By JP Ellison –

In U.S. v. Palazzo, the Fifth Circuit recently reversed a trial court’s decision to dismiss criminal charges against a clinical investigator based upon violation of 21 C.F.R. § 312.62(b), which requires such investigators “to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug.”

As a result of the Fifth Circuit’s decision, the case was sent back to the trial court where the defendant will likely stand trial on fifteen counts of violations of this regulation with the intent to defraud and mislead, a felony, under the Federal Food, Drug, and Cosmetic Act ("FDC Act").

Importantly, nowhere in the Section 505(i) of FDC Act, which was the statutory basis for the charges, does it impose any obligation on clinical investigators.  Rather, Section 505(i) only imposes obligations on “the manufacturer or sponsor” of an IND, not on the clinical investigators.  In fact, Section 505 explicitly states that “[n]othing in this subsection shall be construed to require any clinical investigator to submit direct to the Secretary reports on the investigational use of drugs.”  § 505(i)(4).  Nevertheless, clinical investigators have been prosecuted based upon this statutory section.  These prosecutions have occurred because Section 505(i) mandates that the Secretary of HHS promulgate regulations governing clinical trials conducted under an IND, and in those regulations, including 21 C.F.R. § 312.62, FDA has imposed various obligations on clinical investigators, and in some instances alleged violations of those provisions have resulted in criminal charges. 

FDA’s regulations and the criminal prosecutions of clinical investigators under those regulations have raised a host of complicated constitutional, administrative, and criminal law issues that remain unresolved.

Palazzo is the third federal appellate court to consider the issue of whether criminal liability can be imposed on clinical investigators under the FDC Act.  Despite consideration by three Circuits in thoughtful opinions, the legal landscape remains unsettled and counsel can make non-frivolous challenges to criminal charges based on these and other regulations issued by the FDA under the FDC Act.

The first appellate court to consider the issue of clinical investigator criminal liability was the Ninth Circuit, in U.S. v. Smith, 740 F.2d 734 (9th Cir. 1984).  In Smith, the Ninth Circuit looked at Section 505(i) and concluded that it did not authorize FDA to promulgate regulations that gave rise to criminal liability for clinical investigators.  In reaching this conclusion, the Ninth Circuit relied, in part, upon the principle of the “Rule of Lenity” in interpreting an ambiguous criminal statute.  Id. at 738.  The Ninth Circuit also looked at FDA’s regulations governing clinical investigators at the time, and concluded that the regulations did not impose “a clear duty on investigators to maintain records.”  FDA’s regulations have been revised since Smith was decided, so that portion of the opinion has been superseded by subsequent events.

The second appellate court to consider the issue of clinical investigator criminal liability was the Eighth Circuit in U.S. v. Garfinkel, 29 F.3d 451 (8th Cir. 1994).  In Garfinkel, the Eighth Circuit disagreed with the Ninth Circuit and concluded that Section 505(i) could support criminal charges against clinical investigators.  In reaching this conclusion, the Eighth Circuit first conducted statutory analysis under Chevron U.S.A., Inc. v. Natural Resources Defense Council, 467 U.S. 837 (1984), and concluded that the statutory language of Section 505 was ambiguous.  Following Chevron, the Eighth Circuit then reasoned that deference was owed to FDA’s interpretation that the statute authorized it to promulgate regulations imposing obligations on clinical investigators.  Garfinkel, 29 F.3d at 457.

The Eighth Circuit then conducted constitutional analysis under the Nondelegation Doctrine, which arises out of Article 1, § 1 of the U.S. Constitution and reserves all legislative power to the Congress.  Under the Nondelegation Doctrine, the Executive Branch can promulgate regulations so long as the enabling legislation sets forth “an intelligible principle” to restrain the agency.  29 F.3d. at 458.  The Eighth Circuit concluded that Section 505(i) contained the requisite intelligible principle and thus found that the FDA’s regulations were not constitutionally invalid under the Nondelegation Doctrine.  Despite the Eighth Circuit’s thorough analysis and its discussion of the Ninth Circuit’s earlier Smith decision, Garfinkel did not address or discuss the Rule of Lenity, a point noted by the trial court in the Palazzo case.  See U.S. v. Palazzo, 2007 WL 3124697, *7 n.7 (E.D. La. 2007).  Based on this analysis, the Eighth Circuit concluded that criminal charges could be brought.

The most recent federal appellate court to address the criminal liability of clinical investigators was the Fifth Circuit in Palazzo.  Palazzo does little to clarify the split between the Eighth and Ninth Circuits, however because of what was conceded on appeal.  The Fifth Circuit’s opinion notes: 

If the parties questioned whether § 355(i) [Section 505(i)] provided sufficient guidance for the FDA to promulgate regulations requiring clinical investigators to adhere to certain record-keeping requirements, the non-delegation doctrine would be an issue in this case.  Similarly, if the parties disputed whether § 355(i) authorized the FDA regulation at issue, this Court would need to engage in a Chevron analysis to assess § 355(i)’s statutory construction.

The Fifth Circuit engaged in neither analytical exercise however, because of concessions on appeal.  Rather, the Fifth Circuit simply looked to Section 301(e) to conclude that that Section makes it a prohibited act to fail to maintain or establish any record required under, inter alia, Section 505(i), and that Section 503(a)(1) makes that prohibited act a criminal violation.  (Perhaps accidentally the court cited to the misdemeanor provisions of Section 503 despite the fact that the defendant was charged with felony violations.)  Given the defendant’s concession “that § 355(i) provides the FDA with unambiguous authority to promulgate regulations requiring clinical investigators to adhere to specific record-keeping and reporting requirements,” it is hard to see how the Fifth Circuit could have reached a contrary result.

