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Word on the street (or, more precisely, on the Hill) is that Senator Dorgan is going to offer an importation amendment to the forthcoming (maybe) Big Kahuna health reform legislation. Bad idea. It’s time to introduce the Senior Senator from North Dakota to “brandjacking.”
According to an article in Pharma Times, “A new report has highlighted the rise of pharmaceutical “brandjacking” for popular drugs, which is causing health concerns and damaging the reputation of the sector.” The analysis, published by MarkMonitor, highlights “a parallel online system of pharmaceutical supply and demand” which is being fuelled by continued growth in listings for medicines on business-to-business exchange sites as well as increased traffic to illicit pharmacies.”
As a result, consumers are turning to the internet, says the report, with people visiting both legal and illicit online pharmacies. Also, offshore manufacturers “increasingly embrace B2B exchange sites to sell bulk quantities of branded prescription drugs, often of suspicious quality.” Therefore, cost savings and efficiencies of e-commerce “become even more attractive, presenting a tempting opportunity for online fraud and brand abuse."
MarkMonitor chose six leading prescription drugs and examined nearly 20,000 instances of cybersquatting, the practice of abusing trademarks within the domain name system, a rise of 9%.
The report noted that of the 2,930 online pharmacies found in the study, only four were certified in the VIPPS program by the National Association of Boards of Pharmacy. Furthermore, the non-VIPPS sites offered discounts as high as 90% from the prices offered by certified websites, which indicate, “that the products are of suspicious quality.”
Importation anyone?
According to an article in Pharma Times, “A new report has highlighted the rise of pharmaceutical “brandjacking” for popular drugs, which is causing health concerns and damaging the reputation of the sector.” The analysis, published by MarkMonitor, highlights “a parallel online system of pharmaceutical supply and demand” which is being fuelled by continued growth in listings for medicines on business-to-business exchange sites as well as increased traffic to illicit pharmacies.”
As a result, consumers are turning to the internet, says the report, with people visiting both legal and illicit online pharmacies. Also, offshore manufacturers “increasingly embrace B2B exchange sites to sell bulk quantities of branded prescription drugs, often of suspicious quality.” Therefore, cost savings and efficiencies of e-commerce “become even more attractive, presenting a tempting opportunity for online fraud and brand abuse."
MarkMonitor chose six leading prescription drugs and examined nearly 20,000 instances of cybersquatting, the practice of abusing trademarks within the domain name system, a rise of 9%.
The report noted that of the 2,930 online pharmacies found in the study, only four were certified in the VIPPS program by the National Association of Boards of Pharmacy. Furthermore, the non-VIPPS sites offered discounts as high as 90% from the prices offered by certified websites, which indicate, “that the products are of suspicious quality.”
Importation anyone?
I was pleased to be both a co-chair and a speaker at this year’s Drug Safety Summit. (And particularly so, since we were joined by Sir Alasdair Breckenridge, Chairman of Great Britain’s MHRA -- the Medicines and Healthcare Products Regulatory Agency.)
My panel was ably moderated by Brian Harvey (Sanofis-Aventis and a former colleague from my FDA days). The other panelists were Meredith Manning (Hogan & Hartson) and Florence Ho (Celgene – and another former FDA colleague).
The topic was “Achieving Predictability and Transparency in REMS. Some of the discussion points:
* REMS must be viewed as a “win/win” situation for the agency (it can now move forward and approve drugs with higher risk profiles and have a more direct path for post-market surveillance), for sponsors (who can have their drugs approved with greater alacrity), physicians (who will – at least in theory) have a more complete view of risks and benefits, and patients (who will have additional therapeutic options and will now – at least in certain circumstances – become more complete part of the compliance/adherence proposition).
* Much discussion over where in the drug development process REMS should surface. Acknowledgement that this cannot be done in the absence of data – and confusion as to how to deal with early (even Phase II information) that might be REMS relevant. And “confusion” meaning both scientific uncertainty and internal confusion and discomfort.
