By Kurt R. Karst –      

Commissioner Pamela Jones Harbour of the Federal Trade Commission (“FTC”) recently gave a speech, titled “The Federal Trade Commission’s Perspective on Biosimilars: Current Initiatives and Long-Term Goals.”  This is at least the second speech in which Commissioner Harbour has address the topic of Follow-On Biologics (“FOBs”).  In June 2007, she gave a speech, titled “The Competitive Implications of Generic Biologics,” in which she stated her hope and expectation that the FTC would play an important role in the debate over FOBs.

Commissioner Harbour’s recent speech largely follows up on the FTC’s May 2, 2008 comments provided in response to an April 3, 2008 letter from the House of Representatives Energy and Commerce Committee Subcommittee on Health.  As we previously reported, the letter was sent a to a diverse group of  stakeholders soliciting feedback on how to establish a pathway to allow FDA to approve FOBs.  The FTC’s response and Commissioner Harbour’s recent comments focus primarily on the lessons that can be learned from experience with the Hatch-Waxman Amendments and caution Congress to take care to avoid any “unintended consequences” that could limit or eliminate the benefits of any FOB legislation.  

Commissioner Harbour’s recent speech also follows up on the FTC’s recent announcement and Federal Register notice on the Commission’s plans to hold a workshop concerning “competition provided by developing an abbreviated regulatory approval pathway for follow-on biologic drugs.”  The workshop is scheduled to take place on November 21, 2008 in Washington, D.C.  The FTC plans to issue a report in spring 2009 analyzing the potential impacts of FOBs on the marketplace. 

In her recent remarks, Commissioner Harbour states that “the Commission supports the development of an abbreviated approval pathway for follow-on biologics, balanced by an appropriate recognition of consumer safety and incentives to innovate,” but cautions that “policymakers should tread carefully, to ensure they fully understand the likely competitive implications and long-term consequences of their decisions.”

By Kurt R. Karst –     

Your loyal and intrepid bloggers were in attendance at today's argument before the U.S. Supreme Court in Wyeth v. Levine.  The case has been billed by some as the business case of the century; however, we think such hype is a little overblown, as even a decision against Wyeth would not mean the end of the world for defense attorneys in product liability litigation.  The media feeding frenzy over the highly anticipated oral argument was given some chum late last week when Representative Henry Waxman (D-CA) issued a staff report critical of FDA’s current anti-preemption policy and Wyeth responded to the staff report in a 3-page letter. 

For those of you not familiar with the facts of the case, Diana Levine, a Vermont bass player and author of children’s music, sought treatment for a severe migraine headache and associated nausea and dehydration and was administered Wyeth’s antihistamine PHENERGAN (promethazine HCl) via a delivery technique known as an “IV push” (as opposed to relying on gravity for an IV drip).  PHENERGAN was inadvertently injected into one of Ms. Levine’s arteries, causing gangrene, and leading to the amputation of one of her arms.  The FDA-approved PHENERGAN labeling warned against – but did not prohibit – IV push administration.  Specifically, the PHENERGAN labeling states, among other things: “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” 

Ms. Levine brought a common-law negligence claim against Wyeth in Washington County Superior Court on the theory that Wyeth should have revised PHENERGAN’s FDA-approved label to bar IV push administration.  Wyeth countered that Ms. Levine’s state tort suit was impliedly preempted by federal law.  The jury in the trial court proceeding returned a verdict in favor of Ms. Levine, and the court issued an opinion independently addressing preemption as a matter of law, concluding that the jury’s state-law-based judgment presented no obstacle to FDA’s regulatory objectives.  Wyeth appealed to the Vermont Supreme Court, contending that the trial court erred by failing to hold that Ms. Levine’s common law claims were preempted, because: “(1) Wyeth would have been unable to comply with both Vermont’s common law duty to foreclose IV push injection and FDA’s directive, as evidenced by the drug’s approved label, to retain it; and (2) the claims would obstruct the full accomplishment of FDA’s risk-benefit objective to optimize use of Phenergan by imposition of a duty to foreclose IV push injection.” 