Given Smith, Garfinkel, and Palazzo, what should a clinical investigator do?  First, one need not read or understand these cases to know that it is never prudent for an investigator to intentionally violate the FDC Act or FDA regulations in connection with a clinical trial.  Regardless of criminal liability based upon Section 505(i), there are a myriad of negative consequences, including but not limited to prosecution under other criminal statutes, that could arise from such conduct.  Second, should counsel for a clinical investigator face criminal charges based on Section 505(i) the nondelegation, Chevron, and lenity arguments, among others, should be made and preserved on appeal.  This legal question is far from decided and may end up in the Supreme Court before it is. 

By Kurt R. Karst –      

We previously reported on a lawsuit filed in July 2008 by PhotoCure ASA (“PhotoCure”) against the U.S. Patent and Trademark Office (“PTO”) after the PTO denied PhotoCure’s application for a Patent Term Extension (“PTE”) for U.S. Patent No. 6,034,267 (“the ‘267 patent”) covering the human drug product METVIXIA (methyl aminoevulinate hydrochloride), which FDA approved on July 27, 2004 under New Drug Application (“NDA”) No. 21-415.  In a decision issued earlier this week, the U.S. District Court for the Eastern District of Virginia granted PhotoCure’s Motion for Summary Judgment and denied the PTO’s Motion for Summary Judgment.  The decision, which struck down the PTO's interpretation of “product” in the PTE statute, could have significant implications on previous PTE decisions if the decision is appealed and affirmed by the Federal Circuit.

The PTO’s decision to deny a PTE for the ‘267 patent was based on an analysis of the “first permitted commercial marketing” criterion in the PTE statute.  Specifically, under 35 U.S.C. § 156(a)(5)(A), the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred” (emphasis added).  In recent PTE determinations, the PTO has heavily relied on decisions by the U.S. Court of Appeals for the Federal Circuit in Fisons v. Quigg, 8 U.S.P.Q.2d 1491 (D.D.C.1988), aff’d 876 F.2d 99 U.S.P.Q.2d 1869 (Fed.Cir.1989), and Pfizer Inc. v. Dr. Reddy’s Labs., 359 F.3d 1361 (Fed. Cir. 2004) (“Pfizer II”), to support the Office’s interpretation of the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active moiety” (i.e., the molecule in a drug product responsible for pharmacological action, regardless of whether the active moiety is formulated as a salt, ester, or other non-covalent derivative) rather than “active ingredient” (i.e., the active ingredient physically found in the drug product, which would include any salt, ester, or other non-covalent derivative of the active ingredient physically found in the drug product).  In contrast, the Federal Circuit’s 1990 decision in Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392, 13 USPQ2d 1628 (Fed. Cir. 1990) (“Glaxo II”), construed the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active ingredient.”

Applying the active moiety interpretation of the law, the PTO determined in May 2008 that METVIXIA does not represent the first permitted commercial marketing or use of the product because of FDA’s December 1999 approval of an NDA for Dusa Pharmaceuticals Inc.’s LEVULAN KERASTICK (aminolevulinic acid HCl) Topical Solution, which contains the active moiety aminolevulinic acid (“ALA”).  Thus, according to the PTO, METVIXIA does not represent the first permitted commercial marketing or use of ALA and the ‘267 patent is ineligible for a PTE. 

In reaching its decision that the PTO’s decision to deny a PTE with respect to ‘267 patent covering METVIXIA was “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with the law” under the Administrative Procedure Act, the court explained that it must determine whether it is required to follow the Federal Circuit’s ruling in Glaxo II or Pfizer II.  The court stated that “[i]mportantly, Pfizer II postdated Glaxo II and was a panel decision that the Federal Circuit declined to hear en banc.  ‘[The Federal Curcuit] has adopted the rule that prior decisions of a panel of the court are binding precedent on subsequent panels unless and until overturned in banc.  Where there is a direct conflict, the precedential decision is the first’” (internal citation omitted).   As a result, the court applied the “active ingredient” interpretation adopted in Glaxo II and determined that “the ‘267 patent covering Metvixia satisfies § 156(a)(5)(A), and that the USPTO’s decision to apply the active moiety interpretation and deny PhotoCute a [PTE] under this provision was contrary to the plain meaning of the statute and thus not in accordance with the law.”  The court also stated:

To adopt the active moiety approach would entail construing the term “active ingredient” in such a manner that permits compounds to qualify as ingredients of drugs even when those compounds are not actually present in the drug.  To adopt such a construction would be permissible, in this Court’s view, only if there was support in the legislative history.  But the Court could find no legitimate support for the active moiety approach in the § 156 legislative history.  Therefore, the Court will not construe the “active ingredient” term against its plain meaning by adopting a construction that permits compounds not present in the drug to qualify as the “active ingredient.”

Also worth emphasizing is that the term “active moiety” was indisputably well-known at the time Congress drafted the statute.  If Congress desired to infuse the “active moiety” concept into §§ 156(a) and (f), it could have done so easily by including the term somewhere in either of those two provisions.

The district court’s decision comes on the heels of several recent PTO decisions denying PTEs based on the “first permitted commercial marketing” criterion applying the active moiety interpretation of the statute – see our previous post here.  As such, it seems likely that the PTO will appeal the case to the Federal Circuit.  A Federal Circuit decision affirming the district court’s decision could call into question previous PTE denials using the active moiety interpretation of the statute.

By Ricardo Carvajal –      

Among the myriad proposals to overhaul the nation’s ailing food safety system, at least one calls for splitting off FDA’s food safety programs and incorporating them into a new Food Safety Administration ("FSA") within the U.S. Department of Health and Human Services.  That’s the tack taken in a report issued by the non-profit Trust for America’s Health titled “Keeping America’s Food Safe: A Blueprint for Fixing the Food Safety System at the U.S. Department of Health and Human Services.”  The report appears to have been strongly influenced by a paper included as an appendix titled “Restructuring Food Safety at HHS: Design and Implementation.”  That paper caught our eye because it was authored in part by Michael Taylor, formerly Deputy Commissioner for Policy at FDA, and now on faculty at the George Washington University School of Public Health.

