By John R. Fleder –

It is no secret that the government has devoted considerable resources in recent years seeking to combat what it has contended is wide-spread illegal off-label marketing and promotion of devices and drugs.  Many people believe that the government has created this “problem” because of its long-standing lack of clarity regarding what is, and is not, acceptable practices for drug and device companies.  This uncertainty as to what is or is not illegal conduct has recently become even more cloudy because of positions the government has taken in recent litigation.

United States v. Caronia is just one of many off-label criminal cases.  Caronia was convicted of conspiring to introduce misbranded drugs into interstate commerce because those drugs allegedly did not have adequate directions for use.  His appeal of that conviction has raised some interesting issues in the briefs filed in that case, which are available here, here, and here.

First, it is noteworthy that the United States Court of Appeals for the Second Circuit on its own called for supplemental briefing in the case.  It had the litigants brief the applicability of Sorrell v. IMS Health Inc., 131 S. Ct. 2653 (2011), to the Caronia case.  In Sorrell, the Supreme Court ruled that a Vermont statute regulating certain speaker and content-based restrictions relating to pharmaceutical companies violated the First Amendment of the U.S. Constitution.  The Court of Appeals obviously read Sorrell and presumably thought that it does impact the Caronia appeal in some fashion.

One of the appellate briefs supporting Mr. Caronia’s appeal was filed by the Medical Information Working Group (MIWG), a group composed of eleven major pharmaceutical companies.  The brief argues that the FDA’s off-label regulations “are no less speaker- and content-based than was the law at issue in Sorrell.”  MIWG Amicus Brief at 1-2.  The brief also argues that there is indeed significant ambiguity regarding precisely what speech is proscribed by the FDCA, as construed and applied by FDA and the Department of Justice.

The brief also makes a number of very interesting assertions including that:

• The government has represented to courts that the presence of off-label promotion is a sufficient condition for the government to obtain a misbranding conviction, citing to the government’s proposed jury instructions in the Caronia case, which the court used to charge the jury.  The government stated in the recent Lauren Stevens case, however, that if a company pays a physician to provide an educational presentation to doctors, the manufacturer is subject to criminal prosecution if that physician affirmatively discusses the off-label use, but the same manufacturer will not be subject to prosecution if the physician provides the same information in response to an audience member’s unsolicited request.
• The government has asserted that a manufacturer cannot expressly or implicitly promote the safety or efficacy of an off-label use but can disseminate safety warnings that discourage that use.
• The government represented to the Court of Appeals in Caronia that off-label promotion is not itself a crime.
• The government stated in oral argument that a manufacturer would not be committing a crime by selling a drug or device without adequate directions for use merely because the manufacturer knew that its product was going to be used off-label. Thus, the government told the court that a manufacturer may lawfully ship a drug that it knows will be used by a physician off-label.

The government has also submitted a supplemental appellate brief in the Caronia case.  Seeking to avoid any Sorrell issue, the government is claiming that the fact that a drug was promoted for unapproved uses merely plays “an evidentiary role in” the FDCA, apparently to show that FDA is not really prohibiting speech.  In other words, the government contends that in off-label cases, the government uses the off-label speech as mere evidence of the manufacturer’s intent.  It then claims that Mr. Caronia was not convicted for conspiring to promote off-label uses.  Rather, he was convicted for distributing the drug without adequate directions for use.

While perhaps literally true, this distinction proves too much.  It shows that the government is trying to stretch an “adequate directions for use” theory to prosecute people for off-label use promotion because the statute is silent on whether it prohibits off-label use promotion.  Indeed, the government asserts that it is not restricting the dissemination of information.  Instead, it claims that it is merely following the statutory mandate that certain information must be provided to doctors (presumably only after a full FDA review of the information).  The government thus likens the “adequate directions for use” language to a “disclosure” requirement.  Indeed, the government asserts that the off-label use misbranding charges are intended “to provide the public with reliable information about the medicines they are using.”  It is of course ironic that in fact the FDA is really trying to restrict companies from providing off-label information to the public unless, of course, the FDA has approved the use.

The government also asserts that Sorrell does not alter the First Amendment cases decided before Sorrell which applied less scrutiny over the government’s statutes and regulations than the “heightened scrutiny” the Court applied in Sorrell.  The government also dismisses the MIWG brief as untimely, irrelevant and without merit.  It asserts that “the fact that an unapproved use is widely accepted in the medical community is no assurance that the drug is, in fact, either safe or effective for that use.”  The government also concedes that “to the extent that manufacturers have objective, accurate, and unbiased information about unapproved uses of approved drugs, the misbranding provisions do not prohibit manufacturers from disseminating that information.”   Addressing FDA’s guidance documents on this subject, the government asserts that manufacturers need not comply with the guidance documents but can use them as “clearly defined safe harbors.”

Undoubtedly, there must be someone who can understand, find clear legal support for, and find consistency in, the government’s many pronouncements on off label use and marketing.  That person is surely not the author of this post.

By William T. Koustas –

We have previously reported (here and here) continuing legal saga of the former Purdue Frederick Co. (“Purdue”) executives who are seeking to reverse a Department of Health and Human Services (“HHS”) decision to exclude their participation in federal healthcare programs.  In May 2007, Purdue pleaded guilty to a felony violation of the Federal Food, Drug, and Cosmetic Act (“FDCA”) for misbranding its OxyContin products with the intent to defraud or mislead.  As part of the global resolution, three former senior executives ("Purdue Executives"), pleaded guilty to FDCA misdemeanor charges of misbranding under the “responsible corporate officer” principle, or Park Doctrine.  In November 2007, the HHS Office of Inspector General sent notices of exclusion to the Purdue Executives based on their earlier misdemeanor criminal convictions.  As a result, in 2009, both individuals were excluded from federal healthcare programs for 12 years.

