By Allyson B. Mullen –

Earlier this summer, CDRH issued a new Draft Guidance for the Content of Premarket Submissions for Management of Cybersecurity in Medical Devices (the “Draft Guidance”).  We have previously posted on the Draft Guidance here.  As noted in our earlier post, we considered the Washington Post’s assertion that the Draft Guidance imposed new “tightened standards” which would “allow the FDA to block approval of devices if manufacturers don’t provide adequate plans for protecting them” to be a bit dramatic.  However, it appears as though the Post may have been right. 

We have learned through industry contacts that even before the comment period has even closed on the Draft Guidance (closed on September 12, 2013), FDA has already invoked it as a basis for rejecting at least one 510(k) submission under its relatively new “Refuse to Accept Policy for 510(k)s.”  FDA, Guidance for Industry and FDA Staff, Refuse to Accept Policy for 510(k)s (December 2012).  The particular 510(k) refuse to accept notification that we learned of came less than two months after CDRH issued the Draft Guidance.  As anyone in industry knows, at that point the applicant is usually putting the final touches on the submission, not completely overhauling the software design to address a draft guidance document.  Therefore, it seems unreasonable (let alone unlawful) for FDA to impose compliance with a draft guidance document as part of its Refuse to Accept Policy.

As discussed in our previous post regarding FDA’s Refuse to Accept Policy (here), we raised the concern that in order to assess the “completeness” of a 510(k) submission, the reviewer may perform a substantive review.  The checklist in the Refuse to Accept Policy for a Traditional 510(k) (the “RTA Checklist”) includes three specific questions with respect to software: 1 – does the submission contain a statement that the device contains software or not; 2 – does the “[s]ubmission include[] a statement of software level of concern and rationale for the software level of concern;” and 3 – is “[a]ll applicable software documentation provided based on level of concern identified by the submitter, as described in Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, or the submission includes information to establish that the submitter has otherwise met the applicable statutory or regulatory criteria through an alternative approach (i.e., the submitter has identified an alternate approach with a rationale).”  Refuse to Accept Policy at 35. The RTA Checklist never mentions the Draft Guidance.  Thus, during the acceptance review of this particular submission, it appears as the reviewer must have performed at least a cursory substantive review to determine that the 510(k) was not sufficiently complete due to its failure to address the Draft Guidance. 

It is important not to forget that the standard for 510(k) clearance is whether the device is substantially equivalent to a predicate device, not does the device comply with FDA’s new Draft Guidance.  However, as FDA issues more and more policies and guidance documents, the standard for 510(k) clearance seems to move further from being equivalent to a device currently on the market to meeting FDA’s new heightened standards, including those communicated through draft guidance documents.

In sum, it seems as though devices which contain or use software will not just have a more difficult time getting cleared based on the Draft Guidance, but applicants may have difficulty just getting their 510(k) submissions accepted for review.  Equally, if not more, concerning though is FDA’s expansion of the Refuse to Accept Policy to require compliance with draft guidance documents not even specifically referenced in the RTA Checklists.

By Kurt R. Karst –       

Earlier this week, the Pharmaceutical Research and Manufacturers of America (“PhRMA”), along with several other trade groups – the Maine Pharmacy Association, Maine Society of Health-System Pharmacists, and Retail Association of Maine – and two pharmacists, filed a Complaint and Motion for Preliminary Injunction in the U.S. District Court for the District of Maine against Maine’s Attorney General and Commissioner of Administrative & Financial Services in an effort to bar the state from implementing a state law that would permit the importation of drug products into the U.S. from licensed retail pharmacies located in certain foreign countries.  The state law, enacted on June 27, 2013 (after Governor Paul LePage declined to sign the bill) and titled “An Act To Facilitate the Personal Importation of Prescription Drugs from International Mail Order Prescription Pharmacies,” is scheduled to go into effect on October 9, 2013.

The law is pretty short.  Section one amends 32 MRSA §13731, sub-§1 to state:

1. Applicability. It is unlawful for any person to engage in the practice of pharmacy unless licensed to practice under this Act, except that:

A. Physicians, dentists, veterinarians or other practitioners of the healing arts who are licensed under the laws of this State may dispense and administer prescription drugs to their patients in the practice of their respective professions where specifically authorized to do so by law;

B. A licensed retail pharmacy that is located in Canada, the United Kingdom of Great Britain and Northern Ireland, the Commonwealth of Australia or New Zealand that meets its country's statutory and regulatory requirements may export prescription drugs by mail or carrier to a resident of this State for that resident’s personal use. A licensed retail pharmacy described in this paragraph is exempt from licensure under this Act; and

C. An entity that contracts to provide or facilitate the exportation of prescription drugs from a licensed retail pharmacy described in paragraph B may provide or facilitate the provision of prescription drugs from that pharmacy by mail or carrier to a resident of this State for that resident's personal use. An entity that provides or facilitates the provision of prescription drugs pursuant to this paragraph is exempt from licensure under this Act.

Section two adds 32 MRSA §13799:

§ 13799. Consumer choice preserved

Nothing in this chapter may be construed to prohibit:

1. Ordering or receiving prescription drugs. An individual who is a resident of the State from ordering or receiving prescription drugs for that individual’s personal use from outside the United States by mail or carrier from a licensed retail pharmacy described in section 13731, subsection 1, paragraph B or an entity described in section 13731, subsection 1, paragraph C; or

2. Dispensing or providing prescription drugs. A licensed retail pharmacy described in section 13731, subsection 1, paragraph B or an entity described in section 13731, subsection 1, paragraph C from dispensing, providing or facilitating the provision of prescription drugs from outside the United States by mail or carrier to a resident of the State for that resident's personal use.

Controversy over the importation of drugs into the U.S. is not new.  As we previously discussed, the FDC Act generally prohibits importation of drugs by individuals.  For example, the 1988 Prescription Drug Marketing Act amended the FDC Act to explicitly prohibit the reimportation of drugs manufactured in the U.S by individuals or entities other than manufacturers.  In addition, the 2003 Medicare Prescription Drug, Improvement, and Modernization Act (“MMA”) amended the FDC Act to include provisions authorizing the creation of a system for importation of prescription drugs from Canada, upon certification of safety and cost savings.  The provisions are only effective if the Secretary of Health and Human Services (who has authority over FDA) certifies safety, but that has not yet happened.  In the years since, there have been numerous legislative attempts to permit importation, but each attempt has failed (see, e.g., here).

For its part, FDA has long opposed permitting individual imports of prescription drugs except under very limited conditions.  The Agency has said on many occasions (here, here, and here, for example) that drugs imported for personal use “violate the FDCA because they are either unapproved new drugs[,] labeled incorrectly[,] or dispensed without a valid prescription” and can post safety risks.  FDA has found support for its position on importation in court.  In one case – Vermont v. Leavitt, 405 F. Supp. 2d 466 (D. Vt. 2005) – a federal court concluded that a state plan for importing drugs from Canada violated the FDC Act (see here).

According to PhRMA, et al., Maine’s drug importation law – dubbed an “unauthorized experiment” – “was enacted with the specific goal of encouraging and enabling state health insurers in Maine to direct their customers toward less expensive foreign mail-order pharmaceutical brokers, even though such foreign brokers and the products they supply are not subject to the exacting standards mandated by federal law and so pose serious health risks.”  The state law, say Plaintiffs, violates federal law, and implementation of it would mean that Maine is aiding and abetting violations of federal laws prohibiting unauthorized importation of drug products. 