In October 2006, a divided Vermont Supreme Court upheld the trial court’s ruling, finding that because FDA approval is not required to strengthen warnings, Wyeth could have complied with both state and federal law, that FDA labeling regulations create only minimum labeling requirements, and that state tort liability for approved labels would not frustrate the objective of promoting the public health that led Congress to enact the FDC Act.  The Vermont Supreme Court did not afford any deference to recent FDA statements claiming that “FDA approval of labeling under the [FDC Act] . . . preempts conflicting or contrary State law,” and that “FDA interprets the [FDC Act] to establish both a ‘floor’ and a ‘ceiling,’ such that additional disclosures of risk information can expose a manufacturer to liability under the act if the additional statement is unsubstantiated or otherwise false or misleading.”

Wyeth appealed the Vermont Supreme Court decision to the U.S. Supreme Court.  The question posed to U.S. Supreme Court in this case is:

Whether the prescription drug labeling judgments imposed on manufacturers by the [FDA] pursuant to FDA’s comprehensive safety and efficacy authority under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq., preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.

As additional backdrop for the case, keep in mind that earlier this year in a decisive win for medical device manufacturers, the Supreme Court ruled 8-1 in Riegel v. Medtronic that preemption principles and the 1976 Medical Device Amendments (“MDA”) bar common law claims on the basis of safety or effectiveness of devices approved by FDA under a Premarket Approval Application.  However, unlike the MDA, which amended the FDC Act to include an express preemption provision (FDC Act § 521), the drug provisions of the FDC Act do not contain such a provision. 

(For additional background on the case, Drug & Device Law Blog provides an excellent primer.  Copies of the briefs filed in the case and other background materials are available via the SCOTUS Wiki.)

So on to today’s oral argument, which was argued on Wyeth’s behalf by Seth Waxman, on FDA’s behalf by Deputy Solicitor General Ed Kneedler, and on Ms. Levine’s behalf by David Frederick. . . . 

The Justices showed a keen interest in the case, interrupting all three attorneys of record with questions before they barely spoke their opening sentences.  One line of questioning by the Justices (initiated by Justice Ginsburg) raised the issue of whether the lack of an express drug preemption clause in the FDC Act (as opposed to existence of one with respect to medical devices – see Riegel) is of any significant import.  Not surprisingly, Wyeth and FDA argued that such absence is not significant, as the U.S. Constitution’s Supremacy Clause is controlling, and that preemption should be found. 

Mr. Frederick, who was heavily questioned by Chief Justice John Roberts and Associate Justices Antonin Scalia and Samuel Alito, at one point conceded that preemption would exist in this case had FDA considered and rejected the comparative risks of IV drip versus IV push administration.  But according to Mr. Frederick, FDA was not provided with such information when the Agency approved PHENERGAN, and Wyeth, allegedly knowing the risks of IV push administration, should have presented FDA with such information.  Mr. Waxman and Mr. Kneedler were adamant that FDA was informed and aware of the risks of IV push administration when the Agency approved PHENERGAN – and, in fact, FDA rejected Wyeth’s attempts to amending PHENERGAN’s labeling.  Chief Justice John Roberts summed up this line of argument as follows: if FDA was aware of and considered the risks associated with IV push administration and approved the PHENERGAN labeling, then why wouldn’t preemption apply?

It is always difficult to prognosticate about Supreme Court decisions . . . and we are not willing at this juncture to say whether the Court will rule in favor of or against Wyeth.  That being said, given the tenor of the Court’s questions, which dealt specifically with what FDA knew and what the submissions were, we believe that: (1) an outcome either way is likely to be narrowly focused; and (2) that a narrow outcome could result in additional litigation as to whether preemption is available in any specific set of facts (i.e., a sweeping proclamation of preemption involving all drug labeling is unlikely).  But the Court’s opinion may not be issued for quite a while – perhaps not until mid-2009.  And because it is now less than 24 hours before the election, we should also note for good measure that even if the Court rules for Wyeth, the legal pundits are already speculating that “a Democrat in the White House and a Democratic Congress could erase any preemption protection companies have won in the last eight years.”  In other words, the debate is far from over.  Stay tuned for more.

UPDATE:

• A transcript of today's oral argument in Wyeth v. Levine is available here.
• The Drug and Device Law Blog provides an excellent summary of today's oral argument.

The FDA Law Blog would like to congratulate our colleagues Jim Phelps and Jeff Gibbs on being named among the best Food and Drug Lawyers in Washington, DC, according to "Washington DC's Best Lawyers," in association with the Legal Times.  We've always thought they were top-notch; it's good to see others in agreement!   The best of list was published in a special supplement to the October 31, 2008 edition of The Washington Post. 