Mr. Taylor’s paper raises the question of whether FDA’s dietary supplements and cosmetics programs should be housed in a new FSA or in the medical products agency that would remain once FDA’s food safety functions have been split off.  The paper acknowledges that dietary supplements “are categorized legally as foods and housed in CFSAN.”  However, the paper appears to suggest that perhaps the dietary supplement program should be housed in the medical products agency because:

the supplement category includes not only vitamins, minerals and other clearly nutritional substances but also herbal products and others that are marketed and sought after for their drug-like effects.  In fact, the issue of whether supplement claims cross the line to become, legally, drug claims is a recurring issue.

Similarly, with respect to cosmetics, that paper notes that “one of the recurring issues in cosmetic regulation is whether marketing claims and intended uses for some cosmetic products render them legally drugs.”

It strikes us as curious that the decision of where to house the dietary supplement and cosmetics programs would be based to any degree on the fact that unlawful marketing claims might be made for those products (a problem that needs to be addressed through enforcement), or that some consumers might seek those products out for their “drug-like” effects (what is to become of coffee?).  In any case, we thought that Congress had definitively settled the question as to how dietary supplements should be regulated – as food – and that nothing about the recent or current food safety crises suggests otherwise.  As for cosmetics, their regulatory paradigm has long resembled the one for foods much more strongly than the one for drugs.

It’s not difficult to imagine how the fate of the dietary supplement and cosmetics industries could depend on whether they’re housed in a new FSA or a medical products agency.  As the paper acknowledges in a masterful bit of understatement, “[t]he issue is of great interest to the regulated industries and other stakeholders and thus requires careful consideration.”

In the latest “Enforcement Corner” column for the Food and Drug Law Institute’s Update publication, Hyman, Phelps & McNamara, P.C. attorneys JP Ellison and John R. Fleder discuss the indictment, trial, conviction, and sentencing of Berkeley Nutraceuticals’ former in-house counsel Paul Kellogg.  Mr. Kellogg’s conviction arose out of two distinct series of events – one that the government alleged was designed to cover up an FDA violation, and another that the government alleged was designed to evade the Federal Trade Commission (“FTC”).  The article notes that “[i]f Kellogg’s conviction for conspiracy to obstruct the FDA seems like the work of a criminal mastermind, then Kellogg’s conspiracy conviction relating to the FTC may largely appear that of the unwitting dupe.”  The authors go on to discuss what lessons can be learned from Mr. Kellog’s case. 

By Jennifer B. Davis –

Earlier this week, the United States Court of Appeals for the Eleventh Circuit in Atlanta issued its opinion in United States v. Endotec, Inc., an appeal from the United States District Court for the Middle District of Florida.   We previously reported on the lower court decision here. 

The central issue on appeal was whether various ankle, knee, and jaw implants manufactured and distributed by Endotec qualified as “custom devices” exempt from the FDC Act's premarket approval requirements.  In the district court, FDA sought a permanent injunction against Endotec and its officers to preclude further manufacture and distribution of such devices without the necessary premarket approval.  Siding largely with the company, the District Court held that Endotec’s ankle and jaw implants, but not its knee implants, were exempt “custom devices.” 

On March 30, the Eleventh Circuit affirmed in part and reversed in part, concurring that the distributed jaw implant was a custom device, but not the knee or ankle implants.

The “custom device” exemption, codified at 21 U.S.C. § 360j(b), defines a custom device as one that:

necessarily deviates from an otherwise applicable performance standard or requirement prescribed by or under section 360e of this title if (1) the device is not generally available in finished form for purchase or for dispensing upon prescription and is not offered through labeling or advertising by the manufacturer, importer, or distributor thereof for commercial distribution, and (2) such device –

(A)(i) is intended for use by an individual patient named in such order of such physician or dentist (or other specially qualified person so designated) and is to be made in a specific form for such patient, or (ii) is intended to meet the special needs of such physician or dentist (or other specially qualified person so designated) in the course of the professional practice of such physician or dentist (or other specially qualified person so designated), and

(B) is not generally available to or generally used by other physicians or dentists (or other specially qualified persons so designated).

FDA’s regulation essentially mirrors, but restates the statutory criteria in list format:

Custom device means a device that:

(1) Necessarily deviates from devices generally available or from an applicable performance standard or premarket approval requirement in order to comply with the order of an individual physician or dentist;

(2) Is not generally available to, or generally used by, other physicians or dentists;

(3) Is not generally available in finished form for purchase or for dispensing upon prescription;

(4) Is not offered for commercial distribution through labeling or advertising; and

(5) Is intended for use by an individual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice.

21 C.F.R. §812.3(b).

In applying the custom device criteria, the agency has historically taken a very restrictive view, characterized by the Endotec district court as “so narrow as to make the definition useless.”  As noted in the district court opinion, FDA officials claimed in their trial testimony that devices studied in clinical trials; devices used on more than one patient; devices available in different sizes; and devices having the same basic design as other available devices, cannot be custom devices.