The alleged violations are numerous.  For example, Plaintiffs say that the state law “violates the Foreign Commerce Clause (U.S. Const. Art I, § 8 cl. 3) because it purports to regulate in an area where the federal government possesses exclusive and plenary power,” and that it is also preempted under the Supremacy Clause (U.S. Const. Art. VI, cl. 2) because federal statutes, like the FDC Act Act and the MMA “occupy the field and the Maine law conflicts with and obstructs compliance with those statutes.”  More directly, the Plaintiffs state that the Maine law “rips a hole in the ‘closed’ pharmaceutical delivery system and thus clearly constitutes an obstacle to full and effective implementation of federal goals.  Most obviously, ‘[b]ecause the [Maine] Act authorizes [foreign pharmaceutical vendors] to engage in conduct that the federal Act forbids, it stands as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress.’”

A hearing date on the Plaintiff’s Motion for Preliminary Injunction has not yet been set.  We’ll keep an eye on the court docket and keep you posted.

By Jeffrey N. Wasserstein and Alexander J. Varond –

On September 11, 2013, Adheris, Inc. (“Adheris”) and the Department of Health and Human Services (“HHS”) filed a joint motion requesting the suspension of Adheris’s motion for a preliminary injunction seeking to prohibit HHS from enforcing its final rule restricting certain paid marketing communications.  We posted on that case earlier this week (see here). 

HHS informed the court that that it intends to issue guidance pertaining “to the final remuneration that would be considered ‘reasonable’ for providing refill reminders or other communications about a drug or biologic currently being prescribed to an individual.”  HHS stated that it expects to issue such guidance by September 23, 2013.  In addition, HHS announced that it decided “not to enforce the restrictions on remuneration refill reminders and other communications about drugs and biologics (as set forth in 45 C.F.R. § 164.501) for a period of 45 days . . . or until November 7, 2013.” 

We will keep you posted on this developing issue.

By Jennifer D. Newberger –

The Food and Drug Administration Safety and Innovation Act (“FDASIA”), signed into law in July 2012, requires the Secretary of Health and Human Services (“HHS”) to “post a report—within 18 months (or by January 2014)—that contains a proposed strategy and recommendations on a risk-based regulatory framework pertaining to health IT, including mobile applications, that promotes innovation, protects patient safety, and avoids regulatory duplication.”  FDASIA § 618.  The three entities tasked with developing this report are the Food and Drug Administration (“FDA”), Office of the National Coordinator for Health Information Technology (“ONC”), and the Federal Communications Commission (“FCC”).  As required by FDASIA, a workgroup was formed to assist those entities in making recommendations with respect to the risk-based regulatory framework.

At the workgroup’s most recent meeting on September 4, 2013, its draft recommendations were accepted by the Health IT Policy Committee, which will pass on the information to FDA, ONC, and FCC for further action.  The report of the workgroup recognizes that while there are risks associated with the failure to adequately regulate certain types of health IT, there would also be negative impacts to regulating it too extensively.  The task of the workgroup, and FDA, ONC, and FCC, is to find a way to strike an appropriate balance.

The workgroup has stated that health IT must be assigned to one of two categories:  “subject to risk-based regulatory framework” or “not subject to risk-based regulatory framework.”  The methods for determining how to assign products to one group or another are not clear.  While the workgroup has made progress in this area, there are still no bright-line rules for determining whether a health IT product should or should not be regulated.

The workgroup recommendations are clear that functionality of the product is a key feature in helping to determine whether a product should be subject to regulation.  One note with respect to regulation:  while ONC and FCC can and do impose certain regulatory requirements on varying types of health IT products, when discussing a “risk-based regulatory framework” we assume that the primary regulator is FDA, since the burdens associated with FDA regulation undoubtedly outweigh those of the other two entities combined.

The workgroup describes a number of factors to consider in determining the appropriate level of regulation, including the complexity of the software; intended users; purpose of the software; severity of potential injury from either appropriate or inappropriate use; likelihood of a risky situation arising; transparency of the software operation, data, and knowledge content sources; and the ability to mitigate a harmful condition.  These factors seem to present a reasonable basis for assessing the level of regulation appropriate to a particular health IT product, and indicate that each product or narrow class of product must be assessed individually to determine the appropriate regulatory framework.  These considerations show that even all products that fit into an overarching product type (e.g., clinical decision support software) should not be regulated the same way. 

Perhaps most helpful, the workgroup includes specific recommendations for FDA, ONC, and FCC to consider in developing its risk-based approach.  Of particular interest is the recommendation that health IT should generally not be subject to FDA premarket requirements, with a few exceptions:  medical device accessories, high-risk clinical decision support, and higher risk software use cases.  The recommendations ask that FDA clearly define accessories and high-risk clinical decision support, a task that, while important, may not be accomplished in a reasonable timeframe, given the difficulty of defining those categories of products.  The recommendations also include a suggestion to develop post-market surveillance of health IT, which is consistent with FDA’s stated intent to improve its post-market device surveillance generally.

The workgroup recommendations appear to present a reasonable framework for FDA in assessing whether and which health IT products should be subject to what level of regulation.  The question is now whether and how the agency will adopt those suggestions, and in what period of time.  Even though a report is due to Congress by January of 2014, it will certainly take longer for FDA to develop and implement a workable approach to health IT regulation.

By Jeffrey N. Wasserstein & Alexander J. Varond –

Several months ago, when HHS released the final HITECH rule, we noted that several of the provisions represented a sea change from prior practice (see our previous post here).  Well, the seas have gotten rougher and one company feels that federal court is the safest port in this storm.  (Have we pushed the metaphor too far?)   On September 5, 2013, Adheris, Inc., a company that provides refill reminder and adherence messaging services, filed a complaint (and accompanying memorandum) seeking injunctive and declaratory relief to prohibit the Department of Health and Human Services from enforcing its final rule restricting certain paid marketing communications.  The final rule is scheduled to go into effect on September 23. 

Adheris’s refill reminder and adherence services

Adheris’s core business model involves sending reminders to customers of participating pharmacies to refill their existing prescriptions before their refills are due, and also preparing and sending letters that encourage customers to adhere to their prescribed treatment regimens.  The letters the company sends include “educational information about the medication, safety information, positive reinforcement to stay on therapy, and a direction to follow the treating physician’s advice.”  Adheris’s complaint states its services have a “verifiably significant impact on the percentage of patients still complying with their prescribed regimens at the end of a program period,” and, therefore, improve patient health.  Although pharmaceutical companies are the sponsors of these refill reminders and adherence messages, Adheris does not disclose protected health information to pharmaceutical manufacturers.  According to the complaint, Adheris derived total revenues of $49 million from these services in 2012. 

HHS’s final rule

Before the Health Information Technology for Economic and Clinical Health Act (HITECH Act), which became law on February 17, 2009, pharmaceutical companies could hire pharmacies and pharmacy chains to remind patients to refill their prescriptions, or recommend switching to alternative therapies.  These types of communications were considered treatment communications and did not require a written authorization from the patient to comply with HIPAA.  As we discussed in our prior blogposts (here and here), Congress muddied the water by calling these communications “health care operations” (a separate category under HIPAA) without addressing treatment communications.  The final rule, issued by HHS’s Office for Civil Rights on January 25, 2013, seeks to implement the HITECH Act and requires patient authorization before using protected health information to direct any paid communication recommending a product or service to the patient, regardless of whether the purpose of the communication is treatment or health care operations. 