* Evident frustration about validated tools (the absence thereof). But this was at least somewhat assuaged by the timely release of the FDA’s draft guidance on “Format and Content of Proposed REMS Assessments, and Proposed REMS Modifications.” And it was a cool and refreshing draft indeed.
* And, speaking of draft guidance and validated tools – what about timeliness and the potential for (are you sitting down) – user fees for REMS. Yes, of course REMS development and approval is part of the NDA process. And, yes, they should (at least in theory) be covered under PDUFA fees. But, hey, just thought I’d mention it.
* The issue of both “class” REMS and REMS for generics – the latter combined with the important issue of the intellectual property and patent rights of the innovator.
* Continued discussion as to whether or not companies should wait until the agency asks – or if sponsors should preemptively (you should excuse the expression) provide an outline of a potential REMS plan. This is important not just as an issue of timeliness (as opposed to having the agency introduce the topic in a complete response letter), but also of responsibility. If, as we all want to believe, the FDA must be both regulator of and colleague to industry, then what are the responsibilities of a sponsor relative to (among many other things) surfacing the REMS issue – and at what point in the process.
Nobody said it was going to be easy.
My panel was ably moderated by Brian Harvey (Sanofis-Aventis and a former colleague from my FDA days). The other panelists were Meredith Manning (Hogan & Hartson) and Florence Ho (Celgene – and another former FDA colleague).
The topic was “Achieving Predictability and Transparency in REMS. Some of the discussion points:
* REMS must be viewed as a “win/win” situation for the agency (it can now move forward and approve drugs with higher risk profiles and have a more direct path for post-market surveillance), for sponsors (who can have their drugs approved with greater alacrity), physicians (who will – at least in theory) have a more complete view of risks and benefits, and patients (who will have additional therapeutic options and will now – at least in certain circumstances – become more complete part of the compliance/adherence proposition).
* Much discussion over where in the drug development process REMS should surface. Acknowledgement that this cannot be done in the absence of data – and confusion as to how to deal with early (even Phase II information) that might be REMS relevant. And “confusion” meaning both scientific uncertainty and internal confusion and discomfort.
* Evident frustration about validated tools (the absence thereof). But this was at least somewhat assuaged by the timely release of the FDA’s draft guidance on “Format and Content of Proposed REMS Assessments, and Proposed REMS Modifications.” And it was a cool and refreshing draft indeed.
* And, speaking of draft guidance and validated tools – what about timeliness and the potential for (are you sitting down) – user fees for REMS. Yes, of course REMS development and approval is part of the NDA process. And, yes, they should (at least in theory) be covered under PDUFA fees. But, hey, just thought I’d mention it.
* The issue of both “class” REMS and REMS for generics – the latter combined with the important issue of the intellectual property and patent rights of the innovator.
* Continued discussion as to whether or not companies should wait until the agency asks – or if sponsors should preemptively (you should excuse the expression) provide an outline of a potential REMS plan. This is important not just as an issue of timeliness (as opposed to having the agency introduce the topic in a complete response letter), but also of responsibility. If, as we all want to believe, the FDA must be both regulator of and colleague to industry, then what are the responsibilities of a sponsor relative to (among many other things) surfacing the REMS issue – and at what point in the process.
Nobody said it was going to be easy.
Last Wednesday I chaired the Fourth National FDA Regulatory Symposium. Being the chair gave me the privilege to introduce the event’s keynote speaker, FDA Commissioner Peggy Hamburg.
By way of introduction, I pointed out that everybody benefits from an FDA that leads. This means the agency has to be out in front of every issue for which it is responsible.
Every specific action the agency takes is an opportunity to speak to a larger public health issue. When the FDA confidently leads, other stakeholders follow with their expertise, resources and sense of duty. The FDA must be seen as leading rather than simply participating in the process.
As a former New York City Health Commissioner, Dr. Hamburg has the opportunity to bring to the FDA the ability to view regulatory issues from the viewpoint of the man on the street, the patient -- the consumer. And there are issues aplenty:
• There’s the question of REMS plans.