By Kurt R. Karst –      

Happy Halloween!  Earlier this week, Health News Daily reported that Dr. Sidney Wolfe, Director of Public Citizen’s Health Research Group, was named a permanent member of FDA’s Drug Safety and Risk Management Advisory Committee.  A copy of Dr. Wolfe’s  Curriculum Vitae is available here. 

Throughout his 36-year tenure as Public Citizen’s Health Research Group Director, Dr. Wolfe has repeatedly challenged pharmaceutical companies and FDA regarding drug and other product issues.  For example, earlier this year, Public Citizen sued FDA for failing to respond to a 2006 citizen petition seeking the removal of propoxyphene drug products from the market.  And just yesterday, Public Citizen submitted a citizen petition to FDA requesting that the Agency immediately ban the diabetes drug AVANDIA (rosiglitazone).

So how will Dr. Wolfe affect FDA’s Drug Safety and Risk Management Advisory Committee as a permanent member?  Well, one might only need to look at his recent participation as a temporary voting member at a May 6, 2008 joint meeting of FDA’s Drug Safety and Anesthetic and Life Support Drugs Advisory Committees concerning FENTORA (fentanyl buccal tablet).  During the meeting, Dr. Wolfe reportedly played a significant role in setting the tone that led the committees to vote against approving FENTORA for the management of breakthrough pain in opioid-tolerant patients with chronic pain conditions.  Folks will get to see Dr. Wolfe in action as a permanent advisory committee member when the Drug Safety and Risk Management Advisory Committee meets later this year (in November and December).

By Ricardo Carvajal –

In its most recent response letters to New Dietary Ingredient ("NDI") notifications submitted pursuant to FDC Act § 413(a)(2), FDA included the following paragraph:

Based on the information in your submission, it is possible that a recently enacted law may affect the legal status of dietary supplements containing [the NDI].  Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 331(ll)) prohibits the introduction or delivery for introduction into interstate commerce of any food (including a dietary supplement) that contains a drug approved under 21 U.S.C. 355, a biological product licensed under 42 U.S.C. 262, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In our review of your notification, FDA did not consider whether section 301(ll) or any of its exemptions apply to dietary supplements containing [the NDI]. Accordingly, this response should not be construed to be a statement that a dietary supplement containing [the NDI], if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

We previously reported that FDA began to include a similar paragraph in its “no questions” letters issued in response to GRAS notices.  The inclusion of the above paragraph in response letters to NDI notifications suggests that, at a minimum, FDA is keeping the door open to interpreting “food” as used in § 301(ll) to include dietary supplements.  This is one of the issues on which FDA requested comment  with regard to possible interpretations of § 301(ll).  Although that comment period closed on October 27, numerous requests asking for an extension of the comment period were submitted to FDA.

According to FDA, the deadline for submission of comments has been extended until November 25, 2008.  When asked, FDA officials have responded orally that the extension is party-specific; that is, only those parties that submitted a timely request for an extension can be assured that comments submitted during the extension period will be considered.  However, in the past FDA has ordinarily considered relevant comments even when submitted after the deadline has expired and no extension period is granted, and it would be surprsing for FDA to reject comments on § 301(ll) except from those who have formally requested an extension, given the potential importance of this new section to the food, dietary supplement and drug industries.

By Ricardo Carvajal & Kurt R. Karst –    

On October 28, 2008, FDA announced that the Agency issued Warning Letters to Bayer HealthCare contending that two of Bayer’s products, Bayer Women’s Low Dose Aspirin + Calcium and Bayer Aspirin with Heart Advantage (Heart Advantage), are unapproved new drugs and are misbranded.  Copies of the Warning Letters are available here and here.  The Heart Advantage Warning Letter further contends that the cardiovascular claims in the labeling of that product are not entitled to First Amendment protection because they are false, misleading, or concern illegal activity.  In the alternative, FDA argues that its objections to the claims are permissible under the First Amendment because: (1) FDA’s interest in protecting public health by ensuring that drugs are safe, effective and properly labeled is substantial; (2) the drug approval process, OTC drug review, and associated labeling requirements directly advance FDA’s substantial interest; and (3) that process and those requirements are no more extensive than necessary to serve FDA’s interest.