One exception provided for in the final rule is that refill reminders, adherence communications, and other communications to patients with current prescriptions for that drug do not require authorization if the payment received by the covered entity is “reasonably related to the covered entity’s cost of making the communication.”  As we noted in our prior post, HHS explained that this means that a covered entity cannot profit from the communication.  If the covered entity receives a financial incentive beyond its cost, it must obtain the patient’s authorization.  Because, as the complaint states, Adheris’s service-related expenses far exceed its permissible remuneration, Adheris’s business is threatened by the rule.

It is unlikely, despite repeated requests from industry, that HHS will issue guidance before its final rule goes into effect.  Without guidance from HHS indicating that refill reminders and adherence communications are permitted even where the payments to a covered entity or its business associate may include a profit component, Adheris stands to lose the lion’s share of its business – the complaint states that “substantially all” of the companies that use Adheris’s services have cancelled or are re-evaluating their programs.  Pharmaceutical companies fear that, under HHS’s final rule, using Adheris’s service may expose them to sanctions and other harm for the use of protected health information for marketing purposes.
                                                                                                                           
The complaint

In its complaint, Adheris states that the final rule (referred to as the “Omnibus Final Rule”) violates the First Amendment.  The following paragraph from the complaint nicely summarizes Adheris’s First Amendment position: 

The Omnibus Final Rule places content- and speaker-based burdens on Adheris’s protected speech.  The Omnibus Final Rule is content-based because its restrictions on refill reminders and adherence communications apply only to communications that “encourage individuals to purchase or use a third party’s product or service.” 78 Fed. Reg. at 5596.  The Omnibus Final Rule is speaker-based because it discriminates against speakers who communicate in exchange for payment from “a third party whose product or service is being described.”  45 C.F.R. § 164.501.  HHS itself has explained that the restrictions of the Omnibus Final Rule are triggered only where financial remuneration is provided in exchange for making the communication from or on behalf of the entity whose product or service is being described, and that identical speech funded by anyone other than the manufacturer of a product or provider of a service is permissible without individual authorization. Id. at 5593.  These content- and speaker-based restrictions have already had a serious chilling effect on Adheris’s refill reminders and adherence communications.

Adheris thus asserts that the rule is subject to heightened scrutiny and violates the First Amendment “because its restrictions on refill reminders and adherence communications do not directly advance a substantial government interest in a proportional manner.”

A decision in this case would shed light on the scope of the Supreme Court’s 2011 decision in Sorrell v. IMS Healthcare Inc., which declared that certain restrictions on the use of prescriber-identifying information were unconstitutional.  We blogged on that decision here.  In Sorrell, the Supreme Court held that Vermont’s Prescription Confidentiality Law, which provided that “absent the prescriber’s consent, prescriber-identifying information may not be sold by pharmacies and similar entities, disclosed by those entities for marketing purposes, or used for marketing by pharmaceutical manufacturers,” violated the First Amendment.  The Court further held that the law imposed a content- and speaker-based restriction on the sale, disclosure, and use of prescriber-identifying information and that, when subjected to heightened scrutiny, Vermont’s justifications were insufficient.

Adheris also advanced an administrative law position and argued that:

The HITECH Act, properly construed, does not limit the pre-existing ability of health care providers to make “treatment” communications that are funded by pharmaceutical manufacturers.  Instead, it only limits their ability to make “health care operations” communications when funded by pharmaceutical manufacturers.  42 U.S.C. § 17936(a)(1).  As HHS has previously recognized, refill reminders and adherence communications are “treatment” communications, not “health care operations” communications, when made by health care providers such as pharmacies, and their business associates, such as Adheris.  67 Fed. Reg. 53187.  The HITECH Act does not change the pre-existing definition of “treatment” [and, therefore, those aspects of the Omnibus Final Rule] restricting refill reminders and adherence communications are not in accordance with law.

This is an interesting next issue in the pharmaceutical industry’s struggle with free speech, and we will keep you posted as the case progresses. 

By Jeffrey K. Shapiro –

In 2012, the U.S. Supreme Court held that agency regulations and enforcement policy violate due process if they do not provide fair notice of what is prohibited or required, or are so standardless that they permit seriously discriminatory enforcement.  FCC v. Fox Television, Inc., 132 S.Ct. 2307 (2012) (“Fox”).  (We previously posted about the case here.)  

There are two ways an agency may fail to provide fair notice.  One is to change its policy and apply it without adequate notice to the regulated community.  Fox, 132 S.Ct. at 2319.  Another is to impose requirements based upon subjective judgment without definitions, narrowing context, or settled legal meanings, thereby forcing the regulated community to guess at what is expected of them.  See id. at 2817; U.S. v. Williams, 128 S.Ct. 1830, 1846 (2008). 

If fair notice is not provided, even a warning letter can violate due process if the public rebuke could cause reputational harm and/or could be considered in determining punishment of a subsequent violation.  Fox, 132 S.Ct. at 2318.

As an example of an apparent FDA violation of due process under Fox, consider the 2011 warning letter to the Animas Corporation.  (We previously blogged about the warning letter here.)

As background, under FDA’s Medical Device Reporting (“MDR”) regulation (21 C.F.R. Part 803), a malfunction must be reported to FDA if is “likely” to cause serious injury or death upon recurrence.  21 C.F.R. § 803.50.  In the preamble to this regulation, FDA explains its interpretation of “likely” as meaning a “not remote” probability of serious injury or death.  60 Fed. Reg. 63,577, 63,585 (Dec. 11, 1995). In 1997 guidance, FDA states that once a malfunction has caused a serious injury or death, the agency will presume it is likely to do so again unless two years pass with no additional serious injuries or deaths.

The Animas Corporation incorporated this two year presumption in its MDR procedure.  FDA’s warning letter acknowledged the 1997 guidance, but indicated that the two year expiration of the presumption was no longer acceptable.  This abrupt departure from written guidance, announced in a warning letter, constitutes a failure to provide fair notice very similar to the agency’s conduct in Fox.  As in that case, the lack of fair notice should be considered a due process violation. 

As another example, consider FDA’s general malfunction reporting requirement.  As noted, a malfunction MDR is reportable if its recurrence is “likely” to cause serious injury or death, which FDA interprets as a “not remote” probability.  In this context, the terms “remote” or “not remote” are probability estimates that, unless applied correctly, can mean the difference between not being required to report and committing a civil and criminal violation by failing to report.

Unfortunately, nowhere in the statute, regulation or FDA guidance is “remote” or “not remote” defined or explained.  Nor does either term have a settled legal meaning.  Certainly, FDA has never pointed the regulatory community toward any such settled meaning. 

A dictionary definition of “remote” is “small in degree” or “slight,” as in slight possibility.  This definition does not indicate what the probability cutoff is, nor does it provide adequate qualitative guidance as to how this term should be applied in the context of MDR reporting.

The fact is, the regulated community has been left to guess what the probability cutoff is that makes a malfunction reportable versus not reportable.  What is “not remote”?  Is it 1 in 100?  1 in 1,000?  1 in 10 thousand?  1 in 10 million?  No one knows for sure.  This uncertainty as to what is required, as the Court held in Fox, is a violation of due process.