• And complete response letters.
• And the transparency of complete response letters.
• And biomarkers.
• And guidance on off-label promotion.
• And “net impressions” of DTC materials
• And oversight of social media.
• And of clinical trials.
• And of adaptive clinical trials.
• And follow-on biologics.
• And bioequivalence for generics.
• And GMPs
• And drug importation.
• And counterfeiting.
• And companion diagnostics.
• And the regulation of diagnostics.
• And 510(k) reform.
• And food safety and security.
• And dietary supplements.
• And nutritional health claims.
• And tobacco.
• And early safety signal communications.
• And pandemic preparedness.
• And greater international harmonization.
• And the balance of predictability vs. ambiguity.
• And food from the progeny of cloned animals.
• And the FDA’s working relationships with industry and academia.
• And the Reagan/Udall Foundation – wither the agency’s Critical Path program?
As Walter O’Malley – the man who moved the Brooklyn Dodgers to Los Angeles once commented, “The future is just one damn thing after another.”
The Commissioner began her remarks by commenting, “It’s a lot easier to ask the questions then to answer them.” Zing,
Some additional thoughts from Dr. Hamburg:
* Concerned that the agency “is under-appreciated by the public” (a recent poll shows that, among government agencies, the FDA ranks just one notch above the IRS) “and under-resourced.” In fact, she mentioned that she was going to OMB on Friday (October 2) to defend the FDA’s budget proposal for the coming fiscal year. I promised to pray for her.
* The FDA’s most valuable assets are the “extraordinary public servants” who work at the FDA. Can’t repeat that too many times.
* That to be FDA Commissioner requires “wisdom, common sense, and a sense of humor.” Well said.
* The urgency of the FDA’s Critical Path program and “the urgency to fund robust 21st century regulatory science. “ She aptly defined the agency’s role as “Reviewer, Approver – and Catalyst. And, “We must advocate for it.”
* “Success is not measured in warning letters.” Amen – and courageous of her to say so.
* Similarly, and relative to foreign drug manufacture, “The FDA will never be able to assure safety all on our own.” And that there must be “shared responsibility for global drug inspections.”
* During the Q&A she was asked whether or not the FDA would add comparative effectiveness as a third leg to the approvals process. Her smart response was that the FDA should find ways to share its data with researchers in order to “enrich understanding.” Short answer to direct question – no third leg.
* Per the FDA’s initiative on transparency (led by Deputy Commissioner Josh Sharfstein), Dr. Hamburg said she hoped to have some initial (“incremental”) recommendations by November. Stand by on that one.
Thank you Commissioner.
By way of introduction, I pointed out that everybody benefits from an FDA that leads. This means the agency has to be out in front of every issue for which it is responsible.
Every specific action the agency takes is an opportunity to speak to a larger public health issue. When the FDA confidently leads, other stakeholders follow with their expertise, resources and sense of duty. The FDA must be seen as leading rather than simply participating in the process.
As a former New York City Health Commissioner, Dr. Hamburg has the opportunity to bring to the FDA the ability to view regulatory issues from the viewpoint of the man on the street, the patient -- the consumer. And there are issues aplenty:
• There’s the question of REMS plans.
• And complete response letters.
• And the transparency of complete response letters.
• And biomarkers.
• And guidance on off-label promotion.
• And “net impressions” of DTC materials
• And oversight of social media.
• And of clinical trials.
• And of adaptive clinical trials.
• And follow-on biologics.
• And bioequivalence for generics.
• And GMPs
• And drug importation.
• And counterfeiting.
• And companion diagnostics.
• And the regulation of diagnostics.
• And 510(k) reform.
• And food safety and security.
• And dietary supplements.
• And nutritional health claims.
• And tobacco.
• And early safety signal communications.
• And pandemic preparedness.
• And greater international harmonization.
• And the balance of predictability vs. ambiguity.