The FDA Warning Letters come on the heels of October 14, 2008 letters from Representatives John Dingell (D-MI) and Bart Stupak (D-MI) of the House of Representatives Energy and Commerce Committee to Bayer and the U.S. Department of Health and Human Services asking for information about the marketing of Bayer’s products as part of the Committee’s investigation of direct-to-consumer advertising of drug products.  The letters cite FDA’s May 2000 letter to industry, which recommends against the marketing of combination OTC drug/dietary supplement products.  More recently, the American Herbal Products Association sent FDA a letter that referenced Bayer’s Heart Advantage and asked for clarification of the Agency’s current policy on the marketing of combination OTC drug-dietary supplement combination products. 

By Kurt R. Karst –

Further cementing FDA’s position that a generic applicant can forfeit 180-day exclusivity after patent information is "withdrawn" by the NDA holder, FDA ruled earlier today that Hi Tech Pharmacal Co., Inc. (“Hi Tech”) forfeited 180-day exclusivity after the information on  two exclusivity-qualifying Orange Book-listed patents covering the ophthalmic drug product COSOPT (dorzolamide hydrochloride; timolol maleate) had been withdrawn by the NDA holder, Merck & Co., Inc. (“Merck”).  FDA’s ruling was issued in the U.S. District Court for the District of Columbia around 10:00AM this morning, after the Court decided earlier this month not to grant Hi-Tech’s preliminary injunction motion seeking to prevent FDA from granting final ANDA approval to any subsequent ANDA applicant during Hi-Tech’s period of 180-day exclusivity.  Hyman, Phelps & McNamara, P.C. has represented Hi-Tech in its efforts – thereby explaining our decision not to address, until now, this case on the FDA Law Blog.  Apotex, Inc., a subsequent ANDA applicant, is an Intervenor-Defendant in the case, and Teva Pharmaceuticals USA, Inc., also subsequent ANDA applicant, filed an amicus brief in the case supporting Hi-Tech’s position.

We will spare you all of the details of the case.  Instead, we will focus on FDA’s Letter Decision.  But first, some quick facts . . . .  

Hi-Tech submitted the first ANDA to FDA containing a Paragraph IV certification to three patents listed in the Orange Book covering COSOPT.  This qualified Hi-Tech as a “first applicant” eligible for 180-day exclusivity.  Merck challenged Hi-Tech on one of those patents – U.S. Patent No. 4,797,413 (“the ‘413 patent”) – and Hi-Tech lost.  The ‘413 patent expired on April 28, 2008, but was subject to a period of pediatric exclusivity that expired on October 28, 2008.  Merck did not challenge Hi-Tech on the remaining two patents – U.S. Patent Nos. 6,248,735 (“the ‘735 patent”) and 6,316,443 (“the ‘443 patent”).  Instead, on April 26, 2006, Merck sent a letter to FDA requesting that information on the ‘735 and ‘443 patents be delisted from the Orange Book.  The patents have continued to be listed in the Orange Book, even today. 

Then along comes FDA’s May 2008 Letter Decision concerning 180-day exclusivity for generic PRECOSE (acarbose) Tablets.  In that case, FDA ruled that a request to withdraw patent information from the Orange Book is a forfeiture event under the “failure to market” provisions at FDC Act § 505(j)(5)(D)(i)(I), which were added to the law in December 2003 by the Medicare Modernization Act (“MMA”).  (See our May 11, 2008 post for a discussion of FDA’s acarbose decision.)  Hi-Tech then sent a letter to FDA arguing that the company could not forfeit 180-day exclusivity, and requesting that FDA make a prompt exclusivity decision to allow Hi-Tech to seek judicial relief in case of an adverse FDA decision.  FDA refused to make a decision before October 28, 2008, when the period of pediatric exclusivity on the ‘413 patent expired, and Hi-Tech sued FDA to get an exclusivity decision.  FDA subsequently opened a public docket, and, as mentioned above, the District Court, denied Hi-Tech’s motion for preliminary injunction, but instructed the parties to meet in court at 10:00AM on October 28, 2008 when FDA would issue its Letter Decision. 

