Pharma’s Cutting Edge

PDUFA H.R. 3580 (2007)

In a 405-7 vote, the U.S. House passed legislation reauthorizing PDUFA.  The full-text link to the approved legislation is above.  Here are some highlights of the bill focused on amendments to laws affecting regulation of drugs (devices are also covered under the bill), which must now be passed by the Senate without further amendment (as early as this afternoon) and signed by the President before becoming law.

1. Fees: Total revenues from fees comparable to prior fees are set at $392.8M during FY 2008-2012, a 51% increase over FY 2007 expected revenues. In addition, fees are set aside specifically for drug safety, beginning at $25M for FY 2008, and progressively increasing to $65M by FY 2012.  Congress eliminated the orphan-drug exception to fee collection from companies with more than $50M in gross worldwide revenues for the preceding 12 months prior to the exemption request. Congress authorized collection of an advisory review fee for DTC ads submitted for advisory purposes to FDA prior to their public dissemination. The fee may not exceed $83,000 per advisory review and may not increaase more than 50% year over year. Total revenues from such fees are set at $6.25 M for FY 2008-2012.2. Drug Safety Surveillance: The expected scope and performance of drug safety surveillance supported by FDA is increased, with Congress explicitly authorizing use of “improved adverse-event data-collection systems…and improved analytical tools.”

3. Pediatric Research:  The Pediatric Research Equity Act and The Best Pharmaceuticals for Children Act are reauthorized with minor modifications.

4. FDA Modernization: The Reagan-Udall Foundation is authorized.  This non-profit foundation’s purpose is to advance FDA’s mission to modernize development of medicines, foods, and cosmetics, accelerate innovation, and enhance product safety.  The Office of The Chief Scientist is created to “oversee, coordinate, and ensure quality and regulatory focus of the intramural research programs…” of FDA.  Public-private partnerships between FDA and non-profit institutions to advance FDA’s Critical Path Intiative is established.

5. Conflicts of Interest: Waivers allowing financially conflicted experts to participate in advisory committee meetings are expected to to drop by 5% per year from the base year waiver percentage of 2007 (set as 100%) from 2008 through 2012, such that the percentage of meeting exceptions granted in 2012 will be 75% of that in 2007.

6. Clinical Trial Databases: The amount of information captured for the U.S. trial registry is significantly expanded to include more data pre-trial and links to results from trials, including results that are written in language comprehensible by lay audiences.  Result updates are to be made annually. HHS has three years after passage of PDUFA 2007 to implement this expansion fully.

7. Postmarket studies and surveillance:  Entire sections are added regarding postamarket studies and risk evaluation and mitigation strategies.  Probably the most important new addition is the requirement that sponsors respond to FDA notice of a postmarket safety issue with a supplemental label change.  FDA decides unilaterally when to make such notifications.  The sponsor’s proposed label change change is subject to review and discussions.  However, such discussions may last only 30 days following FDA notification, and within 15 days after conclusion of discussions, FDA may issue an order directing the labeling change. Within 5 days of this order, an appeal may be made using normal dispute resolution procedures.  Similar rules regulate notifications of a need for risk mitigation strategies.  Should sponsors fail to respond appropriately to FDA postmarket safety or risk mitigation notifications, drug products would no longer be qualified for sale in the U.S.

Congress has also authorized development of postmarket risk identification and analysis methods that includes linkages among multiple sources of data, with goals of at least 100,000,000 patients [under analysis] by 2012. FDA is authorized to seek public-private collaborations to improve its postmarket risk identification and analysis methods.

8.  Television and other DTC ads: FDA is given authority to require submissions of TV ads no later than 45 days before they are aired. FDA will establish standards in the next 30 months that will be used to determine whether a major statement relating to side effects or contraindications is presented appropriately. First-offense fines for false or misleading DTC ads are $250,000, with $500,000 per each subsequent violation.  A report on DTC ads and their benefits to subsets of the general population will be filed within 24 months of PDUFA 2007 passage.  A schedule for payments of fines, including fines for recurring violations, has been added to the enforcement rules.

9.  Citizens Petitions:  FDA may now deny a Citizen Petition whose primary purpose is to delay approval of an application and if it does not raise valid scientific or regulatory issues.  The 30-month exclusivity period for generics is extended if a Citizen Petition was filed against its approval and is denied.  The length of extension equals the time period between filing of the Petition and the Agency action on the Petition.  An annual report to Congress describing Petitions that resulted in delayed approvals of generics will be submitted.

10.  Postmarket drug safety information for patients and providers:  FDA must improve its procedures for internet-based dissemination of drug information to include a central clearinghouse of safety data and label information and enabling “patients, providers and drug sponsors to submit adverse event reports thrugh the Web site.” FDA will also establish an advisory committe on risk communication.