• And food from the progeny of cloned animals.
• And the FDA’s working relationships with industry and academia.
• And the Reagan/Udall Foundation – wither the agency’s Critical Path program?
As Walter O’Malley – the man who moved the Brooklyn Dodgers to Los Angeles once commented, “The future is just one damn thing after another.”
The Commissioner began her remarks by commenting, “It’s a lot easier to ask the questions then to answer them.” Zing,
Some additional thoughts from Dr. Hamburg:
* Concerned that the agency “is under-appreciated by the public” (a recent poll shows that, among government agencies, the FDA ranks just one notch above the IRS) “and under-resourced.” In fact, she mentioned that she was going to OMB on Friday (October 2) to defend the FDA’s budget proposal for the coming fiscal year. I promised to pray for her.
* The FDA’s most valuable assets are the “extraordinary public servants” who work at the FDA. Can’t repeat that too many times.
* That to be FDA Commissioner requires “wisdom, common sense, and a sense of humor.” Well said.
* The urgency of the FDA’s Critical Path program and “the urgency to fund robust 21st century regulatory science. “ She aptly defined the agency’s role as “Reviewer, Approver – and Catalyst. And, “We must advocate for it.”
* “Success is not measured in warning letters.” Amen – and courageous of her to say so.
* Similarly, and relative to foreign drug manufacture, “The FDA will never be able to assure safety all on our own.” And that there must be “shared responsibility for global drug inspections.”
* During the Q&A she was asked whether or not the FDA would add comparative effectiveness as a third leg to the approvals process. Her smart response was that the FDA should find ways to share its data with researchers in order to “enrich understanding.” Short answer to direct question – no third leg.
* Per the FDA’s initiative on transparency (led by Deputy Commissioner Josh Sharfstein), Dr. Hamburg said she hoped to have some initial (“incremental”) recommendations by November. Stand by on that one.
Thank you Commissioner.
The AAPS conference regarding extended or modified release formulations of drugs and therapeutic equivalence raised many important public policy questions. The AAPS conference material noted that:
"Demonstration of bioequivalence (BE) between drug products can be made using blood level measurements, pharmacodynamic studies, clinical trials, and/or in
vitro studies. The US regulations deem drug products therapeutic equivalents (TE) if they are both pharmaceutically equivalent and bioequivalent."
But it became clear that current standards of BE do not add up to TE because we know more about the impact of individual variation in how we absorb and process drugs now than when the generic drug reforms were enacted in 1984. So the question is, as Kamal Midha, Ph.D. of University of Saskatchewa, who spoke about existing standards for TE of sustained release products: are current regulations for measuring BE enough?
More to the point: if the public and the FDA are demanding more evidence about the safety and reliability of new products pre and post market (including more information the pharmacodynamics and phamacokinetics of such products), why shouldn't such information be used to establish TE of generic products, particularly those where the amount of a drug released and when is essential to a drug's safety and effectiveness. While it may be true that this issue only affects a handful of drugs, it is also true that these drugs are not only widely prescribed, they are also mostly prescribed in generic form. And post market oversight of this growing market share is not a top FDA priority even as safety has become an critical (path) FDA concern,
So at the end of the day (and the conference) it became clear that better standards for tracking the impact of modified release products with new tools is not to be ignored. Rather than being a way for innovators to escape generic competition, the collection and monitoring of better measures of TE can improve the overall quality of medicines without significant costs to either part of the industry. That is the goal and essence of the Critical Path. To ignore or dismiss concerns about toxicity or adverse events of sustained release products because they are made by generic companies is to suggest that the financial interests of that industry is more important than the public health.
This issue can, as the AAPS meeting demonstrated, can be explored in a way that uses science to clarify issues and stratify risk so that the most important public health issues relative to this product class can be addressed.
"Demonstration of bioequivalence (BE) between drug products can be made using blood level measurements, pharmacodynamic studies, clinical trials, and/or in
vitro studies. The US regulations deem drug products therapeutic equivalents (TE) if they are both pharmaceutically equivalent and bioequivalent."