FDA’s 16-page COSOPT Decision Letter concludes that Hi-Tech forfeited 180-day exclusivity on April 11, 2008, which is 30 months after Hi-Tech submitted its ANDA, and is also the “later of” date under the FDC Act § 505(j)(5)(D)(i)(I) “failure to market” forfeiture analysis.  In FDA’s January 2008 Letter Decision concerning 180-day exclusivity for generic KYTRIL (granisetron), the Agency determined that there must be both an item (aa) and an item (bb) forfeiture event under FDC Act § 505(j)(5)(D)(i)(I) for the Agency to determine a “later of” forfeiture date.  With respect to generic COSOPT, the item (aa) date was April 11, 2008, and the item (bb) event was, according to FDA, July 10, 2006 – 75 days after Merck withdrew information on the ‘735 and ‘443 patents (FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC)).  With respect to Hi-Tech’s argument that FDC Act § 505(j)(5)(D)(i)(I) requires a failure on Hi-Tech’s part (and that Hi-Tech did not “fail” to do anything it was required to do), FDA ruled that the “failure to market” forfeiture provisions “must be read as establishing a ‘no-fault’ forfeiture when an applicant fails to market by one of the identified dates.”  Hi-Tech also argued that the 180-day exclusivity tolling provisions under the Best Pharmaceuticals for Children Act (FDC Act § 505A(m)) should prevent a forfeiture.  FDA, however, ruled that FDC Act § 505A(m) applies only in the pre-MMA context, where 180-day exclusivity could be triggered by a court decision of patent invalidity, non-infringement, or unenforceability. 

FDA’s position for not providing an early exclusivity decision with respect to generic COSOPT – and in other cases as well – is that “[m]aking and advance decision on generic exclusivity . . . would result in FDA making decisions in piecemeal fashion, and FDA could be inundated with such requests from ANDA sponsors.  In addition, FDA would be unable to fully explain the basis for an advance exclusivity decision since many details of ANDAs are non-public until approval, and judicial review would thus be similarly circumscribed.”  FDA also notes that a policy of not making advance decisions “is also consistent with Congress’s choice to vest FDA with the authority to take and give effect to its actions, such as approving drugs, subject to subsequent challenge under the Administrative Procedure Act.”  Notwithstanding these concerns and points, and as we stated in court today, and the judge has articulated on several occasions, such a system leads to unnecessary court fire drills, and, more importantly, can preclude meaningful judicial review of FDA decisions.  FDA would do well to rethink its exclusivity decision-making process.  A status conference on the case has been scheduled for November 7, 2008.

By Anne Marie Murphy —
 
We recently posted on the Consumer Product Safety Improvement Act of 2008 (“CPSIA”), which makes a number of changes to the laws enforced by the Consumer Product Safety Commission (“CPSC”). 
 
Section 102(a)(1) of CPSIA amends the Consumer Product Safety Act (“CPSA”) to require each manufacturer (including an importer or private labeler) of any product that is subject to any CPSC rule, ban, standard, or regulation to issue a certificate that the product complies with such CPSC requirements.  This certification requirement applies to products manufactured after the effective date, which is November 12, 2008.  The certificate must “accompany” each product or shipment of products covered by the certificate.  A copy of the certificate must also be “furnished to each distributor or retailer of the product.”  The CPSA states that a product offered for importation “shall be refused admission” if it is not accompanied by a certificate.
 
On Friday, October 24, 2008, the CPSC posted on its website a “Sample General Certification of Conformity.”  The sample form includes the same information that was presented at a CPSC public meeting on October 2, 2008.  Instructions for completing the certification and a brief list of “frequently asked questions” are also posted.  The CPSC information is available here.

Hyman, Phelps & McNamara, P.C.’s John R. Fleder has now appeared in a Washington Legal Foundation “Legally Brief” YouTube video.  In the 6-minute video Mr. Fleder notes the recent increase in federal False Claims Act cases initiated by private whistleblowers based on alleged “off-label” use promotional activities involving pharmaceutical companies, and explains why recent court rulings have dismissed such cases, and cast doubt on the viability of any off-label use “qui tam” action.

Earlier this month, European drug makers called on the European Union (“EU”) to act on the issue of parallel trading of pharmaceuticals by confining prices for drugs to the specific EU member country they are initially sold.  Drug makers argue that some form of price control is necessary to prevent such a practice, yet was missing from recently endorsed recommendations by the EU.  This issue is not unique to Europe.  In the United States, the debate continues as to whether Americans should be allowed to re-import prescription drugs from Canada or Europe at lower prices than they may be purchased domestically.   

As European law currently stands, suppliers in a lower priced country may purchase excess of a drug product from the drug maker and then re-sell that excess for a higher price in another country without the authorization of the drug company, which results in depriving the original manufacturer of a substantial amount of potential profit.  European drug makers argue that they recognize the problems associated with the rising cost of pharmaceuticals and would like to voluntarily offer different price points to different countries based on their financial capacity.  However, without legal protection from parallel trading, they are reluctant to do so. 