One last point – although not necessarily a due process concern: FDA’s two year presumption stretches the statutory term “likely” to the breaking point, resting on the premise that a malfunction is “likely” to cause serious injury or death if even a single serious injury or death has occurred, without regard for the denominator.  A device might be used 100 times annually or 100 million times annually and a single serious injury trips the presumption in both cases.  This result effectively equates “likely” with any probability of occurrence above zero, no matter how vanishingly small, and “remote” with a nullity.  As subjective as these terms are, there are limits, and a court could well find that this interpretation of “likely” exceeds FDA’s statutory authority.

By Allyson B. Mullen –

On August 28, 2013, FDA’s Center for Devices and Radiological Health issued a draft guidance, “The Applicability of Good Laboratory Practice in Premarket Device Submissions: Questions & Answers.”  This new, short guidance restates the requirements of the Good Laboratory Practices (“GLP”), set forth in 21 C.F.R. Part 58, and provides some additional clarification.

By regulation, GLPs must be followed when “conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products.”  21 C.F.R. Part 58.  The guidance clarifies that nonclinical laboratory studies are in vivo and in vitro experiments which prospectively evaluate a test article under laboratory conditions to determine safety.  Draft Guidance at 4.  In addition, for purposes of the draft guidance, a test article is a medical device for human use.  Id. However, the draft guidance acknowledges that in vitro diagnostic device studies typically do not require compliance with GLPs because they generally use human subjects or specimens derived from human subjects; thus, the testing samples are outside the scope of GLPs.  Id. at 7.

In addition, the draft guidance requires companies submitting medical device marketing and research applications, including, without limitation, 510(k)s, PMAs, and IDEs, to indicate whether the applicable studies being submitted have complied with GLPs.  Id. at 5.  In addition, applicants are now required to include a statement within their submissions indicating that the nonclinical laboratory studies in the submission comply with GLPs.  Id. at 5-6.  This requirement applies to all studies regardless of whether they were conducted in the United States or abroad.  Id. at 7.  To some, it may appear as though this statement is a new requirement for medical device submissions.  For example, 21 C.F.R. § 807.87 does not require applicants to address GLP compliance as part of necessary information in a premarket notification.  However, FDA has been requiring such a statement as part of its “Refuse to Accept Policy for 510(k)s” issued at the end of 2012.  FDA, Guidance for Industry and FDA Staff, Refuse to Accept Policy for 510(k)s, 39 (December 2012). (This indicates how a seemingly innocuous checklist can effectuate changes in practice.)

The draft guidance goes on to explain that if the studies have not complied with GLPs, the applicant should indicate such non-compliance and include an explanation.  Draft Guidance at 6.  The draft guidance also suggests information to provide when a study has not complied with GLPs, including, for example, a detailed list of deviations from the regulations, an explanation of how the sponsor limited study bias, and an explanation of how the sponsor ensured the validity and integrity of the data.  Id. at 6. 

Lastly, FDA concludes the draft guidance with questions regarding testing facilities.  The draft guidance indicates that companies performing nonclinical laboratory testing to support device safety are required to allow FDA to inspect the applicable facilities.  Id. at 7.  Further, if a testing establishment does not permit FDA to conduct such an inspection, FDA will not consider study data generated by such facility in support of a device application.  Id. Therefore, applicants should be advised to choose their testing facilities wisely and ensure that such companies are able and willing to endure an FDA inspection.  Overall, this document will mean more companies will need to pay more attention to GLPs than has been the case.

By Kurt R. Karst –      

We present to you the Biosimilars State Legislation Scorecard.  Links are provided to each piece of legislation.  We also give you a word or two on status.  In most cases, a summary of each bill is provided at the linked-to website.  In general, legislation introduced follows the principles advocated for by organizations such as the Biotechnology Industry Organization – specifically: (1) substitution should occur only when the FDA has designated a biologic product as interchangeable; (2) the prescribing physician should be able to prevent substitution; (3) the prescribing physician should be notified of the substitution; (4) the patient, or the patient’s authorized representative, should, at a minimum, be notified of the substitution; and (5) the pharmacist and the physician should keep records of the substitution.

Biosimilars State Legislation Scorecard

 View State Map

Overview

• Five states (Florida, North Dakota, Oregon, Utah, and Virginia) have enacted laws specifying the circumstances under which pharmacists could substitute biosimilars for reference products.  Three of the laws (Oregon, Utah, and Virginia) include a sunset date.
• Legislation has failed to pass in eleven states (Arizona, Arkansas, California, Colorado, Delaware, Illinois, Indiana, Maryland, Mississippi, Texas, and Washington).
• Two states (Arkansas and Indiana) have referred biosimilar legislation to a study committee for further review.
• Legislation is pending in two states (Massachusetts and Pennsylvania)

Alabama (None)  

Alaska (None)    

Arizona

• S.B. 1438 (2013) – Died on Adjournment

Arkansas

• S.B. 149 (2013) – Died on Adjournment (Recommended for study in the Interim Committee on Senate Committee on Public Health, Welfare and Labor)
• S.B. 386 (2013) – Died on Adjournment

California

• S.B. 598 (2013-2014) – Passed Senate and Assembly; Vetoed by Governor (see here)
• A.B. 1139 (2013-2014) – In Committee

Colorado

• H.B. 1121 (2013) – Senate Committee on Health & Human Services Postpone Indefinitely (effectively dead)

Connecticut  (None)

Delaware

• S.B. 118 (2013) – Died on Adjournment

Florida

• H.B. 365 (2013) – Enacted; Chapter No. 2013-102
• S.B. 732 (2013) – Laid on Table; Companion bill passed (H.B. 365)

Georgia (None)  

Hawaii (None)  

Idaho  (None)  

Illinois

• S.B. 1934 (2013) – Referred to Assignments (effectively dead)

Indiana

• S.B. 272 (2013) – Died on Adjournment
• H.B. 1315 (2013) – Enacted without biosimilar provisions
• Senate Resolution 112 (2013) – Adopted voice vote

Iowa (None)  

Kansas (None)  

Kentucky (None)  

Louisiana (None)  

Maine (None)  

Maryland

• S.B. 781 (2013) – Died on Adjournment

Massachusetts

• H.B. 1927 (2013) – Pending; Joint Public Health Committee (Related Bills: H.B. 3734 and H.B. 3667)

Michigan (None)  

Minnesota (None)  

Mississippi

• S.B. 2085 (2013) – Died on Adjournment
• H.B. 1387 (2013) – Died on Adjournment

Missouri (None)  

Montana (None)  

Nebraska (None)  

Nevada (None)

• The Generic Pharmaceutical Association has identified Nevada as a state in which legislation was “killed”; however, we are not aware of any legislation introduced.