But it became clear that current standards of BE do not add up to TE because we know more about the impact of individual variation in how we absorb and process drugs now than when the generic drug reforms were enacted in 1984. So the question is, as Kamal Midha, Ph.D. of University of Saskatchewa, who spoke about existing standards for TE of sustained release products: are current regulations for measuring BE enough?
More to the point: if the public and the FDA are demanding more evidence about the safety and reliability of new products pre and post market (including more information the pharmacodynamics and phamacokinetics of such products), why shouldn't such information be used to establish TE of generic products, particularly those where the amount of a drug released and when is essential to a drug's safety and effectiveness. While it may be true that this issue only affects a handful of drugs, it is also true that these drugs are not only widely prescribed, they are also mostly prescribed in generic form. And post market oversight of this growing market share is not a top FDA priority even as safety has become an critical (path) FDA concern,
So at the end of the day (and the conference) it became clear that better standards for tracking the impact of modified release products with new tools is not to be ignored. Rather than being a way for innovators to escape generic competition, the collection and monitoring of better measures of TE can improve the overall quality of medicines without significant costs to either part of the industry. That is the goal and essence of the Critical Path. To ignore or dismiss concerns about toxicity or adverse events of sustained release products because they are made by generic companies is to suggest that the financial interests of that industry is more important than the public health.
This issue can, as the AAPS meeting demonstrated, can be explored in a way that uses science to clarify issues and stratify risk so that the most important public health issues relative to this product class can be addressed.
BioCentury reports that late Thursday ...
The Senate Finance Committee night passed an amendment to healthcare reform legislation that would create a $1 billion temporary tax credit over two years for investments in drug R&D by companies with 250 or fewer employees.
The measure, sponsored by Sen. Robert Menendez (D-N.J.) and backed by the Biotechnology Industry Organization (BIO), would cover expenditures made in 2009 and 2010. Companies that don't have a tax liability would have the option to receive the credit in the form of a grant.
In allocating the credits and grants, the amendment instructs the U.S. Treasury to consider only projects that: "show reasonable potential" to "result in new therapies to treat areas of unmet medical need or to prevent, detect, or treat chronic or acute disease and conditions;" or to "reduce long-term health costs in the United States; or to "significantly advance the goal of curing cancer within a 30-year period."
In addition, the Treasury would consider which projects have the greatest potential to create and sustain high quality, high-paying jobs in the U.S. and to advance U.S. biomedical competitiveness.
Projects that received a credit or grant would not qualify for existing R&D or Orphan tax credits, or for bonus depreciation.
The legislation still is subject to modification as it moves through Congress. The Finance Committee is expected to approve America's Healthy Future Act early next week. It will then be merged with legislation passed by the Health, Education, Labor and Pensions (HELP) Committee and sent to the full Senate for a vote. The final Senate bill would have to be reconciled with healthcare reform legislation coming out of the House.
The Senate Finance Committee night passed an amendment to healthcare reform legislation that would create a $1 billion temporary tax credit over two years for investments in drug R&D by companies with 250 or fewer employees.
The measure, sponsored by Sen. Robert Menendez (D-N.J.) and backed by the Biotechnology Industry Organization (BIO), would cover expenditures made in 2009 and 2010. Companies that don't have a tax liability would have the option to receive the credit in the form of a grant.
In allocating the credits and grants, the amendment instructs the U.S. Treasury to consider only projects that: "show reasonable potential" to "result in new therapies to treat areas of unmet medical need or to prevent, detect, or treat chronic or acute disease and conditions;" or to "reduce long-term health costs in the United States; or to "significantly advance the goal of curing cancer within a 30-year period."
In addition, the Treasury would consider which projects have the greatest potential to create and sustain high quality, high-paying jobs in the U.S. and to advance U.S. biomedical competitiveness.
Projects that received a credit or grant would not qualify for existing R&D or Orphan tax credits, or for bonus depreciation.