European drug makers’ renewed calls for the EU to step in and reduce or eliminate parallel trading came after a recent ruling by the European Court of Justice which permits drug companies to reduce trading in their own products only if they receive orders for larger than ordinary requirements.  This result has left drug makers seeking greater rights against parallel traders. 

By Bill T. Koustas

Last week, I presented at the Center for Business Intelligence’s Pharmaceutical Congress on Paragraph IV Disputes with Geoff Levitt of Wyeth on citizen petitions.  The focus of my talk was on new FDC Act § 505(q) – “Petitions and Civil Actions Regarding Approval of Certain Applications” –  which was added to the FDC Act by § 914 of the FDA Amendments Act (“FDAAA”).  A copy of my presentation is available here.

Briefly, FDC Act § 505(q) provides that FDA shall not delay approval of a pending ANDA or 505(b)(2) application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 or § 10.35, unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  Under the new law “[FDA] shall take final agency action on a petition not later than 180 days after the date on which the petition is submitted.”  FDA may not extend the 180-day period “for any reason,” including consent of the petitioner.  FDC Act § 505(q) does not apply to all citizen petitions.  Excluded from the new law are petitions that relate “solely to the timing of the approval of an application pursuant to subsection (j)(5)(B)(iv)” (i.e., 180-day exclusivity), and petitions that are made by an ANDA or 505(b)(2) sponsor “that seeks only to have [FDA] take or refrain from taking any form of action with respect to that application.”  Petitions subject to FDC Act § 505(q) must include a specific certification identified in the new law, and petition supplements and comments must include a specific verification statement. 

As I noted during my presentation, there are several unresolved issues with the new law.  For example, how is “intent to delay” determined by FDA?  FDA’s failure to respond to a citizen petition within 180-days is not a petition denial, but rather “final agency action.”  What does this mean for challenging such “final agency action,” particularly if there is little to nothing in the administrative record from FDA? 

Notwithstanding a growing list of questions about the new law, FDA has begun to provide some guidance.  For example, FDA is reportedly interpreting FDC Act § 505(q) to apply to petitions that are submitted after an ANDA or a 505(b)(2) application is submitted to the Agency.  Why?  FDC Act § 505(q)(1)(A) refers to a “pending application.”  Because FDA will not reveal to a petitioner whether an application is pending, however, a petitioner will not know if the 180-day deadline applies – unless, of course, a generic applicant publicly states it has submitted an ANDA or a 505(b)(2) application or FDA’s ANDA Paragraph IV Certification List provides that notice.  Therefore, if a petition is submitted too soon, the 180-day FDA response deadline would not apply. 

Also, in a recent petition response concerning the approvability of a pending 505(b)(2) application, FDA notes that while FDC Act § 505(q) requires the Agency to take action on a petition within 180 days, the Agency cannot make any final decisions concerning the approvability of NDAs.  Specifically, FDA states in an October 10, 2008 petition response that:

There is no evidence that in enacting section 505(q) of the Act, Congress intended to vitiate an NDA applicant’s procedural rights by requiring that the Agency make decisions that constitute final Agency action regarding the approvability of aspects that are specific to a pending application (e.g., specific claims proposed in a drug product’s labeling) on a piecemeal basis outside of the process established under the Act and regulations.

As the number of citizen petitions subject to FDC Act § 505(q) mounts, we thought it would be useful to provide a mechanism by which to track them.  Hence, the creation of the “FDC Act § 505(q) Citizen Petition Tracker.” The Tracker is an Excel spreadsheet with links to petitions and petition decisions that will appear on the right-hand side of FDA Law Blog.  We will update it as new petitions are submitted and petition decisions are made.  According to information we were able to cull from Regulations.gov, 28 petitions with the FDC Act § 505(q) certification have been submitted to FDA since FDAAA’s enactment.  FDA has thus far denied 11 petitions and granted/denied in part 2 petitions.  Fourteen petitions are pending and one has been withdrawn; however, one of the pending petitions concerns 180-day exclusivity (i.e., FDA-2008-P-0117; Clopidogrel Bisulfate), and FDA presumably does not consider it subject to FDC Act § 505(q).  Another petition – a petition for reconsideration submitted under 21 C.F.R. § 10.33 – was submitted after FDA denied the original petition submitted pursuant to 21 C.F.R. § 10.35, and is presumably not subject to FDC Act § 505(q).  (FDC Act § 505(q) defines a “petition” to mean a written request submitted pursuant to 21 C.F.R. § 10.30 or § 10.35.)