New Hampshire (None)  

New Jersey (None)  

New Mexico (None)  

New York (None)  

North Carolina (None)  

North Dakota

• S.B. 2190 (2013) – Enacted; Chapter 19-02.1

Ohio (None)  

Oklahoma (None)  

Oregon

• S.B. 460 (2013) – Enacted; Chapter 342, 2013 Laws
• H.B. 2705 (2013) – Died on Adjournment

Pennsylvania

• S.B. 405 (2013-2014) – Pending; Senate Public Health & Welfare Committee
• H.B. 746 (2013-2014) – Pending; House Health Committee

Rhode Island (None)  

South Carolina (None)

South Dakota (None)  

Tennessee (None)  

Texas 

• S.B. 190 (2013-2014) – Died on Adjournment
• H.B. 542 (2013-2014) – Died on Adjournment

Utah

• S.B. 78 (2013) – Enacted

Vermont (None)  

Virginia

• S.B. 1285 (2013) – Enacted; Chapter 544
• H.B. 1422 (2013) – Enacted; Chapter 412

Washington

• S.B. 5469 (2013-2014) – Pending (1/2014: by resolution, reintroduced and retained in present status) 
• H.B. 1528 (2013-2014) – Pending (1/2014: by resolution, reintroduced and retained in present status)

West Virginia (None)  

Wisconsin (None)  

Wyoming (None)  

This post, originally posted to the FDA Law Blog on September 4, 2013, opened as follows:

With the news last week that the Assembly in the bellwether state of California passed a bill – S.B. 598 – concerning the substitution of biosimilar and interchangeable biosimilar products for their brand-name reference product counterparts, and with bills currently passed, failed or pending in other states (and the likelihood that legislation will continue to be pushed in several states for some time to come), we thought it was high time to put together a new scorecard – the Biosimilars State Legislation Scorecard – to keep tabs on such legislation.  Once we get a chance, we’ll add a direct link to this new scorecard, along with any others we have created (such as our popular Generic Drug Labeling Carve-Out Citizen Petition Scorecard) to the FDA Law Blog website where our various trackers (Citizen Petition Tracker, Legislation Tracker, 180-Day Exclusivity Tracker, and REMS Tracker) are linked to as well.  We’ll update the scorecards periodically and post separately on items that are particularly newsworthy.

(UPDATE: On September 4th, the California Senate voted to pass S.B. 598 – see here.  The Generic Pharmaceutical Association subsequently issued a press release – as well as a bunch of additional materials – urging Governor Jerry Brown to veto S.B. 598.)

State legislation addressing biosimilar substitution issues has been particularly controversial (see our previous post here).  Indeed, after the California Assembly’s passage of S.B. 598, an FDA spokesperson reiterated concerns previously expressed by FDA Commissioner Margaret Hamburg that “[e]fforts to undermine trust in these products are worrisome and represent a disservice to patients who could benefit from these lower-cost treatments.” 

Others might say that state legislative efforts to address substitution are premature.  After all, FDA has not yet even approved (let alone filed) a Section 351(k) biosimilar application submitted pursuant to the procedures established by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) and discussed in draft FDA guidance (see our previous post here).  Then there’s that April 2012 citizen petition (Docket No. FDA-2012-P-0317) submitted by Abbott Laboratories requesting that FDA not accept for filing, file, approve, or even discuss with any company any application or any investigational new drug application for any biosimilar that cites as its reference product any product for which the BLA was submitted to FDA prior to the date on which the BPCIA was enacted (see our previous post here).  FDA has not yet substantively responded to the petition; however, query whether FDA’s meetings with biosimilar sponsors (see the next paragraph), if they concern pre-BPCIA products, is a constructive denial of the petition (at least in part).  (And, as an aside, there’s ongoing debate about including a 12-year period of exclusivity for biological products in the Trans-Pacific Partnership agreement chapter on intellectual property rights – see our previous posts here, here, here and here, and a recent letter and paper from the Biotechnology Industry Organization here and here.) 

Despite efforts that some have alleged are intended to stymie the nascent biosimilars industry, interest in developing biosimilars remains high.  According to one report, FDA “continues to meet with sponsors interested in developing biosimilar products,” and as of the last week of August 2013, the Agency “had received 57 meeting requests for an initial meeting to discuss biosimilar development programs for 13 different reference products and held 47 initial meetings with sponsors.” 

By Ricardo Carvajal –

In a number of recent class actions, a central allegation has been that a marketer misled consumers by labeling as “all natural” a food that contains a genetically modified organism ("GMO").  Defendants usually invoke the doctrine of primary jurisdiction in an attempt to persuade the court to dismiss or stay the proceedings pending a referral of the issue to FDA.  In the last few weeks, at least two courts have acquiesced.  However, that budding winning streak came to an end last week with this decision out of the Eastern District of New York. 

Finding “unpersuasive” the reasons cited by other courts for invoking primary jurisdiction, the court opined that the issues of fact in the case are “within the conventional experience of judges,” turning as they do on whether the challenged claims could mislead a reasonable consumer.  Further, the court noted that any formal definition of “natural” by FDA would not dispose of the state law claims at issue.  Finally, the court stated that “FDA is unlikely to respond in a timely manner” to the court’s referral, citing as precedents FDA’s refusal to opine on whether high fructose corn syrup is “natural,” and the nine years the agency took to define “gluten-free.”

This is not the first court to decline to invoke primary jurisdiction under similar circumstances.  Nonetheless, by virtue of following on the heels of decisions more favorable to defense counsel, this decision is likely to be especially unwelcome. 

By Kurt R. Karst –      

Last week, Judge Richard Seeborg of the U.S. District Court for the Northern District of California issued an 11-page ruling in a lawsuit filed in December 2012 by the Pharmaceutical Research and Manufacturers of America (“PhRMA”), the Biotechnology Industry Organization (“BIO”), and the Generic Pharmaceutical Association (“GPhA”) challenging a “first in the nation” Safe Drug Disposal Ordinance passed by the Alameda County, California Board of Supervisors in July 2012, and that is slated to go into effect later this year.  In ruling on Cross-Motions for Summary Judgment (here and here; reply briefs here and here), Judge Seeborg refused to find that the Ordinance is a per se violation of the Commerce Clause of the U.S. Constitution.

As we previously reported, the Alameda Safe Drug Disposal Ordinance, like other extended producer responsibility (or “manufacturer take-back”) ordinances and laws, place the primary responsibility for end-of-life management of products on the manufacturers of the products.  The general intent of such laws is apparently to prevent unintentional poisonings and the improper disposal of products into the water treatment system.  

The Alameda Ordinance requires “producers” of “covered drugs” to operate take-back programs after submitting a plan to the county’s Department of Environmental Health.  Such operation includes the creation, administration, promotion, and payment of the program (including the payment of Alamada County’s costs to administer and enforce the Ordinance).  A “covered drug” is defined in the Ordinance generally to include “all drugs as defined in 21 U.S.C. § 321(g)(l) of the Federal Food, Drug and Cosmetic Act,” “including both brand name and Generic Drugs.”  There are several exemptions, however, including exemptions for “nonprescription drugs,” vitamins, supplements, herbal remedies, cosmetics, soap, detergent, “household cleaning products,” biological products for which the producer already provides a take-back program, and certain “[p]et pesticide products.”  Every producer’s take-back program – which may be run by an individual producer or funded by a group of covered producers under a “product stewardship organization” – must accept and dispose of all covered drugs received, no matter who manufactured the drugs, unless excused from that comprehensive obligation by the Department of Environmental Health.  The collection, shipping, and destruction of collected items must comply with all state and federal laws.  A violation of the Ordinance may result in a civil penalty up to $1,000 per day.

PhRMA, BIO, and GPhA alleged in their pleadings that the Alameda Ordinance is a per se violation of the Commerce Clause of the U.S. Constitution, and, in particular, the dormant Commerce Clause, under state and local governments may not enact regulations that unduly interfere with interstate commerce.  According to the trade groups:

The Ordinance represents a per se violation of the Commerce Clause for three distinct reasons.  First, it directly regulates and burdens interstate commerce and its primary purpose and clear effect is to shift the costs of a local regulatory program directly onto interstate commerce and out-of-county consumers.  Second, the Ordinance discriminates against interstate commerce by targeting interstate commerce and products delivered from outside the County for burdens.  Finally, the Ordinance favors local interests by deliberately shifting costs away from local consumers and taxpayers and onto drug manufacturers and pharmaceutical consumers nationwide.