The legislation still is subject to modification as it moves through Congress. The Finance Committee is expected to approve America's Healthy Future Act early next week. It will then be merged with legislation passed by the Health, Education, Labor and Pensions (HELP) Committee and sent to the full Senate for a vote. The final Senate bill would have to be reconciled with healthcare reform legislation coming out of the House.
With generic drugs now making up nearly 70 percent of all medications prescribed in the US it is no surprise that the issues of bioequivalency and interchangeability of branded drugs and generics remained front and center this morning at the second day of the AAPS meeting.
The FDA has come in for a fair amount of criticism from companies and consumers alike. We wrote yesterday about the concerns about bupropion/Wellbutrin and Ambien but these are only two of the cases in which it has been questioned whether drugs certified by the FDA as bioequivalent are indeed therapeutically equivalent.
For a fairly comprehensive treatment of the alleged problems of non-bioequivalent generics , check out Glenn Lammi’s legal brief.
This morning, we had a chance to hear from the FDA and an explanation of when the agency believes there may be grounds to modify the current procedure for approving generics as bioequivalent.
Dr. Robert Temple, Director of the Office of Medical Policy at the FDA’s Center for Drug Evaluation and Research and Acting Director of the Office of Drug Evaluation I, argued that for the large majority of drugs bioequivalency is relatively straight forward but also walked through where differences between two drugs might or might not be indications of the potential for therapeutic efficacy differences.
He opined that for two drugs that meet FDA bioequivalency standards, interchangeability depends on two factors: the sensitivity of the drug effects to differences in concentration and where one is on the dose response curve.
On the first point, it matters a lot whether a drug takes effect slowly or quickly, both in terms of the intended effect and the potential for side effects. When the drug is specially created to take effect quickly or to have high concentrations at certain times, testing the concentration at more time points is an important part of demonstrating that the two drugs really can be substituted for one another without big changes in the effects. Ambien is an example. Another is ADHD drugs which are designed to have high concentrations at some times and lower concentrations at others.
But Dr. Temple indicated that in the case of drugs that may take hours, days, or weeks to work completely, for instance antidepressants, beta-blockers, and coumadin, he felt it is highly unlikely that small deviations in concentration and release would have much of an impact on therapeutic effect. The shape of the curve, arguably, is not as critical.
That speaks against the complaints about Wellbutrin (bupropion) that we heard about, and wrote about, yesterday since the drug’s effects develop over weeks. Indeed, Dr. Temple attributed the complaints about the generic bupropion at least partially to patients blaming reoccurrence of symptoms to the drug change even though they would have returned whichever drug the patient was on. He made a similar argument about patients on anti-seizure medications who say that their seizures came back after they moved to a generic.
On the second consideration in determining whether existing bioequivalence standards are adequate, placement on the curve, Dr. Temple identified cases where the closeness of the pharmacokinetic profiles are important, generally where one is on the steep part of the curve. However, few drugs fall in this area, usually oncology drugs. He suggested that when one is on the plateau, differences in release rate are not very important, offering the example of drugs such as fluoxetine where the drug is equally effective at 20, 40, and 80mg doses and can be taken once a week with little difference in effect from taking it once a day.
When patients are faced with the choice between a branded drug and a generic one – or find themselves put on a generic because their insurer is trying to save money – they are often reassured that the two medications are the same.
But the remarks this afternoon at the AAPS conference in Baltimore of Gerard Sanderink, Director of Metabolism and Pharmacokinetics at Sanofi-Aventis, brought into relief the question of exactly how different drugs can be and still pass the FDA’s current standards for bioequivalence.
And it’s a troubling picture.
Dr. Sanderink described how when Sanofi-Aventis decided to create an extended release version of Ambien that would work for an additional 3 to 5 hours in order to help patients remain asleep, the company tested 8 bi-layer formulations, comprising different proportions of the two included medications and different total doses.