Those who were hoping that the Endotec case might provide some conclusive analysis of the custom device provision won’t likely find it in the Eleventh Circuit opinion.  Although the opinion makes clear that the burden of proof lies with the party claiming the exemption, the court declined (as courts are wont to do) to address any broad based criteria-related question that was not necessary to resolve the specific issue in this case of whether Endotec’s devices were custom devices.  Finding that Endotec commercially advertised its “custom” ankle devices, the court concluded that “the district court erred with respect to one prong of the custom device definition and, because a device must meet all five prongs of the custom device definition, we decline to address the remainder.”  With regard to the knee implants, it found that the defendants failed to show an abuse of discretion by the district court, failed to address the “special need” requirement, and, like the ankle implants, advertised some of the knee implants in violation of the commercial distribution prong.  With respect to the jaw implant, the court found that the Government failed to demonstrate an abuse of discretion by the lower court in determining that device to be a custom device because it was not generally available to, or used by, other physicians.

Discussing issues that have broader applicability than just to custom devices,  the court of appeals rejected the lower court’s conclusion that for FDA to prevail in an injunction case, it had to “demonstrate dangerousness or actual harm with respect to a medical device.”   The court also ruled that the lower court erred when it relied on the conclusion that FDA's "strict interpretation of procedural requirements are resulting in technological innovation being stymied.”  Finally, it concluded that it “is not within the province of the district court (or, this Court, for that matter) to weigh the medical pros and cons of a certain medical device-that is best left to the FDA.”

Simply based on the reversal of the lower court’s decision regarding the status of Endotec’s ankle devices, the agency will surely view this decision as a victory.  The opinion also contains some agency-friendly language noting that it is “all-the-more necessary” to strictly and narrowly construe exemptions to a statutory scheme when the statute is one that addresses public health and safety.  Beyond that, however, we do not think the decision is likely to have a measurable impact on FDA’s current cramped construction of the custom device exemption.

By Kurt R. Karst –      

Earlier today, FDA announced that the Agency has taken enforcement action against several manufacturers of unapproved prescription narcotics.  The 9 Warning Letters issued by FDA concern 14 narcotic drug products, including morphine sulfate, hydromorphone, and oxycodone.  The Warning Letters direct the companies to stop manufacturing and distributing the specific narcotic drug products in certain dosage forms that lack FDA approval.  According to FDA, “[m]anufacturers have 60 days after the dates of the Warning Letters to cease manufacturing of new product, and distributors have 90 days after the dates of the Warning Letters to cease further shipment of existing products.”  (Of course, if the marketing of these products is illegal, that raises the question of why FDA would permit their continued manufacturing for 60 days.)

FDA’s action today is the first drug-based enforcement action the Agency has taken since September 2008, when FDA issued a Federal Register notice concerning unapproved ophthalmic drug products containing Balanced Salt Solution.  It is also the tenth drug-based enforcement action FDA has taken since June 2006 when the Agency announced its new unapproved drug initiative to remove unapproved drugs from the market and issued its final Compliance Policy Guide (“CPG”) on the topic.  FDA’s CPG articulates a risk-based enforcement approach under which the Agency gives higher priority to enforcement action against unapproved drugs in certain categories, including drugs with potential safety risks, drugs that lack evidence of effectiveness, drugs that present a health fraud, and drugs that present direct challenges to the “new drug” approval and over-the-counter drug monograph systems.  FDA’s decision to take enforcement action with respect to certain unapproved prescription narcotics aprears to be due, at least in part, to preserve the integrity of the drug approval process.

We recently reported on oxycodone shortages.  FDA also announced oxycodone shortages just a few days ago.  A couple of the firms noted on FDA’s oxycodone drug shortage list received Warning Letters.  It is unclear the extent to which FDA’s enforcement action might further concerns about drug product shortages.   

By Kurt R. Karst – 

Last week, the U.S. Government Accountability Office (“GAO”) issued a report, titled “Nonprescription Drugs: Considerations Regarding a Behind-the-Counter Drug Class.”  The report updates the Office’s 1995 report on the same topic (see our previous post here).  The updated report was requested by Representatives John Dingell (D-MI) and Bart Stupak (D-MI) in January 2008 after FDA held a public meeting in November 2007 on Behind-the-Counter (“BTC”) availability of certain drugs.  A copy of the 2007 FDA meeting transcript is available here.  FDA has previously considered and declined to create BTC drug status.  Specifically, in April 2004, FDA denied – without substantively discussing BTC status – a citizen petition requesting that the Agency “switch Nicotrol Inhaler (Nicotine Inhalation System) from prescription only to over-the-counter status TO BE SOLD ONLY UNDER A PHARMACIST’S SUPERVISION as a third class of drugs.” 

According to the GAO report, there are two general views on how a BTC drug class would be used in the U.S.  The first view is that BTC drugs would be a permanent drug class – similar to the current prescription and Over-the-Counter drug ("OTC") classes – insofar as there would be no expectation that BTC drugs would eventually switch to the prescription or OTC class.  The second view is that a BTC drug class would function as a transition class for some drugs and a permanent class for other drugs, such that “[a] drug being switched from prescription to nonprescription would spend time in the transition class, during which the suitability of the drug for OTC status could be assessed.”

The 1995 GAO report concluded that “[l]ittle evidence supports the establishment of a pharmacy or pharmacist class of drugs in the United States at this time, as either a fixed or a transition class, and that “[t]he evidence that is available tends to undermine the contention that major benefits are being obtained in the countries that have such a class.”  The bottom line in the 2009 report is less clear, presumably because the focus of the report was to describe arguments supporting and opposing the creation of a BTC drug category, evaluate BTC drug systems in five countries that have evaluated drug classification since 1995 (i.e., the U.S., Australia, Italy, the Netherlands, and the United Kingdom), and note issues important to establishing a BTC drug class in the U.S.  The GAO report concludes that:

Arguments supporting and opposing a BTC drug class in the United States have been based on public health and health care cost considerations, and reflect general disagreement on the likely consequences of establishing such a class.  Proponents of a BTC drug class suggest it would lead to improved public health through increased availability of nonprescription drugs and greater use of pharmacists’ expertise.  Opponents are concerned that a BTC drug class might become the default for drugs switching from prescription to nonprescription status, thus reducing consumers’ access to drugs that would otherwise have become available OTC, and argue that pharmacists might not be able to provide high quality BTC services.  Proponents of a BTC drug class point to potentially reduced costs through a decrease in the number of physician visits and a decline in drug prices that might result from switches of drugs from prescription to nonprescription status.  However, opponents argue that out-of-pocket costs for many consumers could rise if third-party payers elect not to cover BTC drugs. 