The trade groups also alleged that even if the Ordinance is not a per se infringement of the Commerce Clause it is still unconstitutional, because “[i]ts burden on interstate commerce is inherently excessive because the County could accomplish all of the purported benefits of a take-back program without any interstate burden,” such as “by developing and conducting the take-back program through government officials paid by the local taxpayers or consumers served by the program.” 

Using the U.S. Supreme Court’s two-tiered approach, laid out in Healy v. Beer Institute, 491 U.S. 324 (1989) and Brown–Forman Distillers Corp. v. New York State Liquor Auth., 476 U.S. 573 (1986), to analyze whether a state or local economic regulation violates the dormant Commerce Clause, and the application of that two-tiered approach by the U.S. Court of Appeals for the Ninth Circuit in National Collegiate Athletic Ass’n v. Miller, 10 F.3d 633 (9th Cir. 1993), where the Ninth Circuit explained that a local regulation will be found to be a per se violation of the dormant Commerce Clause if it “1) directly regulates interstate commerce; 2) discriminates against interstate commerce; or 3) favors in-state economic interests over out-of-state interests,” Judge Seeborg ruled that the Alameda Ordinance does not violate the dormant Commerce Clause.

Starting the with prongs 2 and 3 – i.e., the “discriminatory prongs” – Judge Seeborg said that the Alameda Ordinance cannot be invalidated as per se improper under either of these  prongs.

Here, plaintiffs contend that the Ordinance is a per se violation of the clause under any and all of the three prongs.  As opposed to the first prong, the second and third prongs both contain an element of discrimination—i.e., that a challenged regulation favors local commerce over interstate commerce, or in-state entities over out-of-state entities.  Plaintiffs argue there is such a discriminatory effect here because costs that would ordinarily be borne primarily by Alameda County—and hence its own taxpayers—are being shifted on to the community of producers as a whole, most of whom are based elsewhere. . . . 

The “discrimination” on which plaintiffs would rely, is indisputably not being visited on out-of-state producers as a means of favoring in-state producers. . . .   In the absence of “differential treatment favoring local entities over substantially similar out-of-state interests,” the kind of discrimination potentially prohibited by the dormant Commerce Clause is not implicated.  Accordingly, the Ordinance cannot be invalidated as per se improper under either the second or third prongs.

Moving on to prong one, under which a regulation may be per se invalid if it “directly regulates interstate commerce,” Judge Seeborg found that the Alameda Ordinance “is not specifically directed at regulating interstate organizations and has no remotely similar consequence to any conduct occurring outside county borders,” and therefore, cannot be found to be violative of the Commerce Clause.  According to the court:

The Ordinance applies to producers who elect to sell their products within Alameda County, regardless of where the producers are based or the product originates.  Nothing in the structure of the Ordinance targets producers on the basis of their location—they are being required to participate in providing take-back programs because they sell prescription drugs in the county, not because they are out-of-state actors.  Nothing in the Ordinance will require, as a practical matter, any producer to alter its manner of doing business in any jurisdiction outside Alameda County, although producers will be free to use programs that they may already be using elsewhere, provided they meet the standards of the Ordinance.

Judge Seeborg was also not convinced by arguments that the Alameda Ordinance is equivalent to a tariff, saying that the Ordinance shares none of the salient features of a tariff.  Moreover, wrote Judge Seeborg, “the happenstance that most producers of prescription drugs are located outside Alameda County is insufficient to transform what is fundamentally a local measure into one that could be found to burden interstate commerce impermissibly.”

The win for Alameda County might reinvigorate other similar initiatives around the country.  Indeed, legislation has been introduced in California – S.B. 727 – that would create a statewide take-back program.  King County, Washington is also in the process of enacting a drug take-back program, called the Secure Medicine Return Rule and Regulation.  In addition, it is possible that efforts to establish a nationwide drug take-back program will now proceed.  In 2011, Representative Loiuse Slaughter (D-NY) introduced H.R. 2939, the Pharmaceutical Stewardship Act of 2011.  The bill did not gain much traction at the time and died, but could resurface in the future. 

It is unclear whether any of the trade groups will appeal Judge Seeborg’s ruling, or whether a challenge to the King County, Washington regulation will be mounted.  We’ll be keeping our eyes open for developments.

By Ricardo Carvajal –

Is the word “source” (just “source” – not “good source” or “excellent source”) a nutrient content claim?  FDA seems to think so, as reflected in a paragraph in this warning letter that escaped our attention when it issued in March 2011.  FDA stated:

Your Organic Clover Sprouts product label bears the claim “Phytoestrogen Source[.]” Your webpage entitled “Sprouts, The Miracle Food! – Rich in Vitamins, Minerals and Phytochemicals” bears the claim “Alfalfa sprouts are one of our finest food sources of . . . saponin.” These claims are nutrient content claims subject to section 403(r)(1)(A) of the Act because they characterize the level of nutrients of a type required to be in nutrition labeling (phytoestrogen and saponin) in your products by use of the term “source.” Under section 403(r)(2)(A) of the Act, nutrient content claims may be made only if the characterization of the level made in the claim uses terms which are defined by regulation. However, FDA has not defined the characterization “source” by regulation. Therefore, this characterization may not be used in nutrient content claims.

The issue resurfaced in class action litigation via a couple of recent California federal district court decisions filed on the same day.  In Clancy v. Bromley Tea Co., Plaintiff alleges that Defendant made unlawful and deceptive claims for certain tea products.  Defendant argued preemption on the ground that Plaintiff sought to impose requirements greater than those imposed under the FDCA and its implementing regulations.  Defendant argued that the claim “source of” (as in “natural source of antioxidants”) was not defined as characterizing the level of a nutrient, and therefore was not prohibited under federal law.  The court agreed that the claim was undefined, but pointed to the above-quoted warning letter’s conclusion that “source” claims are nutrient content claims – albeit ones that are undefined – and refused to dismiss Plaintiff’s claim as preempted.

In Trazo et al. v. Nestle USA, Inc., Plaintiffs allege that Defendant makes false and misleading claims for certain of its products.  As in Clancy, Defendant raised preemption.  Defendant argued that its product labels claimed only that the products were a “source” of antioxidants – not a “good source.”  Therefore, the requirements applicable to “good source” nutrient content claims were inapplicable to Defendant’s claims.  The court agreed: “To the extent that Plaintiffs seek to regulate the term ‘source’ in the same manner as ‘good source,’ going beyond the boundaries of the regulation, this claim is preempted.”

Perhaps these cases illustrate how the technical nature of food labeling regulations, and differences in how counsel interpret those regulations and frame the issues for the court, can lead to divergent results.

By Kurt R. Karst –      

Public shaming has been used as a type of punishment for centuries and has taken on many forms.  In Colonial America, for example, physical forms of shaming and humiliation like stocks and pillory were common.  And who could forget Nathaniel Hawthorne’s The Scarlet Letter, in which a fictional seventeenth century Hester Prynne was forced to wear a scarlet “A” on her chest to show her crime of adultery. 