The Purdue Executives filed suit against HHS seeking to reverse their exclusion.  The United States District Court for the District of Columbia affirmed the HHS exclusion decision.  The Purdue Executives appealed the district court decision to the United States Court of Appeals for the District of Columbia Circuit. 

The Purdue Executives have argued that: 1) their misdemeanor convictions are not an excludable offense under 42 U.S.C. § 1320a-7(b)(1); 2), and that the exclusion was an abuse of discretion and arbitrary and capricious as their convictions were merely based on the fact that they were “responsible corporate officers” and never had intent or actual knowledge of the company’s wrongdoing.

On Monday September 19, 2011, the government filed its appellate brief in the case.  The government argues that HHS properly excluded these individuals from federal healthcare programs because they have been found guilty of criminal charges “related to” the fraud and unlawful distribution of a controlled substance (OxyContin) pursuant to 42 U.S.C. § 1320a-7(b)(1), (3).  The government further notes that HHS applied the “intuitive, ordinary reading of that phrase [related to] consistent with [HHS’] longstanding interpretation of the statute.”  Government Brief at 12.  As such, the government argues, “the Purdue Executives’ failure to fulfill their responsibility to prevent and detect Purdue employees’ fraudulent misbranding of OxyContin amply ‘related to’ fraud in connection with the company’s fraudulent delivery of OxyContin” thus, supporting the HHS exclusion of the Purdue Executives.   Government Brief at 12-13.   The government also otherwise defended the exclusion decision, including the length of the exclusion.

Oral argument in the D.C. Circuit is set for December 6, 2011.  The Purdue Executives will have the opportunity to submit a Reply Brief in the meantime.      

By Karla L. Palmer & John A. Gilbert –

Last week Senator Herb Kohl (D-WI) introduced a bill (S. 1560) to facilitate controlled substance access for residents of residential long-term care facilities.  The proposed bill, which would amend the federal Controlled Substances Act (“CSA”), specifically  21 U.S.C. §§ 802 and 829, is a long-awaited resolution for long-term care patients’ inability to obtain much-needed, faster access to controlled pain medication.  As Senator Kohl stated,  “The law should prevent suffering, not make it worse …. Unfortunately, DEA’s [controlled substance] crackdown has left elderly nursing home residents waiting for hours or even days for relief from excruciating pain.  This legislation would help end these needless and avoidable delays.”  

The 2011 bill traces its origins back to at least October 2009 when Senator Kohl, who is Chairman of the Special Committee on Aging and a Member of the Judiciary and Appropriations Committees, corresponded with Department of Justice ("DOJ") concerning long-term care patients’ lack of access to controlled substances in emergency situations (and attached proposed legislation along with that correspondence).  Because of DOJ’s perceived delay in taking action, and then-acting DEA Administrator Michelle Leonhart’s delay in addressing this serious issue, Senator Kohl placed a senatorial hold on Leohnart’s pending nomination as DEA Administrator, preventing the nomination from proceeding to the full senate until the DEA made “more progress towards our goal of ensuring that nursing home residents get timely access to the prescription drug care they need.” Kohl added, “[e]very day nursing home patients continue to suffer from agonizing pain and we need an interim solution as soon as possible.”   

Senator  Kohl lifted his hold on Leonhart’s nomination, however, only after the Department of Justice (and Attorney General Eric Holder personally) provided assurances in December 2010 that DOJ would deliver draft legislation in the beginning of 2011 outlining certain changes to the CSA.  This proposed bill appears to make good on this promise.

The amendments to the CSA would permit nurses or licensed health care professionals (i.e., designated agents) to transmit a practitioner’s oral prescription for a schedule II-IV controlled substance to DEA-licensed pharmacies.  In exchange, nursing homes, practitioners, and pharmacies would have to account for the controlled substances in a rigorous manner.  Senator Kohl stated that the changes are necessary to permit long-term care patients in chronic and debilitating pain access to schedule II substances much faster than waiting for the written prescription of a practitioner: Waiting serves only to deny the patient more immediate access to much needed pain medication. 

Note that DEA had issued a policy statement in October 2010 to permit nursing home residents to more quickly access certain controlled substances, but not schedule II drugs.  Under that policy, a nursing home’s licensed health care professionals can, acting as an authorized agent of a physician, transcribe the physician’s oral prescription for schedule III, IV or V medications to a pharmacy for dispensing.  However, the policy statement did not go far enough; it does not permit the oral transcription from a practitioner to an agent for a schedule II drug, many of which are those that are most urgently needed to treat pain in a long-term care environment. 

Senator Kohl’s proposed legislation would amend the CSA to give DEA statutory authority, unlike the DEA October 2010 policy statement, to allow licensed health care professionals to transmit prescriptions for schedule II controlled substances.  Titled the “Nursing Home Resident Pain Relief Act of 2011,” a physician will be able to authorize the administrator of the long-term care facility to designate nurses and other appropriately licensed health professionals to act as “facility designees,” or agents.  The facility designee will be able to transmit a prescription and administer pain-relieving controlled substances to residents whose medical conditions warrant immediate pain relief, based on the transmission of a valid oral prescription from the registered practitioner to the facility designee.  Under the proposed law, an administrator of a long-term care facility will be able to designate one or more qualified individuals to serve as a designee for the administration of controlled substances, and the practitioner will similarly authorize in writing the scope of the authorization, i.e., for none, some or all controlled substances regardless of their schedule.   