The GAO report also goes on to comment that “[a]ll five study countries have increased nonprescription drug availability since 1995; however, the impact of restricted nonprescription drug classes on drug availability is unclear.”  The report also identifies several issues that need to be addressed before a BTC drug class is established in the U.S.  In particular, the GAO report states that:

Pharmacist-, infrastructure-, and cost-related issues would have to be addressed before a BTC drug class could be established in the United States.  The roles and responsibilities of pharmacists in a BTC drug class that would need to be considered include defining pharmacist responsibilities for dispensing BTC drugs, ensuring that pharmacists provide the necessary BTC counseling, and determining whether additional training would be needed for pharmacists and pharmacy staff.  In addition, whether or not there is a sufficient pharmacist workforce to make such a class viable would need to be determined, and pharmacists’ new role would need to be communicated to the public. Ensuring that pharmacies have the data infrastructure necessary to provide pharmacists with patient information and the physical infrastructure to protect consumer privacy would also be important.

Whether the GAO’s report will lead to the introduction of legislation to create a BTC drug class remains to be seen.  Legislators are presumably reviewing the report in detail to gauge the need for and the potential impediments to the creation of a BTC drug class. 

By Ricardo Carvajal –      

The latest Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention (CDC) gives credence to a possible link between higher intake of sodium and an increased risk of hypertension.  According to CDC, nearly 70% of U.S. adults should be limiting their intake of sodium to 1,500 mg/day (@ 2/3 teaspoon of salt), considerably lower than the estimated average daily intake of 3,436 mg/day for those age 2 and older. (Current dietary guidelines recommend a limit of 2,300 mg/day, but a lower limit of 1,500 mg/day is recommended for those in certain at-risk groups.)  CDC recommends that health-care providers “inform their patients of the evidence linking greater sodium intake to higher blood pressure.”

In an accompanying editorial note, CDC states that “[p]ublic health actions to reduce sodium intake likely will include 1) reducing the sodium content of processed foods; 2) encouraging consumption of more low-sodium foods, such as fruits and vegetables; and 3) providing more relevant information about sodium in food labeling.”  CDC further states that current percent daily value information in nutrition labeling of packaged foods “is likely to mislead the majority of consumers, for whom the 1,500 mg/day limit is applicable.”  As an example of a public health strategy to reduce sodium intake, CDC cites New York’s efforts to reduce sodium levels in processed and restaurant foods.

In 2005, the Center for Science in the Public Interest filed a citizen petition asking FDA to revoke the GRAS status of salt, require a reduction in the amount of salt in processed foods, and reduce the daily value for sodium to 1,500 mg/day, among other actions.  In response to the petition, FDA held a public hearing in November 2007.  The citizen petition is still pending.

By Susan J. Matthees –

FDA announced last week that it had added the first unapproved new animal drug to the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (i.e., the Index) since the Agency began accepting submissions last February.  The drug, Ovaprim, is indicated “[f]or use as a spawning aid in ornamental finfish broodstock.”  Placement on the Index allows the sponsor, Western Chemical, to sell Ovaprim without having the drug approved by FDA. 

The Index was created as part of the Minor Use Minor Species ("MUMS") Animal Health Act of 2004, which was passed with the intention of making more drugs available for treatment of minor species and uncommon diseases in major animal species.  Minor species are all animals other than the 7 major species (dogs, cats, cattle, horses, swine, chickens, and turkeys).  The Act was intended to increase drug availability by modifying the Federal Food, Drug, and Cosmetic Act in three ways. 

First, the Act allows a company to ask FDA’s Center for Veterinary Medicine to grant “conditional approval” of a drug.  Conditional approval permits a sponsor to sell a drug for up to 5 years before collecting all necessarily efficacy data.  However, the sponsor must demonstrate that the drug is safe.  Second, for drugs that have a very limited potential for marketing, FDA can add a drug to the Index, as it did yesterday for Ovaprim.  Finally, FDA can grant an animal drug a similar designation as human Orphan Drugs.  Sponsors who receive this designation can receive up to 7 years of marketing exclusivity.

FDA granted the first conditional approval in early 2007, but the Agency has not announced any other conditional approvals.  FDA granted the first designation in 2005 for the drug Florfenicol (Aquaflor®), and has been actively granting designation over the past 4 years. 

It is difficult to draw many conclusions from yesterday’s announcement since it was the first time that FDA has accepted a drug for the Index, and it remains to be seen whether the Index will increase the number of drugs available for minor uses and minor species.  However, the Index may soon prove to be very popular among the ornamental finfish of the country.

By Jennifer B. Davis & John R. Fleder –

In a March 17, 2009 opinion in United States ex rel Roop v. Hypoguard USA, Inc., the United States Court of Appeals for the Eighth Circuit held that the Relator’s qui tam allegations concerning Defendant’s alleged failure to submit FDA-required medical device reports (“MDRs”) for defective blood glucose monitors was insufficient to meet the Fed.R.Civ.P. 9(b) requirements for pleading fraud with specificity.  Affirming the lower court’s dismissal of Relator’s pre- and post-judgment motions to file a First Amended Complaint, the Eight Circuit determined that Relator’s proposed First Amended Complaint “failed to cure deficiencies in the initial Complaint” because it “did not plead with particularity the details of any false Medicare reimbursement claim presented to, or paid by, the United States or its agent.  Nor did it allege with particularity how any product defect or failure to submit MDR reports to the FDA was material to . . . the government’s decisions to pay countless unidentified Medicare reimbursement claims submitted by Hypoguard distributors.”