Public shaming is still used in contemporary America – even in the food and drug space.  For example, back in 2007, the CEO of a medical device company agreed to wear, as part of a plea agreement for marketing an unapproved device, a yellow shirt bearing the inscription “I WAS CONVICTED OF VIOLATING THE FDCA” (see here and here).  Earlier this week, in fact, FDA, as part of changes to the law made by the 2012 FDA Safety and Innovation Act (“FDASIA”), began posting on the Agency’s website redacted correspondence concerning drug and biologic sponsors’ non-compliance with the Pediatric Research Equity Act (see here).  There also seems to be a growing trend in FDA responses to certain citizen petitions alleging misuse of the petitioning process to delay generic drug competition.

By way of background, the FDC Act was amended by the 2007 FDA Amendments Act (“FDAAA”), and again by the 2012 FDASIA, to add Section 505(q), titled “Petitions and Civil Actions Regarding Approval of Certain Applications.”  FDC Act § 505(q) is intended to prevent the citizen petition process from being used to delay approval of pending ANDAs, 505(b)(2) applications and 351(k) biosimilar applications, and says that FDA shall not delay approval of a pending application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  FDA must respond to such petitions within 150 days of receipt and report to Congress each year on the Agency’s implementation of the statute.  FDA’s latest report to Congress is available here.  

One provision in Section 505(q) – FDC Act § 505(q)(E) – allows FDA to deny a petition based on intent to delay.  It states:

If the Secretary determines that a petition or a supplement to the petition was submitted with the primary purpose of delaying the approval of an application and the petition does not on its face raise valid scientific or regulatory issues, the Secretary may deny the petition at any point based on such determination.  The Secretary may issue guidance to describe the factors that will be used to determine under this subparagraph whether a petition is submitted with the primary purpose of delaying the approval of an application.

FDA has not yet used this provision to summarily deny a citizen petition.  In guidance (Docket No. FDA-2009-D-0008) and in a proposed rule to implement FDC Act § 505(q), FDA has avoided discussing the provision.  In both documents, FDA merely states that the Agency may issue guidance with respect to the factors it would consider in making such a determination.  Presumably, FDA is hesitant to divine a petitioner’s intent to delay.  Indeed, in a 2009 report to Congress, FDA commented that “[a]lthough a petition may not raise persuasive scientific or regulatory issues when those issues have been reviewed by FDA, a petition can easily raise valid scientific or regulatory issues.”  In that report, FDA acknowledges that the Agency “could issue guidances describing petitions filed under certain circumstances that would give rise to the presumption that a petition was filed with the primary purpose to delay approval” of an application, but says that “given the statutory standard in 505(q)(1)(E) for summary denial of petitions, the agency does not believe issuing a guidance on delay would allow the summary denial of petitions under this provision.  Without any significant impediment to filing a late petition, such as summary denial, it may be difficult to encourage the early submission of petitions under 505(q).”  Moreover, FDA commented that if the Agency “was able to issue a summary denial or brief response to a petition, the agency would still want to have an adequate internal record that the merits of any relevant substantive issues had been addressed in the consideration of affected applications.”

Given FDA’s position with respect to the implementation of FDC Act § 505(q)(E), and presumably in an effort to “encourage the early submission of petitions under 505(q),” the Agency appears to have turned to a different mechanism: public shaming. 

The first instance of a recent citizen petition public shaming that comes to mind is FDA’s April 9, 2012 denial of a 2006 petition (Docket No. FDA-2006-P-0007) – a non-505(q) petition because it was submitted to FDA before the enactment of FDAAA in 2007 – concerning the approval of generic Vancomycin HCl Capsules.  Buried in the 87-page petition response at pages 74-75, FDA comments:

FDA notes that you have petitioned FDA in a fashion analogous to interrogatories in civil discovery, demanding answers to more than 170 individual factual questions related to the Agency's development of the vancomycin bioequivalence recommendation.  This is an improper use of the citizen petition process.  The petition procedure enables parties to “petition the Commissioner to issue, amend, or revoke a regulation or order, or to take or refrain from taking any other fonn of administrative action.”  “Administrative action” is defined in relevant part as “evcry act, including the refusal or failure to act, involved in the administration of any law by the Commissioner.”  The “action” you request the Agency to take here – to respond directly to factual questions regarding certain Agency decisions – is secondary to your underlying challenge of those decisions.  In the interest of a thorough evaluation of the many issues you raise, however, FDA has incorporated these questions and the events referenced therein in its consideration of your petition.

FDA was more bold in a February 2013 denial of a September 2012 505(q) citizen petition (Docket No. FDA-2012-P-1028) concerning the approval of generic Buprenorphine drug products.  In response to comments alleging anticompetitive conduct, FDA said that the Agency would not deny the petition pursuant to FDC Act § 505(q)(E).  Instead, “[t]he Agency has, however, referred this matter to the Federal Trade Commission, which has the administrative tools and the expertise to investigate and address anticompetitive business practices.”

That brings us to the most recent allegations lodged by FDA – the boldest yet that we have seen – against a petitioner.   In an August 2013 denial of a March 2013 petition (Docket No. FDA-2013-P-0247) concerning the approval of generic Zoledronic Acid Injection, in a section titled “III.  Misuse of Petition Process,” FDA comments:

This Petition represents a particularly egregious misuse of the FDA citizen petition process for what appears to be the purpose of delaying generic competition.  Novartis first submitted an incomplete version of this Petition on Thursday, February 28, 2013, and submitted the corrected version on Friday, March 1,2013, just one day before the pediatric exclusivity attaching to the ‘130 patent expired, which would have allowed approval of tentatively approved ANDAs on Monday, March 4,2013.

FDA carefully evaluates assertions that the approval of a drug will put patients at risk, and Novartis’s claims required consultation with experts within the Agency.  That process resulted in some minor changes to the proposed labeling of the generic products, but, as this Petition response demonstrates, the assertions in the Petition were found to be without merit.  We note that the 25-day delay in approval of the AND As was entirely the result of the timing of Novartis’s Petition, rather than its merits.  Had the Petition been filed, for example, even one month before the date on which pediatric exclusivity associated with the ‘130 patent expired, these issues would have been resolved in time for approval of the ANDAs on that date.  Moreover, according to the certification to the Petition, the information on which the Petition was based became known to Novartis on or about November 8, 2011 (Petition at 7).  Had the Petition been submitted within a reasonable time after that date, the Agency could have considered its merits and taken final agency action within the time period contemplated under section 505(q) of the FD&C Act, and resolved the matter before ANDAs were eligible for approval.

FDA’s allegations have drawn a sharp rebuke from Novartis in the form of an August 23rd Request to Supplement the Record and Petition for Reconsideration.  Novartis requests FDA “to strike Section III in its entirety or, in the alternative, to modify any conclusions in Section III based on mistaken inferences resting on prior incomplete information regarding the Petition’s timing.”  According to the petition, “[e]ven if FDA believes that Novartis should have submitted its petition earlier, and wishes to encourage other sponsors to do so, Novartis asks that FDA delete the statements that Novartis ‘misuse[d]’ the petition process, as that and related statements are contrary to the evidence.”

FDA’s decisions not to use FDC Act § 505(q)(E) to deny a petition, but to instead comment on or otherwise allege misuse of the citizen petition process, could be an effort by the Agency to pass the buck on enforcement . . .  and not just to the Federal Trade Commission.  Indeed, FDA’s statements could be used in private litigation to support allegations that companies violated the antitrust laws (see here). 