The proposed law also allows for a facility designee to transmit an oral prescription for a schedule II medication during an emergency in limited situations.  The proposed law requires detailed pharmacy verification of oral prescriptions transmitted by facility designees, including a requirement that, not later than 72 hours after dispensing the controlled substances pursuant to an oral prescription, the pharmacy will be required to transmit a copy of the prescription document that it received from the facility designee to the prescribing practitioner.  The practitioner must then endorse and return within 5 days to the dispensing pharmacy the copy of the prescription that it received from the pharmacy.  The dispensing pharmacy must attach the practitioner-endorsed prescription to the document that the pharmacy received from the facility designee.  If the pharmacy does not receive an endorsed prescription from the practitioner within the 5-day period, the pharmacy is prohibited from dispensing other controlled substances for the long-term care facility until endorsements are received.  The pharmacy is required to notify DEA if the physician endorsement is not received within a 10-day period of time — beginning on the date on which the pharmacy transmitted notice to the prescribing practitioner.  The proposed bill invites the Attorney General to define by regulation the term “oral prescription.”  In addition to permitting a facility designee to transmit and dispense a controlled substance prescription, the bill also modifies and codifies regulations for dispensing in emergency situations, which are currently set forth at  21 C.F.R. § 1306.11(d).  

The bill would also require that all parties to the transaction keep and maintain written records documenting each step in the prescribing and dispensing process.  The requirements include a written attestation by the facility designee verifying that the designee has spoken personally with the prescribing practitioner and that all the required information provided by the practitioner was completely and accurately recorded.  If the facility designee transmits the prescription to a pharmacy by facsimile, that facsimile will serve as the original written prescription and must be maintained by the pharmacy in accordance with the CSA and its regulations. 

The legislation provides strong criminal and civil penalties under the CSA, including individual or personal liability for long-term care administrators for the wrongful acts of facility designees, for diverting drugs or violating recordkeeping requirements. 

Hyman, Phelps & McNamara, P.C.’s Ricardo Carvajal will be presenting at the following upcoming conferences on food law and policy.

The ASQ Food, Drug, and Cosmetic Division's 22nd West Coast Conference on Dietary Supplement Challenges will address cGMPs, analytical issues, the FSMA, and FDA’s draft guidance on new dietary ingredients. The conference will feature presentations by senior FDA officials, including Daniel Fabricant, Director of CFSAN's Division of Dietary Supplement Programs (see here). The conference is scheduled for September 30 in Anaheim.

The market research firm ORC International is hosting Functional Foods Claims: Capitalizing on Trends & Opportunities, a seminar that will feature proprietary research and an expert panel on food and beverage claims. The seminar is open to branded food and beverage companies, retailers, and ingredient suppliers to industry. Companies wishing to register for the seminar should contact Carolyn Werbler at answers@orcinternational.com. The seminar is scheduled for October 4 in Chicago.

IFT’s Food Policy Impact will feature a keynote speech by FDA Deputy Commissioner for Foods Michael Taylor and presentations on food safety and food labeling (see here). The conference is scheduled for December 1 in Washington, DC. The conference will be preceded by IFT's two-day short course on food labeling, scheduled for November 29-30 (see here).

By Kurt R. Karst –      

On September 19th, FDA announced the issuance of a revised version of the Agency’s June 2006 final guidance document/Compliance Policy Guide (“CPG”) (FDA Docket No. 2003D-0478), titled “Marketed Unapproved Drugs – Compliance Policy Guide Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs.”  The revised guidance is further evidence of FDA’s stepped-up enforcement efforts under the so-called “Unapproved Drugs Initiative.”

FDA’s June 2006 CPG articulated the Agency’s risk-based enforcement approach to taking enforcement action with respect to the manufacture and distribution of marketed unapproved drugs.  Under that policy, FDA gives higher priority to enforcement action against unapproved drugs in certain categories, including drugs that present direct challenges to the “new drug” approval and over-the-counter drug monograph systems (e.g., when a drug is approved under an NDA and other companies market the same product without approval). (An article we authored that appeared in RAPS Focus a couple of years ago discussing the world of marketed unapproved drugs is available here.)

The revised CPG, which is issued for immediate implementation, says that FDA’s risk-based enforcement approach continues to apply, but only to unapproved drug products on the market as of September 19, 2011:

The enforcement priorities and potential exercise of enforcement discretion discussed in this guidance apply only to unapproved drug products that are being commercially used or sold as of September 19, 2011. All unapproved drugs introduced onto the market after that date are subject to immediate enforcement action at any time, without prior notice and without regard to the enforcement priorities set forth below. In light of the notice provided by this guidance, we believe it is inappropriate to exercise enforcement discretion with respect to unapproved drugs that a company (including a manufacturer or distributor) begins marketing after September 19, 2011.

FDA’s announcement states that although the June 2006 CPG has “established an orderly approach for removing unapproved new drugs from the market,” such products “continue to come onto the market illegally,” because of, among other things, “competition with other unapproved drugs that are already on the market, and not yet subject to a public FDA announcement regarding future enforcement actions,” and “increased market share opportunity is perceived following FDA actions that removed another unapproved drug from the market.”

Will there be a sudden wave of enforcement actions in the coming months as FDA seeks to implement the revised CPG?  Stay tuned. 