In a March 20, 2009 opinion in United States ex rel Poteet v. Lenke, the United States District Court for the District of Massachusetts held that Relator’s qui tam action against multiple spine surgeons and device distributors alleging receipt of kickbacks from Medtronic, Inc. and Medtronic Sofamor Danek U.S.A. in exchange for off-label promotion of INFUSE Bone Graft/LT-CAGE® was barred by the prior public disclosure of Relator’s allegations in previously filed lawsuits and the media, and by the Relator’s failure to meet the Fed.R.Civ.P. 9(b) requirements for pleading fraud with specificity.  In its application of the Rule 9(b) specificity requirement, the court found that Relator’s Amended Complaint was “devoid of specific allegations linking the distributor defendants to the general allegations of kickbacks and the filing of false claims with the government.”  It further observed that the Relator had failed to specify “which distributors were involved in the scheme, and how they were involved,” or “whether the recipients of the gifts ever purchased Medtronic products or filed a claim for medicare benefits,” “[ ]or . . . that these gifts caused a false filing with Medicare.”  Quoting a leading First Circuit FCA/Rule 9(b) opinion, United States ex rel. Rost v. Pfizer, Inc., 507 F.3d 720, 733 (1st Cir. 2007) (see our post about that case here), the court further found that the Relator’s Amended Complaint “contains ‘no factual or statistical evidence to strengthen the inference of fraud beyond possibility.’”

We have earlier reported on the case of Hopper and Hutto v. Solvay Pharmaceuticals, Inc., where the United States District Court for the Middle District of Florida dismissed a qui tam False Claims Act case involving allegations that the defendants had engaged in an alleged off-label marketing scheme with regard to the drug Marinol.  On March 13, 2009, the defendants filed their appellate brief with the United States Court of Appeals for the Eleventh Circuit.  On March 24, 2009, the Washington Legal Foundation filed an amicus curiae brief in that Court supporting the defendants’ position that the Eleventh Circuit should affirm the lower court’s dismissal.  Hyman, Phelps & McNamara P.C. is one of the counsel of record for the defendants in that case.

By Ricardo Carvajal –      

In June 2008, the Technical Committee on Dietary Lipids of the International Life Sciences Institute sponsored a workshop titled “Towards Dietary Reference Intakes for Omega-3 Fatty Acids.”  A summary of the workshop participants' conclusions is now published in the Journal of Nutrition. The publication contends that the government should reassess data on the health effects of eicosapentaenoic acid (“EPA”) and docosahexaenoic acid (“DHA”) and consider setting a Dietary Reference Intake (“DRI”) for those substances.  (A DRI is a reference value that provides the recommended intake of a nutrient.  DRI’s are set by the Food and Nutrition Board of the National Academy of Sciences.)  The publication, “Towards Establishing Dietary Reference Intakes for Eicosapentaenoic and Docosahexaenoic Acids,” is available here.

In a prior blog posting, we discussed FDA’s proposed rule to prohibit nutrient content claims for EPA and DHA.  That proposed rule is based on FDA’s determination that there is no authoritative statement identifying a reference value for EPA and DHA.  Subsequently, a citizen petition was submitted to FDA that raises several challenges to FDA’s proposed rule.  

By Kurt R. Karst –      

In a scathing 52-page opinion issued earlier today, the United States District Court for the Eastern District of New York takes FDA to task over the Agency’s August 24, 2006 approval of a supplemental NDA (“sNDA”) for Barr Pharmaceuticals, Inc.’s emergency contraceptive PLAN B (levonorgestrel) Tablets, 0.75mg and denial of a citizen petition requesting FDA to switch PLAN B (and all emergency contraceptives like it) from prescription-only to OTC status without age or point-of-sale restrictions.  FDA’s August 24, 2006 approval permitted Over-the-Counter (“OTC”) use of PLAN B in women 18 years and older and maintained prescription status for women 17 years old and younger.  As we previously reported, another attempt to vacate FDA’s PLAN B approval failed when the United States District Court for the District of Columbia ruled in March 2008 that plaintiffs lacked standing to assert the claims in the complaint, and because the plaintiffs also failed to exhaust their administrative remedies.

Today’s decision is filled with intimate details of the FDA PLAN B decision-making process.  Here are the exact words of the court's decision:

Putting aside for the moment the specifics of the many claims brought by plaintiffs and the details of each of the FDA’s decisions, the gravamen of plaintiffs’ claims is that the FDA’s decisions regarding Plan B – on the Citizen Petition and the SNDAs – were arbitrary and capricious because they were not the result of reasoned and good faith agency decision-making.

Plaintiffs are right.  The FDA repeatedly and unreasonably delayed issuing a decision on Plan B for suspect reasons and, on two occasions, only took action on Plan B to facilitate confirmation of Acting FDA Commissioners, whose confirmation hearings had been held up due to these repeated delays.  The first occasion involved the confirmation of then-Acting FDA Commissioner Lester M. Crawford, who froze the review process for seven months in 2005. In order to overcome a hold that had been placed on his nomination by two Senators, the Secretary of Health and Human Services promised that the FDA would act on Plan B by September 2005.  After Dr. Crawford was confirmed by the Senate in July 2005, however, he reneged on the promise and, instead, delayed action another eleven months to pursue, and then abandon, a rulemaking with respect to Plan B. There is also evidence that when the FDA finally decided to approve non-prescription use of Plan B for women 18 and older, it did so to facilitate the confirmation of Commissioner Crawford’s successor, then-Acting FDA Commissioner Andrew C. von Eschenbach, whose confirmation certain Senators had vowed to block because of the continued delays on Plan B.

