Pharma’s Cutting Edge

S. Sen. Grassley: Secures independent review of FDA approvals based on narrow health benefits - FierceBiotech

In his letter to the GAO, Sen. Grassley asks for an investigation into FDA’s use of surrogates for product approval and whether FDA has appropriately followed up drugs approved initially based on surrogate markers.  He cites recent examples of Avandia and Vytorin as cases where the system hasn’t worked as intended.

Is he right?

Avandia was aproved on the basis of a surrogate marker, HbA1c, but the marker is a surrogate for the effects of chronic hyperglycemia on the body.  It is not a proven surrogate for the outcome of heart disease, as Sen. Grassley implies. 

The effects of chronic hyperglycemia in patients with Type 2 diabetes that are well established include heightened risks of diabetic microvascular disease, which is associated with diabetic nephropathy, retinopathy, and neuropathy and their sequelae.  There is decent evidence that reduction in chronic hyperglycemia reduces the risk of these serious health outcomes.

There is also reasonable evidence for associations of chronic hyperglycemia with other diabetes sequelae that relate to microangiopathies.  The evidence for an independent effect of chronic hyperglycemia in Type 2 diabetes on macrovascular diseases, which include heart disease, is much weaker.  Therefore, to say that FDA failed in its duties by approving a drug based on its effects on hyperglycemia alone is disingenuous. 

On the other hand, I’ve long supported large premarketing simple safety studies for drugs to be used chronically in large populations (see here, for example), so if Sen. Grassley’s intention is to try to make such studies a requirement, I support him.  I just don’t support his implication that FDA shouldn’t have relied on reduction in HbA1c as a demonstration of efficacy.  It was then and is now an adequate surrogate endpoint for many of the detrimental effects of chronic hyperglycemia due to Type 2 diabetes.

The other chosen example, Vytorin, is another poor one to use against the choice of a surrogate to claim eficacy.  As I’ve explained in an earlier post, the ENHANCE study did not establish the lack of efficacy of Vytorin or Zetia, as Sen. Grassley implies.  It merely demonstrated that in a highly selected population of patients with atypical hypercholesterolemia, the use of Zetia with statin failed to reduce progression of carotid intimal thickness, itself an unproven surrogate measure for the outcome of cardiovascular death or disability.  Genuine cardiovascular outcomes studies with this class of drug are underway.

Was Sen. Grassley wrong to imply that makers of drugs used to lower LDL-C or raise HDL-C should be required to do hard outcomes studies prior to approval?  Yes and no.  For the statin class, there’s little doubt that using LDL-C as a surrogate is justified, given the benefits on heart disease risk reduction shown with several class members, at least in patients with established heart disease at baseline.

For other classes of drugs, including the class containing Zetia/Vytorin, I think he’s mostly right, with one exception.  There are some diseases independently associated with high cholesterol in the blood that are amenable to treatment with drugs that lower blood cholesterol.  However, these conditions are rare and typically affect only those patients with very high lipid levels.  So, generaly speaking, I agree with the implication and with the sentiment.  Drugs used to lower LDL-C that will be used primarily by people like me who hope to reduce their risk of heart disease should be studied rigorously in the premarket setting, and such study should include evaluation of their effects on disease outcomes, rather than unproven surrogates (both LDL-C and CIMT, in the case of Zetia/Vytorin).

After I had fnished reading the recent Supreme Court decision in Riegel v. Medtronic and some news reports describing the supposed implications of the decision for pharma, I was confused.  Were the implications for pharma product liability cases broad and profound or narrow and limited?  Certainly, the upcoming Wyeth Supreme Court case will have its own implications for pharma, but, in the meantime, I turned to my colleague Greg Glass, editor/owner of the Paragraph Four Report, to lend his opinion to the Court’s Medtronic decision.  Here’s what he said:

As for the [Medtronic]  case, you have to read it very narrowly. It appears that the gist of the lawsuit was that the plaintiff did not have much to go on in suing Medtronic. The product [apparently] was contraindicated for the use for which it was administered to the poor guy, and the balloon was filled to 10 atmospheres, rather than the maximum [recommended] pressure of 8.  So, it appears that there was not much product liability theory to go on. ([The situation would have been different] if the facts instead were that the product was used for its intended use and the balloon ruptured at 4 atmospheres).

So, the plaintiff, being “creative,” asserted the product failed to meet certain design and manufacturing standards.

The point of the law [MDA], and the FDCA for that matter, was to create a uniform approval and safety standard. For example, what would happen if Texas passed a law that required new drugs to have three controlled studies before the product could be sold in Texas? So, the idea is to have one set of rules — federal law — to control these things.

[Following this ruling], you can still sue under state laws in state courts for product liability cases — but those laws can’t create higher manufacturing and approval standards than what federal law creates. Federal courts are harder to get into and usually don’t hear the standard product liability cases.

That seems pretty clear to me.  If the device doesn’t work as it’s supposed to, according to the FDA, plaintiffs still have the opportunity to sue in state court under product liability laws.  But if the device is pushed beyond its recognized (labeled) limits, as the facts supported in this case, plaintiffs can’t sue in state court using a state law that creates a tougher standard for the product than the FDA recognizes.

As expected, the Senate voted by unanimous consent to send PDUFA 2007 (incorporating the Senate’s FDA Revitalization Act or FDARA) to the President for his signature.  The bill’s text can be found in the link in yesterday’s post.

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.

PDUFA Reauthorization: Almost There

As Motley Fool and others are reporting, we can expect to see the 2007 bill reauthorizing the Precription Drug User Fee to emerge from conference committee this week, as FDA will give notices of layoffs to 2,000 employees on Sept. 21 without the legislation passing both houses and being signed into law by the president.  Conference committee sessions are closed to the public.  Congressional aides have been reporting that language providing a pathway for FDA approval of biosimilars aka biogenerics has been removed from consideration of the PDUFA legislation but could be debated as part of stand-alone legislation later this year.

I will report on the contents of the proposed PDUFA legislation as it is made public.  It’s fair to assume that morale and workflow are being disrupted within FDA while it awaits word on the bill.  It’s also fair to assume that such distractions are not good for sponsors.