FDA’s announcement follows a major enforcement action from earlier this year on marketed unapproved cough, cold, and allergy drug products, which spawned two lawsuits against FDA (see our previous post here).  FDA is also embroiled in litigation concerning marketed unapproved Morphine Sulfate Oral Solution (see our previous post here).

By Anne Marie Murphy –

FDA and the Office for Human Research Protections ("OHRP") have jointly announced the issuance of a draft guidance document on “Exculpatory Language in Informed Consent.”  HHS and FDA regulations have long prohibited the use “exculpatory language” in informed consent documents for clinical research that is federally funded or regulated by the FDA.  Exculpatory language means language that causes a study subject to waive or appear to waive a legal right or release or appear to release those conducting the study from liability.  For example, an informed consent form that asks the study subject to waive the right to compensation for any injury that may be sustained in the study would be prohibited. 

Earlier guidance from the agencies said that language that asks a study subject to waive any rights to a biological specimen obtained during the study was likewise prohibited.  The new draft guidance takes a different position.  Recognizing that it has long been common industry practice to obtain such specimens from study subjects without compensation, and noting that there are no federal or state laws or policies that suggest study subjects have any legal right to such compensation, the new guidance concludes that language in an informed consent form is not “exculpatory” if it informs subjects that by agreeing to allow the use of their specimens in research, they are giving up any legal right to their specimens. 

The draft guidance includes several examples of statements that would be acceptable and examples that would be exculpatory and therefore prohibited.  For example, the agencies consider the following statements acceptable to be included in a consent form: 

“Although the results of research, including your donated materials, may be patentable or have commercial value, you will have no legal or financial interest in any commercial development resulting from research”;

“By agreeing to this use, you are giving up all claims to any money obtained by the researchers from the commercial or other use of these specimens.”

Comments on the draft guidance should be submitted by November 7, 2011.

By Karla L. Palmer & Jeffrey N. Gibbs –

Marking a significant victory for the pharmaceutical compounding industry, a Florida federal district court ruled that FDA did not have authority to enjoin the “long-standing, widespread, state-regulated practice of pharmacists filling a veterinarian’s prescription for a non-food producing animal by compounding from bulk substances.”  United States v. Franck’s Lab, Inc., No. 5:10-cv-147-Oc-32TBS (M.D. Fla. filed Sept. 9, 2011) at 80.  While the case involved pharmacy compounding, its implications extend much more broadly to other areas of FDA law.  Significantly, the court chastised the FDA for trying to “eradicate the line” between what would be considered unlawful manufacturing and the traditional compounding of animal medications.  After engaging in a detailed historical, regulatory and legal analysis of pharmaceutical compounding, the court held that FDA’s attempted assertion of authority over “traditional pharmacy compounding in the context of a pharmacist-veterinarian-patient relationship is contrary to [the] congressional intent” of the Federal Food, Drug and Cosmetic Act (“FDCA”).  Id. at 70.  The court further held that the undisputed evidence in the case demonstrated that allowing FDA to enjoin a pharmacist’s “traditional state-authorized practice of bulk compounding of animal drugs could destabilize the pharmacy profession and leave many animal patients without necessary medication.”  Id. at 74-75.

We previously blogged about the court’s earlier denial of FDA’s motion for a preliminary injunction against Franck’s Lab back in 2010.  Recall that FDA filed its lawsuit against Franck’s after 21 Venezuelan polo ponies died as a result of a mathematical compounding error, which the Florida Board of Pharmacy had investigated and resolved.  Despite the state’s thorough resolution of the pony matter, FDA inspected Franck’s facility on several subsequent occasions, issued a Form 483 citing various observations, which primarily concerned “perceived quality assurance and training issues.”  Id. at 5.  Franck’s responded to the Form 483, asserting that the violations were the province of the Florida Department of Health and not FDA, among other defenses.  Instead of  further discussion with Franck’s, the FDA sought an injunction in April 2010 to halt Franck’s distribution of animal drugs compounded from bulk substances, claiming that Franck’s was engaging in illegal animal drug manufacturing in violation of the FDCA.  Id. at 5-6.  (The court spent several pages of its opinion reviewing Franck’s history of compliance with state pharmacy laws, its cooperation with the FDA - citing letters to the agency dating back to at least 2004 - and Franck’s understanding that its compounding activities were lawful.)    

The court stated at the outset of its opinion on summary judgment that FDA “acknowledges that this is the first time it has sought to enjoin a state-licensed pharmacist from bulk compounding of animal medications.”  Id. at 6.  Indeed, FDA made it clear to the court that it was staking “the bright line position that any compounding of animal medications from bulk substances violates … the FDCA, even when conducted by a state-licensed pharmacist for an individual animal patient pursuant to a valid veterinary prescription.”  Id. at 7.  FDA asserted that it “essentially can enjoin a pharmacist’s state-authorized practice of animal drug compounding even where a single medication is compounded pursuant to a valid prescription.”  Id. at 38.  FDA further contended that a “traditional compounding practice implicates the same concerns under the FDCA as the mass-production, mass-marketing, and mass distribution of unapproved animal drugs by an unlicensed manufacturer.”   

In response to FDA’s claims, Franck’s submitted industry, fact, expert and other declarations supporting its position that it was not engaging in unlawful manufacturing of unapproved animal drugs.  The FDA failed to present evidence refuting Franck’s position, despite having an “ample opportunity” to do so, “resting instead on its position that compounding animal drugs from bulk … constitutes a per se violation of the FDCA.”  Id. at 8, 45.  The court noted that FDA also claimed that this was a “simple case” because “the literal, plain language of the 1938 FDCA gave the agency enforcement authority to prevent pharmacists from bulk compounding medications for non-food producing animals.”  Id. at 38, 39.  

