalence standards when approving a generic drug?"

It also threw into relief the debate about unilateral labelling changes for generics, he continued: "There's a discrepancy between the law that says labelling must be the same and the regulations, which allow for changes in warnings and labelling.

"The FDA has repeatedly told the generics industry you can't go forward until it's determined that the change is appropriate for the brand, and then all manufacturers of that drug must change their labelling at the same time," he added.

For Brown, though, the main impact of the current focus on NTI equivalence was "how it enables the brand side to argue more persuasively" by suggesting "mixed signals" from the FDA.

He cautioned that if comments such as those made by Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, at the GPhA's Fall Technical Conference in October 2010 were "taken out of context, and they're not based on science but anecdote, those things are hard to clarify when you have five minutes in front of a legislative committee". 

This sort of "campaign of misinformation" had given credence to state-level carve-outs, Brown said. In 2008, for example, a total of 80 carve-out bills were introduced in 35 US states, although only three of these ended up as legislation. Tennessee saw a 29 per cent increase in brand usage through Medicaid after a carve-out provision was passed for epilepsy drugs, costing the state "millions" of dollars, Brown noted. 

The GPhA said it was surprised and frustrated by what it saw as loose interpretations of ambiguous remarks by Woodcock in October. In Johnston's view, media attention managed to transform what was essentially an observation about physical or functional differences between generics and brands into unprecedented (from an FDA official) assertions about therapeutic equivalence.

Woodcock did raise the question of product discrepancies that could "lead to scepticism" about the equivalence of the FDA-approved generics, such as significantly larger tablets, a bad taste or drugs that smell unpleasant. 

According to Brown, any inference from Woodcock's remarks conflicted markedly with statements made by the FDA about bioequivalence and therapeutic equivalence during the past 10 to 20 years.

Furthermore, Johnston said, the agency had already re-examined the regulatory criteria used to underpin the substitutability of NTI drugs "in a very thorough way" at least twice since they were introduced in 1984.

More specifically, the retrospective analysis conducted by Davit et al found that only around 10 per cent of the NTI drugs examined would have failed to meet the tighter 90-111 per cent confidence interval criteria for bioequivalence studies used by some other regulatory authorities.

In that light, Johnston suggested, taking another look at the bioequivalence standards for NTI drugs was 'less a scientific decision than a policy proposal'.

He believed more stringent regulations would come, although the FDA had been 'quite explicit' that already marketed NTI generics would not need to be retested. First, though, the FDA must define NTI drugs and he thought that could be the hard part.

The Author
Peter Mansell
is a freelance writer and journalist in the pharmaceutical and healthcare sectors

To comment on this article, email

31st March 2011


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