_________________________________________________

There’s lots of well-intentioned stuff here, although one has to wonder how well some of the “wish list” items for FDA future operational improvements can be encouraged into action by legislation.  It seems to me as if  Congress is trying to substitute itself for effective FDA and HHS leadership, and that will never work.  Indeed, the best potential FDA leaders will be discouraged from taking the job if Congress is viewed as their micromanager.  That said, at least this Congress has made it known explicitly what it overwhelmingly believes are the top priorities for this Agency, and its hard to argue against their priorities.

The New England Journal of Medicine: This Week’s Table of Contents

The NEJM must consider this week’s Perspectives concerning rosiglitazone and follow-on biologics of great public importance–they’ve made them both freely available, along with accompanying correspondence on Cliff Rosen’s rosiglitazone Perspective from FDA, GSK (Dr. Krall), and from Rosen himself. 

Also, in the current issue, and also fully available for free, is correspondence refuting the association of rosi with MI.  Michael Bracken from Yale calls attention to lack of concordance between the Peto odds reported by Nissen and both the risk and common odds ratios.  I previously discussed why the common odds ratio was more a appropriate method to use than the risk ratio, but I didn’t discuss Peto vs. common ORs, because, well, because I didn’t.  It’s an adavnatge of being my own editor.  The fairly esoteric discussion necessary to explicate this letter fully leaves me bored just thinking about it, let alone motivated to write about it.  However, if a dear reader feels compelled to comment on odds ratio esoterica, by all means doon’t let my lack of enthusiasm for doing so myself stop you.

First up is Dr. Rosen and dear old rosi.  Rose chaired the recent FDA advisory committee hearing, in which the panel recommended, nearly unanimously, that FDA not remove rosi from the market.

The basic plot of the rosiglitazone story quickly became obvious to the advisory committee: a new “wonder drug,” approved prematurely and for the wrong reasons by a weakened and underfunded government agency subjected to pressure from industry, had caused undue harm to patients.

Off to a rousing start.  Here’s more:

These data suggest that we urgently need to change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary end points. This is not a radical proposal: 20 years ago, the FDA shifted its primary efficacy end point for osteoporosis drugs from bone mineral density (a reasonable surrogate for the risk of fracture) to fractures themselves. Without a regulatory sea change with regard to diabetes drugs, we are certain to be in the same position 5 years from now that we are in now: we will again find ourselves in possession of a new wonder drug that is designed to treat a devastating chronic disease but that may do more harm than good.

Hmmm…Will FDA notice that Dr. Rosen forgot (benefit of the doubt) to mention that hyperglycemia is not only a surrogate marker of disease but also a condition worthy of treatment itself?  You guessed it…Slam.  FDA is nothing if not keenly observant.  Well, that and the fact that they write the rules governing approval of antihyperglycemia drugs in the U.S. helps.  Thus quote FDA:

All drugs currently approved for the treatment of diabetes are indicated to improve glycemic control. Reductions in glycated hemoglobin levels directly reflect improved glycemic control, leading to a lessening of hyperglycemic symptoms, including polydipsia, polyuria, and blurred vision. In this respect, the FDA views a reduction in the level of glycated hemoglobin as a well-validated surrogate for a beneficial effect on the immediate clinical consequences of diabetes.

Dr. Rosen’s oversight aside, his underlying observation, that for chronic-use drugs FDA must demand of sponsors more thoroughly defined safety profiles prior to marketing than they have been., is spot on  If the U.S. had a highly effective postmarketing surveillance program in place, I might feel differently, but, inexcusably, the U.S. is a long way from this goal.  Until then, large safety studies pre-marketing should be de rigeur for chronic-use drugs intended for large treatment populations.

The follow-on biologics Perspective is by Richard Frank of Harvard. 

The prospect of the loss of patent protection for tens of billions of dollars’ worth of biopharmaceuticals increases the urgency of the need for a regulatory policy that promotes price competition and preserves the safety and efficacy standards that Americans expect from prescription drugs. In my opinion, the Hatch–Waxman framework is not sufficient to cover both relatively simple biopharmaceuticals and very large and complex molecules—a new regulatory framework is needed. Because of the need for complex, situation-specific judgments, the FDA should be granted a great deal of discretion. The conflicting goals of bolstering price competition in biopharmaceutical markets and preserving the incentives for innovation call for a nuanced policy that must be based on the best current science and key features of the economics of biopharmaceutical markets — not on the impassioned claims of the interested parties.

Couldn’t have said it better.  To Senators Hatch, Waxman, Clinton et al. get on the ball.  Time is a wastin’ and the world is a waitin’.