The court disagreed with FDA’s “maximalist” portrayal of its own statutory authority.  Also, as underscored by its 80-page opinion, the court disagreed that the case was a “simple” one.  After undertaking a historical review of pharmaceutical compounding and compounding in bulk, the court reviewed FDA’s fifty-plus years of its “regulation” of compounding practices.  It found untenable the agency’s position that, for over fifty years since enactment of the FDCA, it did not assert its authority to regulate pharmacy compounding; nevertheless, “once it has shown a violation of the statute (i.e., that a ‘new animal drug’ has been distributed without an approval or exemption in place), it enjoys unfettered enforcement discretion” to take action.  Id. at 41.  The court also addressed the illogicality of FDA’s inconsistent regulatory positions in the 2002 and 2003 pharmacy compounding Compliance Policy Guides (“CPG”) (that address human and animal compounding, respectively) by presenting the following hypothetical: “A pharmacist who compounds medication from bulk for ingestion by a horse is akin to a manufacturer and subject to an FDA enforcement action, while the same pharmacist compounding medication from bulk for ingestion by the human rider of that horse is not.”  Id. at 30. 

After engaging in a Chevron analysis about the statutory construction of the FDCA’s new animal drug approval process, the type of bulk pharmaceutical compounding at issue, and FDA’s failure to engage in notice and comment rulemaking, the court ultimately held that it is simply unreasonable for FDA to assert that, even when “charitably viewed,” the FDCA is ambiguous concerning whether Congress intended the agency to regulate compounding.  Id. at 77.  In addition, the FDA should have been on notice that its “statutory authority to regulate traditional, state-licensed veterinary pharmacy compounding was questionable.”    

The court was troubled that FDA never “attempted to test its views” about bulk compounding for non-food producing animals by “notice and comment review.”  Id. at 74.  Several in the industry (including Franck’s) had long argued to FDA that its decidedly more hostile 2003 CPG guidance, which included FDA’s position that compounding animal drugs from bulk substances was a practice akin to manufacturing, represented a significant departure from previous guidance, and would cause many animals and the industry to suffer needlessly.  (Unlike earlier guidance, the 2003 CPG, “without explanation,” did not acknowledge, among other things: (1) the utility of compounding from bulk; (2) the circumstances under which doing so would absolve the pharmacist from regulatory action; and (3) the permissibility of the practice for non-food producing animals.)  The court noted that, notwithstanding numerous communications from industry and Congress over the years, the FDA failed on its promise to promulgate the revised guidance.  Id. at 30-33.  Many of the criticisms leveled by the court against FDA’s veterinary CPG would apply equally to enforcement actions against drugs compounded for humans that rest of the theory that all compounding is illegal.

Given FDA’s predilection for issuing guidance documents instead of proceeding through rulemaking, this part of the court’s decision may have broad applicability.  A recurring criticism of FDA’s use of guidance documents instead of rulemaking is that the agency does not “attempt[] to test its views” through the more rigorous rulemaking process.  See id. at 74.  Unless reversed on appeal, this language will be cited in many other challenges to FDA’s employment of guidance documents, such as regulation of laboratory developed tests and research use only products, to name a few examples.

By Jamie K. Wolszon –

On August 31, Hyman, Phelps & McNamara, P.C. (“HPM”) submitted comments to FDA’s June 1 Draft Guidance regarding research use only (“RUO”) products (see our previous posts here and here).  Although HPM supports many parts of the Draft Guidance, in its comments, it objected to FDA statements indicating that the manufacturer must halt selling to a customer if the manufacturer knows or has reason to know that the customer is using the product for a clinical diagnostic use.  HPM also expressed concerns with statements in the Draft Guidance that suggest that only certain types of research could qualify for RUO status. 

HPM maintained that these statements in the Draft Guidance represent a departure from past agency regulations, case law and policy, would have sweeping implications for multiple categories of FDA-regulated products, and can only be issued through notice-and-comment rulemaking.

HPM stated that the manufacturer’s representations, not what the manufacturer knows or had reason to know, should determine the intended use of the product.  The agency’s expansive and novel approach to intended use has broad implications for other regulated products, such as drugs, biologics, and devices.  HPM argued that FDA should not require manufacturers to immediately halt selling RUO products based on customer behavior.  HPM also called on the agency to clarify that all types of research qualify for the RUO exemption. 

If FDA insists upon these aspects, according to the HPM comments, FDA should only do so through notice-and-comment rulemaking.  HPM’s views that rulemaking is required is supported by a recent decision by a Florida district court rejecting FDA’s request for an injunction against a compounding pharmacy.  

Over thirty comments were submitted, including comments from representatives of manufacturers, laboratories, and academic institutions.  These comments criticized the proposal for: requiring manufacturers to police the activities of their customers; inappropriately expanding the concept of intended use; limiting patient access to standard-of-care laboratory-developed tests that had been appropriately validated in accordance with the requirements of the Clinical Laboratory Improvement Amendments of 1988 ("CLIA"); impeding research and the development of new tests; interfering with the practice of medicine; and violating the Administrative Procedure Act.  Virtually all comments criticized one or more of these aspects of the draft guidance.

By Wes Siegner, John R. Fleder & Ricardo Carvajal –

In U.S. v. Scenic View Dairy, LLC, et. al., the government prevailed on summary judgment in an injunction action against dairy farms alleged to market cows bearing unlawful drug residues.  Although nominally a veterinary drug case, the court’s decision offers a number of gems of general interest.