These political considerations, delays, and implausible justifications for decision-making are not the only evidence of a lack of good faith and reasoned agency decision-making. Indeed, the record is clear that the FDA’s course of conduct regarding Plan B departed in significant ways from the agency’s normal procedures regarding similar applications to switch a drug product from prescription to non-prescription use, referred to as a “switch application” or an “over-the-counter switch.”  For example, FDA upper management, including the Commissioner, wrested control over the decision-making on Plan B from staff that normally would issue the final decision on an over-the-counter switch application; the FDA’s denial of non-prescription access without age restriction went against the recommendation of a committee of experts it had empanelled to advise it on Plan B; and the Commissioner – at the behest of political actors – decided to deny non-prescription access to women 16 and younger before FDA scientific review staff had completed their reviews.

. . . [N]o useful purpose would be served by continuing to deprive 17 year olds access to Plan B without a prescription.  Indeed, the record shows that FDA officials and staff both agreed that 17 years olds can use Plan B safely without a prescription.  The FDA’s justification for this age restriction, that pharmacists would be unable to enforce the prescription requirement if the cutoff were age 17, rather than 18, lacks all credibility.

The court ultimately vacated FDA’s citizen petition denial and remanded the matter back to FDA for the Agency to “reconsider its decisions regarding the Plan B switch to OTC use.”  In addition, the court also ordered FDA to permit Barr, within 30 days, “to make Plan B available to 17 year olds without a prescription, under the same conditions as Plan B is now available to women over the age of 18. 

By Kurt R. Karst –      

We previously reported on a complaint filed by Wyeth Holdings Corporation and its Fort Dodge Animal Health Division (collectively “Wyeth”) in the U.S. District Court for the District of Columbia against FDA and the U.S. Patent and Trademark Office (“PTO”) under the Administrative Procedure Act (“APA”) requesting declaratory and injunctive relief with respect to Wyeth’s request for a Patent Term Extension (“PTE”) for U.S. Patent #4,916,154 (“the ‘154 patent”).  The ‘154 patent covers Wyeth’s new animal drug CYDECTIN (moxidectin) Pour-On.  Earlier today, the District Court granted FDA’s Motion to Dismiss or Alternatively for Summary Judgment and denied Wyeth’s Cross-Motion for Summary Judgment.

By way of background, under the PTE statute at 35 U.S.C. § 156(g)(4), certain patents covering animal drugs are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review.  As with other FDA-regulated products, such as human drugs and medical devices, the “regulatory review period” is composed of a “testing phase” and a “review phase.”  For animal drugs approved under FDC Act § 512, the “testing phase” begins on the earlier of the effective date of an Investigational New Animal Drug (“INAD”) exemption or the date a major health or environmental effects test on the drug was initiated, and ends on the date a New Animal Drug Application (“NADA”) is “initially submitted” to FDA under FDC Act § 512(b).  The “review phase” is the period between the initial submission and approval of the NADA.  FDA’s PTE regulations at 21 C.F.R. § 60.22(f) clarify that a marketing application “is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application.”  The CYDECTIN PTE case concerns when the NADA was “initially submitted” to FDA. 

FDA first approved CYDECTIN on January 28, 1998 under NADA #141-099.  The NADA was submitted under FDA’s Phased Data Review Policy and Administrative NADA process.  An Administrative NADA “is a new animal drug application that is submitted after all of the technical sections that fulfill the requirements for the approval of the new animal drug . . . have been reviewed by [the Center for Veterinary Medicine (‘CVM’)] and CVM has issued a technical section complete letter for each of those technical sections.”  The human drug and medical device counterparts to the Administrative NADA are the statutory “Fast Track” process and the Modular Premarket Approval Application process, respectively.  Both of these processes permit a type of rolling submission and review of marketing application sections.  (FDA and the PTO have previously addressed both processes with respect to PTE issues.)

In March 1998, Wyeth timely submitted an application to the PTO requesting a PTE with respect to the ‘154 patent.  In that application, Wyeth calculated a PTE based on the date the company submitted the first technical section to its INAD (i.e., August 8, 1995).  Using this date, Wyeth calculated a new expiration date of the ‘154 patent of January 28, 2012. (The original expiration date of the ‘154 patent was April 10, 2007.) 

In September 2006, FDA issued a Federal Register notice stating the Agency’s determination that the date NADA #141-099 was initially submitted to FDA was on January 13, 1998, when the final NADA component was submitted to the Agency.  In the notice, the Agency also stated that “[i]t is FDA’s position that the approval phase begins when the marketing application is complete.”  In November 2006, Wyeth submitted a request for reconsideration and revision of the regulatory review period.  Wyeth argued that August 8, 1995 is the controlling date for PTE purposes.  On May 7, 2008, FDA denied Wyeth’s request, stating that “it is FDA’s position that the approval phase for purposes of [PTE] begins when the marketing application is complete, including all technical sections and the CVM complete letters.”  Wyeth promptly sued FDA alleging that using the August 8, 1995 date for purposes of calculating the PTE regulatory review period is consistent with Congress’ intent in passing the PTE provisions at 35 U.S.C. § 156 and with FDA’s PTE regulations at 21 C.F.R. 60.22(f), and that a mere 16-day approval period “is unreasonable.”