As of today, FDA’s track record in meeting the 180-day response deadline is encouraging.  According to available information, only one pending petition is outside the deadline – FDA-2008-P-0185 concerning Minocycline HCl (SOLODYN). We are not aware of any action yet to litigate FDA’s failure to timely respond to that petition.

By Kurt R. Karst    

On October 20, 2008, FDA announced the availability of a highly anticipated draft guidance document, titled “Tropical Disease Priority Review Vouchers.”  The draft guidance discusses FDA’s implementation of FDC Act § 524 – “Priority Review to Encourage Treatments for Tropical Diseases” – which was added to the law by § 1102 of the FDA Amendments Act (“FDAAA”) to encourage the development of new drug and biological products to treat certain tropical diseases for which there are no or few available treatments by offering a new transferable voucher incentive for obtaining FDA approval for products for such diseases.  FDA is also reportedly planning to hold a public meeting to discuss the new voucher program. 

We first posted on the so-called “treat and trade” program in May 2007 when FDAAA was still being debated.  Briefly, FDAAA amended the FDC Act to create a new transferable priority review program in which applicants for new chemical entities for “tropical diseases” that have received priority review receive a “priority review voucher” entitling the holder to a 6-month FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock. The priority review voucher may be used or sold by the company granted the voucher for an application “submitted after the date of the approval of the tropical disease product application.” The tropical diseases that can qualify an applicant are enumerated in new FDC Act § 524(a)(3), and include “infectious disease[s] for which there is no significant market in developed nations and that disproportionately [affect] poor and marginalized populations, designated by regulation by [FDA].” Applicants that use a priority review voucher are required to pay FDA a priority review user fee in addition to other required user fees, and no such fee may be waived, reduced, or refunded. FDA will establish the amount of the priority review user fee before the beginning of each fiscal year, but has not yet done so for Fiscal Year 2009. 

The idea to stimulate tropical disease drug development by offering a voucher system was first proposed in a 2006 Health Affairs article authored by Duke University professors David Ridley, Henry Grabowski and Jeffrey Moe.  (See additional background information here.)  Since then, there has been significant speculation as to the price such a voucher would fetch on the market.  Some have speculated that a voucher could bring $300 million or more; however, given FDA’s recent willingness to let PDUFA goal dates slip, it is unclear how much money a company might be willing to invest in such a voucher that might not carry with it the initially intended benefits.  But we might find out soon.  Novartis’ orphan drug-designated malaria treatment COARTEM (artemether; lumefantrine) (currently under FDA review with a December 2008 action date) and Vioquest Pharma’s orphan drug-designated LENOCTA (sodium stibogluconate) for the treatment of cutaneous leishmaniasis are two drugs that might qualify for a voucher.  The success of the tropical disease voucher program could also determine whether interested parties might pursue expanding the law to apply to other types of products, including counterterrorism products.

FDA’s draft voucher guidance is largely styled as a question-and-answer document, and is presumably based on inquiries FDA received on § 524 and related discussions with sponsors.  FDA anticipates that the Agency will receive approximately 5 voucher requests annually from 5 sponsors and 5 notifications of intent to use a voucher from 5 sponsors annually. FDA notes in the draft guidance that sponsors should notify the Agency of their intent to use a priority review voucher (including the date on which the sponsor intends to submit the application) at least 1 year before use.  Each transfer should be documented with a letter of transfer.  Although FDC Act § 524 allows for only a single actual transfer of the voucher from the original recipient to another sponsor, FDA notes in the draft guidance that “contractual arrangements such as the use of an option or transfer of the right to designate the voucher’s recipient could comply with the terms of the statute.”   

By Kurt R. Karst

Hyman, Phelps & McNamara, P.C. is very pleased to announce that Anne Marie Murphy and Michelle L. Butler have been named Directors of the firm, and that Larry K. Houck has been named Of Counsel.  Ms. Murphy’s practice focuses on drug development issues. She serves on the Human Subjects Research Board for George Mason University.  Ms. Butler’s practice focuses on pharmaceutical, medical device, and healthcare law, including civil litigation, and related matters involving the Federal Trade Commission and the Consumer Product Safety Commission.  Mr. Houck’s practice area encompasses controlled substances and regulated chemicals as well as state licensing/registration compliance issues.