Critical to Sanofi-Aventis was that the new pill would have three essential properties. It would offer patients the same quick absorption to help them get to sleep, it would offer medication to keep them asleep, and it would not leave any residual impairment in the morning.
One of the eight formulas “won” the aptly named Scheherzade trial and became what we now know as Ambien CR but what is interesting is what the other seven variations can tell us about the inadequacy of the FDA’s present procedure for approving generics as bioequivalent.
The winning formula took the crown in part because it left no lingering effects in the morning when compared to placebo. This was not true of some of the other formulas, which in some cases continued to have a residual impact long after the subject had woken up. As Dr. Sanderink’s presentation today showed, the pharmacodynamic profiles of the eight versions differed quite widely.
Yet, under the current FDA rules, all of the alternative Ambien formulations would pass a bioequivalence test against the chosen version. Right now, the agency only tests drug concentrations at 1.5 hours and then 1.5 hours to infinity.
That means that drugs that leave a lot more impairment in the morning can be sold as if they are identical to the original. And so can drugs that lack the properties of sleep initiation and sleep maintenance that make physicians and patients alike turn to Ambien CR.
Instead, Sanofi-Aventis wants the FDA to look at 0-3 hours, 3-6 hours, and 6 hours plus, covering the three important phases of the drug’s operation, initiation, maintenance, and wake-up.
I must agree with Dr. Sanderink: Classical bioequivalence criteria are insufficient, at least for this type of drugs, and the FDA should move to a more nuanced and tailored approach to evaluating whether generic drugs are sufficiently similar to the originals. To do otherwise is to do harm to patients, the companies that made the innovator drugs, and the agency’s own reputation.
It seems pretty clear that when patients who take Ambien CR to both fall and stay asleep are told their new generic will do the same thing, they won’t be satisfied with a pill that fulfills only half of that promise.
But that’s just what they may get with generic zolpidem. Ambien CR is specially formulated so that the medication it contains is dispensed so that patients both drop off and remain asleep so any variation in these concentrations can mean patients may wake up long before they want to.
Yet, the FDA only tests the concentration of generic zolpidem at 1.5 hours and then 1.5 hours to when the drugs stops being measurable in the system, which does very little to ensure that the drug concentrations match those of the branded drug over course of the 7 or 8 hours that it is patients’ systems. Especially since 90 percent of the drug enters the body after 1.5 hours.
Who thinks this is acceptable?
Similar concentrations at one single point is hardly strong evidence that the two drugs are actually bioequivalent.
What’s more, generics that dispense their contents in a different way can actually be dangerous since the drug may linger in patients’ systems longer than it should. That can mean day time sleepiness and reduced coordination.
Sanofi-aventis, which makes Ambien CR, has a simple solution and a reasonable request: test generics for the concentration during 0-3 hours, 3-6 hours, and more than 6 hours. As Gerard Sanderink of sanofi-aventis explained this afternoon, this would assure that the generic was bioequivalent on all of the main dimensions of Ambien CR, sleep initiation, sleep maintenance, and residual effects.
It’s a proposal that’s good for patients – and innovator companies. Why is the FDA dragging its feet?
The first sessions this afternoon at the AAPS Meeting focus on bupropion, otherwise known, in its branded form, as Wellbutrin. With the introduction three years ago of a generic for the antidepressant, patient switched to generic bupropion began to complain that the new drug was not working as well as the branded version had. They reported reduced control of their depression or even suicidal symptoms.
Theoretically at least, the two drugs were the same for all intents and purposes. The FDA had evaluated the data on the generic before approving it and certified that the branded and generic drugs were bioequivalent.
Yet, patients were reporting in increasing numbers, particularly online via patient advocacy sites, that this was not so. Now drugwonks and the Center for Medicine in the Public Interest are both on the record discussing why the internet is not a reliable source of data on medical information, and calculating prevalence of side effects is no exception to this.