The District Court reviewed the case under the familiar framework of Chevron U.S.A. Inc. v. Natural ResourcesDefense Council, Inc., 467 U.S. 837 (1984).  Finding that both FDA and Wyeth had advanced  plausible readings of the PTE statute – “FDA contends that there was no ‘application’ until Wyeth submitted its Administrative NADA; and Wyeth contends that the application was ‘initially submitted’ upon its submission of the first technical section” –  the court determined under Chevron Step 1 that the statute is ambiguous, thereby necessitating review under Chevron Step 2. 

Under a Chevron Step 2 analysis, the court ruled that:

Wyeth has not met its burden here because the court finds the FDA’s arguments to be more persuasive than those made by Wyeth.  Indeed, the FDA’s construction runs true to the text and defines “initially submitted” in a manner “that is reasonable in light of the legislature’s revealed design.” . . . .  Accordingly, the court cannot say that the FDA’s interpretation is based on an impermissible construction of the statute, nor can the court find that the FDA’s interpretation violates the APA.

It is unclear whether Wyeth will appeal the decision.  We will update you as we learn more information.
 

By Riëtte van Laack & J.P. Ellison –

The Seventh Circuit’s March 12, 2009 decision in United States v. Farinella starkly shows what can happen when, as the court concluded, a prosecutor relies on bad facts for the government and combines that with no controlling law, an ineffective government expert witness, and questionable courtroom conduct. [link to decision].  In Farinella, this unfortunate combination resulted in an order directing a judgment of acquittal and a five-page broadside attack on the entire prosecution case.

Briefly, the case involved a criminal prosecution arising from a defendant changing the “best when purchased by” date on salad dressing by about 18 months before selling the salad dressing to discount stores.  A jury convicted the defendant of wire fraud and introducing a misbranded food into interstate commerce with intent to defraud or mislead.  The district court judge had earlier sentenced the defendant to five year probation, a fine, and forfeit of more than $400,000 for his “gain” from his sales of the relabeled product.  The defendant appealed and the government cross-appealed.  In a sharply worded opinion by Judge Posner, the Seventh Circuit reversed and directed an acquittal on all counts. 

From reading the opinion, it seems that the appellate court was particularly disturbed by the lack of a record evidence to support the government’s theory of the case and by the lead prosecutor’s conduct.  The opinion correctly observes that  “best when purchased by” labeling is not required and neither the Food, Drug, and Cosmetic Act (“FDC Act”) nor FDA regulations address such labeling.  Thus, the charge of misbranding could only stand if re-labeling of the product was false or misleading as a matter of law.

The Court concluded that a shelf stable product such as the salad dressing was edible for years after it has been manufactured.  Without any evidence, the prosecutor implied that the product was deteriorated and tasted “foul [and] rancid” after the “best when purchased by” date.  Moreover, the prosecution presented no evidence that consumers were misled by the change of the “best when purchased by” date or that there was a uniform food industry understanding of the meaning of “best when purchased by” date.  Nevertheless, without any citation to a law or regulation or some written document, FDA’s expert witness offered testimony implying that a change of the “best by date” required FDA approval.  As the Court of Appeals pointed out “to prove a person guilty of having made a fraudulent representation, a jury must be given evidence about the meaning . . . of the representation claimed to be fraudulent.”  The appellate court found no such admissible evidence. 

Presumably, because he was so distressed by the government’s case, Judge Posner’s decision does not provide much guidance about what may constitute criminal misbranding of a food.  In this regard, it is worth noting that under section 201 (n) of the FDC Act, it states that “in determining whether the labeling . . . is misleading there shall be taken into account . . . the extent to which the labeling . . . fails to reveal facts material in light of such representations.” 

According to FDA, “food can be safe forever from a foodborne-illness standpoint – but if shelf-stable food has been on the shelf for an extended period of time, you might not want to eat it because the quality may not be good . . . . FDA does not require an expiration date for shelf-stable foods, since the storage time for these foods is a quality issue, not a food safety concern.”  

Judge Posner noted that there was no evidence that the re-labeling posed a threat to human safety.  However, many food fraud adulteration and misbranding convictions have involved no threat to human safety.   The decision also makes much of the fact that an FDA employee called at as an expert witness “was not just improper and inadmissible but incoherent.”  The Court’s opinion excoriated the prosecutor by name.  Its displeasure with the prosecutor’s tactics may well have dictated the outcome of the case.

By Ricardo Carvajal –      

The Augusta Chronicle reports that the Georgia legislature will soon be sending new food safety legislation to Gov. Sonny Perdue for his signature.  Senate Bill 80 (S.B. 80), which was unanimously approved by both houses, directs the Commissioner of Agriculture to issue regulations that would require food processing plants to establish and maintain written food safety plans, and to test for the presence of poisonous or deleterious substances. The types of plants, foods, and substances subject to testing, as well as the frequency of that testing, would be determined by regulation. Testing would not necessarily have to be conducted by a third party, but it would have to be conducted in accord with standards and procedures established by the Commissioner. 

If testing indicates the presence of a substance that would render a food adulterated, the test result would have to be reported to the Department of Agriculture within 24 hours.  The applicable adulteration standard under Georgia law is the same as that in FDC Act section 402(a)(1) (i.e., a food is adulterated if it bears or contains any poisonous or deleterious substance which may render it injurious to health; but, in case the substance is not an added substance, such food shall not be considered adulterated under this paragraph if the quantity of such substance in such food does not ordinarily render it injurious to health).  Failure to report the test result would be a prohibited act.  Records of all testing performed would have to be maintained for two years and made available for inspection.

The prospect that S.B. 80 will become law could complicate efforts to develop federal food safety legislation, particularly if other states follow Georgia’s lead and amend their own food safety laws.  Federal legislators will have to grapple with the thorny question of whether to preempt state laws that impose different or more stringent requirements than those being contemplated at the federal level.  In the absence of federal preemption, the food industry would be left to face a patchwork of differing requirements across the country – a most unhappy prospect.