Defendants operate three dairy farms from which they periodically cull cows for sale to slaughterhouses for human beef consumption.  On numerous occasions, USDA/FSIS detected new animal drug residues that were above tolerance levels in the edible tissues of Defendants’ cows.  The government alleged in part that Defendants violated § 301(a) of the FDC Act by delivering food for introduction into interstate commerce that was adulterated within the meaning of § 402(a)(2)(C)(ii) and § 402(a)(4), and also violated § 301(k) by adulterating drugs while held for sale and after shipment in interstate commerce.

FDC Act § 402(a)(2)(C)(ii) deems a food adulterated “if it is or if it bears or contains… a new animal drug (or conversion product thereof) that is unsafe” under § 360(b).  Based on relevant provisions of the FDC Act and its implementing regulations, the court held that a drug is unsafe if the drug’s use is extralabel (i.e., the drug is used in a manner that does not accord with the approved labeling), unless used “by order of a licensed veterinarian in the context of a valid veterinarian-client-patient relationship” (“VCPR”).  Even if there exists a VCPR, the drug is unsafe if its use results in illegal tissue residues.  In finding that the drugs at issue were unsafe, the court relied in part on sworn affidavits in which Defendants admitted to extralabel use, thereby rendering moot the possible existence of a VCPR.  FDA routinely requests inspected companies to sign “affidavits” on FDA forms that are filled in with information that is written by the FDA inspector.  As this case illustrates, such affidavits can be powerful evidence against a company in any civil or criminal case that FDA subsequently brings based on the inspection.  There is no requirement that companies sign such affidavits, and, except in very rare circumstances and after review by counsel, companies would be best served by not signing (or even reading or listening to the inspector read) such affidavits.

Section 402(a)(4) deems a food adulterated “if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health.”  The government argued that Defendants’ failure to maintain adequate drug treatment records (i.e., records that document dosage, route of administration, and withdrawal period) constituted an insanitary condition whereby Defendants’ food may be rendered injurious to health.  The court agreed, relying in part on an FDA Compliance Policy Guide that articulated the same position – a timely reminder of the potential impact of guidance documents, notwithstanding the fact that they are not legally binding.  In passing, the court rejected Defendants’ argument that the Bioterrorism Act’s exemption of farms from recordkeeping requirements applied to drug treatment records.

With respect to the alleged violation of § 301(k), the court held that Defendants’ extralabel use of the drugs rendered those drugs unsafe, and therefore adulterated.  Further, the court agreed with the government that the criterion of “held for sale” in § 301(k) is “satisfied if the item is used for any purpose other than personal consumption.”

Notably, although the court found that an injunction was appropriate, it also found that the government had sought an injunction that was too broad.  The court disclaimed any intent to put Defendants out of business, and expressed concern about the terms and the length of the injunction.  The court noted that, “if the record-keeping is put into compliance as a system and by the individuals, then the problems will be largely solved.”  The court therefore concluded that a permanent injunction was not necessary.  Finally, the court noted that “without knowing the specific facts and background of injunctions entered by other district courts, this Court is not too impressed with the fact that such injunctions exist.”

By Susan J. Matthees –

The Center for Inquiry, a non-profit organization with a mission to “promote scientific inquiry,” recently submitted a Citizen Petition to FDA requesting that the Agency initiate rulemaking for a proposed rule that would require all homeopathic drugs to be tested for effectiveness and, until the drugs are tested, require all advertisements for the products carry to state “WARNING:  The FDA has not determined that this product is safe, effective, and not misbranded for its intended use.” 

FDC Act § 505 prohibits a new drug from being introduced into interstate commerce without an application approved by FDA based, in pertinent part, on substantial evidence of effectiveness.  Although homeopathic drugs are not exempt from FDC Act § 505, most are marketed under FDA’s Compliance Policy Guide (“CPG”) “Conditions Under Which Homeopathic Drugs May be Marketed” and are not approved by FDA.  Pursuant to the CPG, marketed homeopathic drugs must meet the standards for strength, quality, and purity set forth in the Homeopathic Pharmacopeia of the United States, must have indications included in a Materia Medica, and must be labeled in accordance with the FDC Act and FDA’s regulations. 

The Center for Inquiry does not explicitly ask FDA to revoke the CPG, remove homeopathic drugs from the market, or approve homeopathic drugs; the only explicit requests are that FDA use its authority to require efficacy testing for homeopathic drugs and a warning label for homeopathic drugs that are not tested.  The petition is short on legal analysis, and instead is dedicated to explaining that scientific evidence demonstrates that homeopathic drugs are not effective.  In particular, the Center for Inquiry mentions a product manufactured by Boiron as a product that allegedly has no credible scientific evidence of effectiveness.  As you may recall, a federal court in California recently decided to allow a case against Boiron to proceed.  The plaintiffs in that case allege that Boiron violated the California Legal Remedies Act and the California Unfair Competition Law and committed common law fraud by marketing homeopathic drugs that are not effective.  The Center for Inquiry does not mention the California case. 

The Practising Law Institute ("PLI") has released a new Medical Devices Law and Regulation Answer Book 2011–12, edited by Suzan Onel (K&L Gates LLP) and Karen M. Becker (Becker & Associates Consultants).  This Q&A guide is intended to orient and guide those new to the industry, and to be a useful annotated resource for the more experienced regulatory professional.  It has 19 chapters covering a wide range of topics in the life cycle of a medical device, including:

• Device Premarket Submissions 
• Post Market Considerations 
• In Vitro Diagnostic ("IVD") Devices 
• Interacting with FDA 
• International Considerations 
• HIPAA’s Impact on Manufacturers

The book has more than 30 contributors from leading law firms and consulting firms specializing in medical device work.  In the interest of full disclosure, we (proudly) note that Jeff Shapiro, a Director of our firm, contributed Chapter 3 on Device Premarket Submissions.  We also received a free review copy.