However, the internet was not the only place that complaints were accumulating about generic bupropion. And an in vitro study done by one of the sites receiving these complaints revealed that 34 percent of the contents of the generic was being released in the initial two hours. That percentage was only 8 percent for the branded drug. Despite concerns about the bioequivalence of the two versions, the FDA reiterated that the two were the same.
Since then, this line has been maintained. One of this afternoon’s speakers, Dr. Paul Fackler, Vice President of Biopharmaceutics in Global Generic R&D at Teva Pharmaceutical, one of the companies making the drug and the first to produce a generic of bupropion, argued that the data does show that the release pattern of the drugs is indeed very similar.
There is one obvious source of doubt of this, despite Dr. Fackler’s lovely graphs, is that they are simulations, not creations of actual data. The argument for this is that only so much blood can be drawn from volunteer subjects so producing a full graph over the drug’s 20 hour half life is unfeasible. Yet, the simple fact that they are simulations leaves the numbers very open to questions.
The second issue, and one that has existed since the beginning of the controversy over the bioequivalence of branded and generic bupropion, is that the FDA tested only the 150mg dose, not the 300mg dose. As Dr. Fackler explained this afternoon, an in vivo waiver was granted on 300mg. With the larger dose being the target of many of the reports of therapeutic inequivalence, it seems short sighted of the FDA not have asked for data on 300mg after complaints began to stream in, if not during approval.
Well, the actual title of the conference is "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products". But the core issue of the conference is whether the generic version of extended release drugs -- used widely to treat pain, mental illness, Parkinson's, and bacterial infections -- deliver the medicine to the right place at the right time in the right amount. Too much can be painful, even deadly. Too little can cause setbacks. The drug might be cheaper but the outcome is costly.
To date no one has kept track of the total impact on patients. In part that's because until 2007 generic companies were not require by the FDA to monitor the effect of their products in the marketplace and only then it was limited to opioid based painkillers. The increased use of generic lamotrigine is strongly associated with increased physician visits and hospitalizations. The same goes for switching patients to a generic version of other anti-convulsants, anti-depressants, etc.
The key question of the conference is what can companies do to assure that all medicines affect us in more or less the same way. As I have written before, one step in the right direction is to hold drugs that are supposed to have the same benefit and same risks to the same standards of post market evaluation. Another approach, to be discussed by Gerard Sanderink of Sanofi will be how to use biomarkers to more precisely predict dose response and absorption of products in the earliest stages of development and periodically in the post market.
The conference may seem mundane. However the fact that Bob Temple is showing up indicates just how serious the FDA is about this issue. And more generally, it underscores the fact that the public at large is unaware of the importance of how a drug is delivered. Discovering a medicine is half the battle. Making sure it is delivered safely and effectively is as important.
Accordingly, CMPI will be covering the AAPS conference "live" with bloggers and a video crew in a effort to "deliver" the modified release message in a way that it interesting and timely.
To date no one has kept track of the total impact on patients. In part that's because until 2007 generic companies were not require by the FDA to monitor the effect of their products in the marketplace and only then it was limited to opioid based painkillers. The increased use of generic lamotrigine is strongly associated with increased physician visits and hospitalizations. The same goes for switching patients to a generic version of other anti-convulsants, anti-depressants, etc.
The key question of the conference is what can companies do to assure that all medicines affect us in more or less the same way. As I have written before, one step in the right direction is to hold drugs that are supposed to have the same benefit and same risks to the same standards of post market evaluation. Another approach, to be discussed by Gerard Sanderink of Sanofi will be how to use biomarkers to more precisely predict dose response and absorption of products in the earliest stages of development and periodically in the post market.
The conference may seem mundane. However the fact that Bob Temple is showing up indicates just how serious the FDA is about this issue. And more generally, it underscores the fact that the public at large is unaware of the importance of how a drug is delivered. Discovering a medicine is half the battle. Making sure it is delivered safely and effectively is as important.
Accordingly, CMPI will be covering the AAPS conference "live" with bloggers and a video crew in a effort to "deliver" the modified release message in a way that it interesting and timely.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