FDA’s Office of Combination Products (“OCP”) recently released a draft guidance entitled “New Contrast Imaging Indication Considerations for Devices and Approved Drug and Biological Products.”  The draft guidance permits diagnostic imaging device makers to expand labeling for use with a contrast agent or radiopharmaceutical even if there is no change in the labeling for the imaging drug.  This document was released as part of an effort to “ensure timely and effective review” of imaging devices used with contrast agents or radiopharmaceuticals, as mandated in the 2007 Medical Device User Fee Amendments commitment letter.

OCP’s draft guidance is addressed to the problem of how to bring to market an imaging device intended to take advantage of a new indication for a previously approved imaging drug, when the drug manufacturer is not inclined to seek a change in its own labeling or otherwise cooperate in the clearance or approval process for the device.

The draft guidance is the first ever to implement a so-called “umbrella” approach to the imaging device labeling as a potential resolution of the problem. It permits the new indication for the imaging drug to be added to the imaging device labeling even if the indication is not added to the drug labeling.

OCP has, however, included significant restrictions. First, the umbrella device labeling would likely be developed through the more burdensome PMA process rather than the 510(k) process.  Second, the sponsor would likely be required to conduct a clinical trial employing both the drug and device to support the new indication.  Finally, the new indication would have to be consistent with the drug labeling and could not require any change in the formulation, dose, rate and route of administration of the drug. If the latter type of changes were required, then the umbrella device labeling approach would not be permitted under this guidance.

Despite these restrictions, OCP’s draft guidance represents a promising step forward toward resolution of the vexing issues created by innovation in devices that have an impact on the use of previously approved drugs.  This draft guidance, in the circumstances when it applies, should enable the imaging device manufacturer to promote a new indication for an imaging drug in conjunction with its device, even if the drug manufacturer does not seek a change in the drug labeling.

By Jeffrey K. Shapiro

FDA recently published a new draft guidance document on potency tests for cellular and gene therapy (“CGT”) products.  The FDC Act requires that all biological products meet agency requirements for safety, purity, and potency before such products will be approved, but historically the agency and IND sponsors have faced challenges in establishing appropriate standards for potency testing for these complex types of products.  In the early years of CGT development, some pivotal clinical studies for CGT products were placed on clinical hold for lack of appropriate potency tests.  In the ensuing years, FDA and industry have learned a great deal about developing such tests for these products.  The draft guidance seeks to provide sponsors with the benefit of this learning.

The draft guidance makes clear that FDA recognizes that measuring potency of CGT products is a complex and evolving process.  Thus, the draft guidance recommends “an incremental approach to product characterization testing, including the development of potency assays,” and explains that the potency measurement “may change significantly” as the product is developed.  Although clinical study data “is not a practicable quantitative measure of potency,” FDA states that a manufacturer may use clinical study results “to establish a correlation between the product’s clinical efficacy and a potency measurement.”  FDA further recommends that manufacturers begin considering potency early and gather and evaluate data throughout the preclinical and clinical development of the product in order to determine the best method for measuring potency. 

The guidance also provides recommendations for determining what criteria to use to measure potency and the types of methods that may be able to make these measurements.  First, FDA states that manufacturers should develop potency measurements that “reflect the relevant biological attributes” of the product.  FDA uses a gene therapy vector to illustrate this recommendation, explaining that potency tests for a gene therapy vector should incorporate both the measure of “the ability to transfer a genetic sequence to a cell and the biological effect of the expressed genetic sequence.”  Second, FDA outlines three possible assays for measuring potency, including biological assays, non-biological analytical assays, and an assay matrix, and provides details on the types of data that should be gathered for those assays.   

Adequate potency testing becomes a critical issue for manufacturers in Phase 3 of CGT product development.  The draft guidance states that a manufacturer’s “potency assay design and acceptance criteria should be sufficient to assure that a well-characterized, consistently manufactured product was administered during your pivotal study(ies).”  Therefore, it is important that manufacturers develop appropriate potency testing.      

Although the draft guidance does not create any new regulations and “does not operate to bind FDA or the public,” it is evidence of FDA’s current thinking on CGT product approval.  The draft guidance applies only to CGT products that are reviewed by FDA’s Office of Cellular, Tissue, and Gene Therapies, but it signals FDA’s increasing comfort with for these products.  With luck, this draft guidance will help more manufactures bring these important products to market.

By Susan J. Matthees