The single volume Medical Devices Law and Regulation Answer Book 2011–12 is $235 and is available for a 30-day free examination.

The table of contents is unusually detailed because it shows the questions that the book answers in each chapter.  The table of contents (and other information about the book and the contributing authors) can be found here.  The FDA Law Blog is pleased to offer its readers a 25% discount off the purchase price.  When ordering, contact Andrew Given at 212-824-5887 or agiven@pli.edu and let him know you would like the FDA Law Blog discount.

By Ricardo Carvajal –

FDA and FSIS have published a notice seeking information on issues related to reduction of dietary sodium.  Last year, the CDC determined that the government’s recommendation to limit sodium to no more than 1,500 mg/day applied to nearly 70% of adults (those deemed to be at greater risk for hypertension), but even the higher recommended limit of 2,300 mg/day has proven difficult to meet.  Average intake among those over 2 years of age is nearly 3,500 mg/day.  According to CDC, 40 percent of daily sodium intake comes from grain-based products (regulated by FDA) and 30 percent comes from processed meat products (regulated by FSIS).  Given the government’s estimate that 75% of dietary sodium is added during food manufacture and restaurant preparation, the topic of sodium reduction is of obvious interest to industry.

The notice catalogues 25 years’ worth of government and industry efforts to help consumers reduce sodium intake.  Given little progress on the issue, the two agencies are now “considering potential ways to promote gradual, achievable and sustainable reduction of sodium intake over time,” and acknowledge the need for “research on a variety of issues, including the development of possible targets” for sodium reduction.  The notice acknowledges that a number of factors “may inform judgments about appropriate opportunities for sodium reduction,” including the role of sodium in food safety, its impact on food processing, and the fact that consumers prefer salty foods.  The notice seeks information on a number of sodium reduction issues, including current industry initiatives, potential effective strategies, incentives for innovation in reformulation, establishment of targets, potential unintended consequences, and economic impacts.

Those wishing to submit information should note that any information not marked confidential “will be included in the public version of the official record without prior notice.” 

By Carmelina G. Allis - 

Below is a summary of some of the key issues discussed during FDA’s September 12 and 13, 2011, public meeting on the recently issued draft guidance document for mobile med apps.  During the meeting, FDA also requested input on how to regulate stand-alone software that provides clinical decision support, even though those support systems are not specifically addressed in the draft guidance.

In general, FDA received positive feedback regarding the draft guidance document on mobile apps.  However, it is clear that the agency still has some work to do, in particular, it needs to define the regulatory landscape in the area of stand-alone clinical decision support software.  There are some unanswered questions in both areas, as you will see from the discussion below:

Mobile Medical Apps

• There were three main proposals regarding mobile medical apps: (1) FDA should classify apps based on the level of risk to patient health; (2) FDA should issue guidance to explain what kinds of apps and/or claims the agency will not regulate; and (3) there should be a way to ensure that apps do not adversely affect the main device they connect to (and vice versa), such as requiring good software practices.

• Because many app “manufacturers” are not FDA-regulated entities, the draft guidance document needs clarity and information in order to help those that are having to learn the regulatory landscape.  The discussion on mobile medical apps centered around what does “intended use” mean and how to apply it.  A simple roadmap that helps entities/individuals to determine “how do I know that I am a mobile med app manufacturer” was suggested.

• The discussion on mobile med apps as “accessories” centered around proposals that FDA classify accessories based on intended use and functionality rather than specific characteristics or technology.

• There was some discussion that the draft guidance goes too far – for example, could general-purpose websites that have dosage calculators fall within the definition of a mobile medical app if that website (and, thus, the dosage calculator) can be accessed via a mobile phone?

• Another issue discussed was that of “interoperability” – there are apps that get information from many different sources/devices, and then an action is triggered.  How does FDA intend to regulate those apps?  Some suggested a risk-based approach.  However, the problem with the risk-based approach is how to define it: the risk if something goes wrong with the app vs. the risk that the use of the app poses?  FDA’s Bakul Patel noted that the agency discusses those issues internally all the time, but that at the end of the day, the issue is about patient safety.  Another issue regarding interoperatibility relates to who has the regulatory burden to ensure safety and effectiveness.  Is it the app manufacturer only?  But how do you ensure that the hardware (e.g., the iPad or Android platform, which FDA has said will not regulate) is safe for a particular app?

• It was suggested that FDA not discourage people from being able to make claims about the platform because of fear of becoming a medical device.  This issue came up because of comments regarding the Ford car that will supposedly provide access to apps specifically targeted to diabetics.  Does the car become an accessory to the app?  Does it all depend on the claims made by Ford?  Or could FDA allow certain claims and not regulate the car?

Stand-Alone Clinical Decision Support Systems

• FDA said that the factors it generally considers on how to regulate stand-alone clinical decision support systems involve: (1) the level of impact on subject health/condition; (2) the degree of acceptance in the clinical practice; and (3) the ability to identify erroneous output (due to incorrect output or clinically wrong information).

• There appears to be a strong concensus among some that national/international standards should be imposed/required to ensure that clinical decision support systems adhere to good software practices.