In Milestone, FDA Pushes Genetic Tests Tied to Drug - WSJ.com

Kudos to Anna Wilde Matthews, from the Wall Street Journal (Subscr. Req.), who has done a superb job documenting some of the practical difficulties of implementing genetic predictors of therapeutic response in clinical practice.  Here’s a snippet from her piece:

Some specialists say testing hasn’t been proved to reduce the risks of the drug. They fear patients who don’t get the tests and run into trouble will sue doctors, citing the drug’s label. While Medicare covers the tests, which generally cost between $300 and $500, major insurers such as Aetna Inc., WellPoint Inc. and Cigna Corp. don’t. The insurers say they need more evidence about the benefits.  “It would be irresponsible and potentially harmful to suggest that testing be used, or even mentioned, in the label,” said University of Washington professor Ann Wittkowsky in an interview before the FDA’s decision. “It is fascinating science, but it is not yet ready for prime time.” Larry Lesko, director of the clinical pharmacology office at the FDA, says the agency has “substantial” evidence to support the new label and hopes it will improve safety by informing doctors.

Dr. Lesko’s hope for a benefit of the genetic predictors is commendable; it shows he’s open to supporting new ways of improving the safety of potentially dangerous drugs.  It’s also irrelevant to prescribers and insurers who need evidence of actual benefit, not just the hope of benefit, to guide their practices.  Before FDA supports the widespread use of such theranostics, it must require theranostics vendors, or in some cases drug manufacturers, to perform the clinical studies needed to support their use.

In the absence of such studies, doctors prescribing warfarin should not deviate from their current empirical dosing practices using measurement of INR to gauge response.  The one exception to this recommendation is a high suspicion of genetic predisposition to atypical warfarin pharmacokinetics based on a suggestive family or personal history.  In such cases, the prior probability of a positive test might warrant its use prior to dosing.

Data on genetic predictors:

In today’s NEJM, Jerry Avorn is once again given the editorial spotlight to wax sardonic at the expense of drug manufacturers:

Fast-forward to 2007, when the same company sought FDA approval for etoricoxib (Arcoxia), a new drug in the same class. Merck had initially proposed — and the agency had approved — a study comparing etoricoxib with diclofenac, an NSAID that many worried carried its own cardiac risk. Several years and millions of dollars later, Merck presented the FDA with trial evidence that etoricoxib caused roughly the same number of cardiac events as diclofenac. But this time, the FDA allowed its sharpest internal critic, David Graham, to present data to the advisory committee on the implications of approving another cyclooxygenase-2 inhibitor with potentially dangerous cardiac side effects. Had the company used a more appropriate comparator, naproxen, Graham and the others argued, the increased cardiovascular risk would have been clear. The committee voted overwhelmingly against approval. If diclofenac also presented a cardiac risk, the committee agreed, then the FDA should not approve a new product with no proven advantage that might confer the same hazard.  Not only did this decision fly in the face of the original study design, it was also a sharp departure from the conventional FDA view that a new drug in an established class need not be any safer or more effective than its predecessors. The committee’s vote was so lopsided that the agency, still embarrassed at having missed the risk of myocardial infarction associated with rofecoxib during 5 years of widespread use, could not but agree with its recommendation.

I’m guessing FDA didn’t cite embarassment in its non-approval letter to Merck.  I’m also guessing that no one in power at FDA regards its view that any new drug need be no safer than a predecessor as “conventional”.  Rather, I’m fairly certain that they regard it as the letter of U.S. federal law.  I’m sure I’ve posted relevant content from the Food Drug and Cosmetic Act previously, but here it is again.  The Act states that approval is granted for a new drug aplication unles one of the following criteria is met:

(d) If the Secretary finds, after due notice to the applicant in accordance with subsection (c) and giving him an opportunity for a hearing, in accordance with said subsection, that (1) the investigations, reports of which are required to be submitted to the Secretary pursuant to subsection (b), do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; (2) the results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; (3) the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to determine whether such drug is safe for use under such conditions; or (5) evaluated on the basis of the information submitted to him as part of the application and any other information before him with respect to such drug, there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; or (6) the application failed to contain the patent information prescribed by subsection (b); or (7) based on a fair evaluation of all material facts, such labeling is false or misleading in any particular; he shall issue an order refusing to approve the application. If, after such notice and opportunity for hearing, the Secretary finds that clauses (1) through (6) do not apply, he shall issue an order approving the application. As used in this subsection and subsection (e), the term ‘‘substantial evidence’’ means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence.

You’ll notice that the law makes no mention of evidence of superiority to predecessor drugs. In the Arcoxia case, FDA did not act out of embarassment, nor did it have to skirt the law to deny approval of Arcoxia, as Avorn suggests.  There were several legitimate–that is, legal–grounds for nonapproval.