• Others suggested that regulatory requirements for clinical decision support systems should be based on intended use and risk.  Two general types of support software systems were outlined: (1) those that provide generic decision support, such as providing summaries of clinical articles or anecdotes, which FDA has said it does not intend to regulate, and (2) those that provide patient-specific support.  Among the latter, three main types were discussed:

– systems that provide or assist with simple functions;
– systems that provide assistance with therapeutics; and
– systems that assist with diagnoses.

No particular regulatory approach was proposed, as the landscape of clinical decision support systems varies immensely on intended use, intended population, functionality, and technological characteristics.  For example, while some clinical decision support systems are based on simple rules, like medication reminder software, others are based on more complex algorithms, such as assisting medical practitioners with diagnoses assessments or computing chemotherapy doses.  One possible approach not publicly discussed at the meeting would be for FDA to create a classification regulation requiring 510(k)s with special controls that applies to a well defined, but broad group of stand-alone clinical decision software (e.g., a classification regulation for software intended to assist medical practitioners with therapy determinations).

At this time it is difficult to advocate a particular regulatory pathway to clients for these device types, because there are no classification regulations that apply to many of these stand-alone clinical decision systems.  In addition, FDA has not defined what system types it intends and does not intend to regulate.  And because the 510(k)/de novo pathway is unpredictable and inefficient, manufacturers are unwilling to pursue any specific pathway to market until FDA further defines the regulatory landscape.  FDA does not want to be inundated with de novos or PMAs (which would be the default for lack of a predicate device), both of which are time-consuming and resource-intensive regulatory processes.  And that is why the suggested approach of creating a regulation with special controls for a defined, but general-scope stand-alone clinical decision support system looks appealing.

By Kurt R. Karst –      

September 12th marked the beginning of the eighth round of Trans-Pacific Partnership (“TPP”) negotiations, which are taking place in Chicago, Illinois.  The TPP is an Asia-Pacific regional trade agreement being hammered out among the United States and eight other partners.  The TPP would cover trade in goods and services and also includes a proposed chapter on intellectual property.  As we previously reported, the chapter on intellectual property is where the latest battle over biologics exclusivity is happening, and which was the subject of several letters from Members of Congress sent earlier this year. 

In a new round of letters reported on by Patent Docs, several U.S. Senators urge U.S. Trade Representative (“USTR”) Ron Kirk to support a 12-year period of exclusivity for biological products.  Colorado Senators Mark Udall (D) and Michael Bennett (D) state in their letter that “[b]eginning the biologics negotiations on an intellectual property standard consistent with U.S. law will make sure that Coloradans can continue to lead the world in the innovation of biologics while also assuring a reasonable pathway for biosimilar products.”  Meanwhile, another letter signed by a bipartisal group of 37 U.S. Senators says that they are united in urging the USTR to “propose a strong minimum term of regulatory data protection for biologics consistent with U.S. law.”

On the same day the letters were sent to USTR Kirk, the USTR issued a white paper outlining a new strategic initiative, titled “Trade Enhancing Access to Medicines” (or “TEAM”).  The TEAM strategy, which is supported by the U.S. Agency for International Development, is “designed to deploy the tools of trade policy to promote trade in, and reduce obstacles to, access to both innovative and generic medicines, while supporting the innovation and intellectual property protection that is vital to developing new medicines and achieving other medical breakthroughs,” according to the white paper.  “The TEAM initiative reflects fresh thinking about trade and access to medicines.  It is about more than allowing access to medicines.  It is about working with trading partners to develop strong and common standards to help drive access – propelling the TPP countries to the front of the line for important innovative medicines and for generic competition, while promoting U.S. jobs and exports.”

The USTR’s white paper identifies several goals, including:

Expedite access to innovative and generic medicines through a “TPP access window”: Promote the availability of life-saving and life-enhancing medicines in TPP markets and simultaneously establish a pathway for generics to enter those markets as quickly as possible by conditioning obligations to apply certain pharmaceutical-specific intellectual property protections on the requirement that innovators bring medicines to TPP markets within an agreed window of time.

The white paper is silent on the term of any biologics exclusivity period; however, we note that President Obama’s Budget for Fiscal Year 2012 proposed that “beginning in 2012, innovator brand biologic manufacturers would have 7 years of exclusivity. . . .”  A letter sent to President Obama this past summer concerning TPP negotiations stated that “[w]ere the TPP ultimately to contain a 12 year biologics exclusivity provision, it would impede the ability of Congress to achieve the Administration’s proposed 7 year change without running afoul of U.S. trade obligations.”

By Riëtte van Laack –

As we previously reported, on December 29, 2010, the Food Safety Inspection Service ("FSIS") published its final rule on nutrition labeling of single ingredient meat and poultry products and ground or chopped meat and poultry products. The new rule requires nutrition labeling on the major cuts of single-ingredient raw meat and poultry products and on all ground or chopped meat and poultry products, with or without added seasonings, unless an exemption applies. The new rule also provides that a lean percentage statement of the fat percentage may be included on ground or chopped product that does not meet the regulatory criteria for a “low fat” label as long as the label meets certain specified criteria.  The rule takes effect on January 1, 2012. 

In August, FSIS issued a notice, informing Inspection Program Personnel of the upcoming implementation date of this rule and instructing the Inspection Personnel to make plant management aware of the final rule and the implementation date of January 1, 2012.  In further efforts to prepare industry for the implementation of this rule, FSIS announced a series of webinars regarding the implementation of the rule. 

FSIS’s website includes a presentation that gives an overview of the nutrition labeling final rule and its requirements, and answers to questions that were submitted via askFSIS.