In my last post, I  discussed what I believed would be the basis for debate and concern among the panelists at Wednesday’s FDA DMEDP Advisory Committee–the benefit to risk balance of the drug in light of modest efficacy and risk of suicidality.  This was indeed the topic of much of the committee’s deliberations.  As you now know, the committee voted unanimously (14-0) against approval of rimonabant due to a perceived unfavorable benefit to risk balance.  They also voted unanimously that Sanofi-Aventis hadn’t sufficiently characterized the safety profile of the drug.

What does this mean?  It means that this FDA division and its outside advisers, and probably much of CDER along with them, is taking the position that they want real, sustained evidence of benefits when risks during chronic use of a drug are small in number but potentially fatal.  Stated differently, risk tolerance is low among this regulatory body, and it wants to see relatively more evidence of benefit to counterweigh a risk of a serious adverse event than in the past (I’m thinking 2 to 3 years ago).  With rimonabant, they looked at a drug intended for chronic use that was associated with modest, reversible benefits on weight and markers of cardiovascular disease; no long-term cardiovascular outcome evidence; tolerance issues that promoted drug discontinuation, and an uncommon but potentially fatal adverse effect.  In the current regulatory climate, rimonabant never stood a chance.

Perhaps DMEDP and its advisers would have thought differently had rimonabant been a drug developed to treat a disease without the social baggage of obesity.  In this country, many people, including many health professionals, still consider obesity a condition caused solely by sloth and overindulgence that should be treated by willpower alone.  But I don’t think so.  Rather, I believe that this division and its advisory committee members are simply willing to be more paternalistic than in recent history, in light of missteps made by prescribers, pharmacists, sponsors and others that have led to a series of recent, high-profile drug recalls and new prescribing warnings for marketed drugs.  In essence they’re saying:  “The American public is either unable or unwilling to responsibly manage its use of new drugs.  Until that situation changes, we must intervene by taking away the tough decisions…by limiting the choices that are available to it.”

I haven’t seen FDA place a lot of the blame on itself for the inability or unwillingness of prescribers and users of new drugs to manage their use responsibly, but most senior folks at FDA must know that through their inability to demand creation and dissemination of effective prescribing information, and through their inability to demand creation of and to enforce effective new-drug risk management plans, and through their unwillingness to require the types of large trials needed to define risk before marketing that they shoulder part, perhaps most, of the blame.  None of this has to do with the needed resources for postmarketing surveillance being requested in the new PDUFA negotiations; I’m only speaking of what needs to happen before a drug reaches the market.  For that, FDA has said it has the resources it needs to do the job well.  So, why hasn’t it?

Sponsors, for their part, also shoulder significant blame for the rise of paternalism at FDA.  Perhaps they just missed seeing the writing that has been on FDA’s wall for the past few years, but I think they saw it quite clearly and chose in some cases to ignore it, hoping it would go away, and in others to address it weakly, with a wink to their investors.  Now they must overcome this guilty-until-proven-innocent mentality to market new drugs for chronic disease states, not to mention the formulary and insurance coverage hurdles awaiting new drugs once approved for marketing.  The regulatory landscape won’t change for quite a while.  If anything, we haven’t seen the top of this wave.

Sponsors, if you hadn’t heeded prior warnings, you’ve now been clearly warned:  It’s up to you and you alone to demonstrate that your new chronic-use drugs work as intended, using highly relevant and generally accepted measures of effectiveness; that they can be used safely, where safely means that the risk of use is very clearly outweighed by the benefit, even if that means you must find ways to limit risk by restricting the user base and creating redundant methods of safeguarding their proper use.  New chronic-use drugs must also be priced so as to be fiscally viable to large purchasers, and their value must not be a matter of faith but rather of overwhelming evidence.  Which other companies are in late stages of development with CB1 antagonists?  That would be Pfizer, Merck, and Solvay/BMS.  We’ll see soon if they have been paying attention.

Sanofi-Aventis made many of the right moves with rimonabant.  They misstepped by not gathering safety information in a way that could be used to create a sound risk-management strategy. There is time for them to make amends, in part, by gathering more evidence of both efficacy and safety.  Should S-A be able to generate evidence from the CRESCENDO outcomes study already in progress that very obese users (i.e. BMI >40) experience a meaningful reduction in their risk of cardiovascular events while using rimonabant, they will go a long way towards tipping the scales in favor of benefits.  In the meantime, S-A must collect more evidence from Europe that shows the drug can be used safely in the “real world”.  This, combined with some way of predicting suicidality through the use of simple baseline measures, other than or in addition to weight and history of depression, should suffice to create a viable risk management strategy.  Whether S-A would want to launch in the U.S. with a restrictive prescribing strategy and its attendant black-box warnings is another question.