By Kurt R. Karst –      

In June 2013, FDA announced the issuance of a draft guidance document, titled “Expedited Programs for Serious Conditions – Drugs and Biologics” (Docket No. FDA-2013-D-0575).  As we previously reported, the draft guidance, as well as a related Manual of Policies and Procedures, provides important insight into FDA’s breakthrough therapy designation program, which was created by the 2012 FDA Safety and Innovation Act (“FDASIA”) (see our summary here).  But the draft guidance does much more than that.  It serves as a de facto desktop reference for FDA’s four expedited programs: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation. 

Section VII.C. of the draft guidance, titled “Evidentiary Criteria for Accelerated Approval,” describes several factors FDA weighs in assessing whether the available evidence is sufficient to allow the Agency to conclude that a proposed “surrogate endpoint” – i.e., an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms – is “reasonably likely to predict clinical benefit” and thereby constitute the basis for accelerated marketing approval, which is often referred to as a “Subpart H” approval.  This section of the draft guidance has not been the focus of much attention since the draft guidance was published.  But that could change with a recent analysis submitted as a comment to FDA on the draft guidance.

The analysis, conducted by Hyman, Phelps & McNamara, P.C.’s Frank J. Sasinowski and Alexander J. Varond, notes that the importance of Subpart H as a regulatory innovation and vehicle for providing patients suffering with serious and often rare diseases where there is inadequate available therapy has taken on significant added importance with two recent milestones.  First, FDASIA revised the statutory provisions of Subpart H to “facilitate somewhat broader use of accelerated approval to expedite patient access to important treatments for serious conditions[,] . . . provide additional flexibility[,] . . . provide clarification concerning the use of clinical endpoints[,] . . . [and] make clear that FDA has the authority to consider pharmacologic or other evidence . . . in determining whether an endpoint is reasonably likely to predict clinical benefit,” according to FDA.  Second, on September 25, 2012, the President’s Council of Advisors on Science and Technology released a report, titled “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation” (see our previous post here), that addresses the complexities of developing new medicines for Americans and that instructs FDA to expand the use of its Subpart H authority.  

According to the comment, “[t]he linchpin of the FDA Subpart H system was, and is, the surrogate endpoint that is ‘reasonably likely to predict clinical benefit’ (or intermediate clinical endpoint that is ‘reasonably likely to predict ultimate clinical benefit.’).”  But “[t]here have been many misunderstandings of this Subpart H system,” say the comments. 

Some have thought that it meant that the quantum or quality of evidence was somehow reduced, and the statutory requirement of “standard evidence of effectiveness” was in some way, in whole or in part, skirted or deferred.  While this seems not to be the case in statute, regulation or policy, the other extreme is just as likely not to “serve the public well” (quoting the Presidential Report at p. 59).  The other extreme is the view that unless the surrogate is validated, it cannot be relied upon in a Subpart H approval decision.  This is sometimes found in reviews that conclude that the Sponsor’s evidence failed to satisfy the standard of approval because the trial(s) attempted prove both the drug’s effect on the surrogate as well as on the clinical benefit and the clinical benefit showing was not robust enough to validate the drug’s effect on the surrogate.

Between these two extremes, there has existed a gaping hole that has begged to be addressed for nearly 3 decades and that is – what is the regulatory and evidentiary foundation for FDA’s determination that an unvalidated surrogate is capable of supporting a Subpart H approval.  Now the FDA in its June 2013 Draft Guidance has tackled this and laid out clearly discrete principles and factors.

With that backdrop, the analysis looks at each of the 19 Subpart H approvals (that are not for AIDS or cancer) in order to discern the types and patterns of evidence that FDA has found adequate to be the foundation for those Subpart H approval precedents from 1992, when the accelerated approval regulations were promulgated, to the present.  Each of the 19 Subpart H approval precedents is “scored” based on the factors laid out in Section VII.C. of FDA’s draft guidance according to the weights and scoring of the comment authors.  (The authors’ methods for conducting the analysis are laid out in the comment.) 

In the end, the comment authors conclude that FDA has shown great flexibility in applying its Subpart H standards to therapies under its review.  For example, “although most of the time a clear understanding of the pathophysiology of the disease process will facilitate access to reliance upon a surrogate, the absence of a complete understanding of the disease process or even the existence of a relatively weak understanding of the disease process is not, in and of itself, incompatible with Subpart H,” write the comment authors. 

FDA’s penchant for flexible application of evidentiary standards for drug approval not only exists with respect to Subpart H approvals, but in other contexts as well.  As we previously reported, a 2011 report authored by Mr. Sasinowski concluded that “two of every three orphan drugs approved show FDA’s historic flexibility in its review of effectiveness data on orphan drug therapies.” 

By Kurt R. Karst –      

Earlier this year, FDA’s Dallas District Office issued a Warning Letter to Sovereign Pharmaceuticals, LLC (“Sovereign”), a pharmaceutical contract manufacturing facility located in Fort Worth, Texas, containing a rather interesting – and quite perplexing – violation tagged under the heading “Unapproved and/or Misbranded Drug Products.”  Specifically, with respect to Sovereign’s Over-the-Counter (“OTC”) cough/cold drug products Certuss, Certuss-D, and Trexbrom, FDA’s Warning Letter states: 

Certuss, Certuss-D, and Trexbrom contain the active ingredient chlophedianol, which is an acceptable antitussive active ingredient.  However, chlophedianol cannot be combined with the particular active ingredients phenylephrine (in the case of Trexbrom) or guaifenesin (in the cases of Certuss and Certuss-D) because there is no way to write adequate directions for use that would meet the dosing direction and dosage limit requirements for each individual active ingredient (21 CFR 341.40).  For example, the monograph states phenylephrine and guaifenesin are to be dosed every 4 hours (21 CFR 341.80(d)(1) and 21 CFR 341.78(d), respectively) and chlophedianol is to be dosed every 6 to 8 hours (21 CFR 341.74 (d)(1)).  Therefore, if chlophedianol is used in combination with either phenylephrine or guaifenesin, there is no way to write directions for use with a dosing interval that works for each of these active ingredients. [(Emphasis added)]

FDA’s statements above that OTC drug products with active ingredient combinations that appear to be permitted under a monograph, but that contain conflicting dosing directions, cannot be lawfully marketed caught our attention because the Agency has said otherwise for decades.  Indeed, FDA’s OTC drug regulations require that when the time intervals for active ingredients conflict, the manufacturer should choose directions for the combination product that do not exceed any maximum dosage limits.  Specifically, FDA’s regulation at 21 C.F.R. § 341.85(d), titled “Labeling of permitted combinations of active ingredients,” and included in the Agency’s OTC drug monograph for cold, cough, allergy, bronchodilator, and antiasthmatic drug products, states:

When the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.

Similar statements appear in other OTC drug monographs at 21 C.F.R. § 333.160(d) (topical antimicrobial drug products), § 346.52(d) (anorectal drug products), § 347.60(d) (skin protectant drug products), § 349.79(d) ophthalmic drug products ), § 352.60(d) (sunscreen drug products), and § 358.760(d) (dandruff drug products).  

What each regulation says in essence is that when the directions for use of an OTC combination drug product results in a conflict in time intervals, the directions should be written to ensure that the maximum dosage limits established under the applicable monograph for the individual ingredients are not exceeded.

Furthermore, with respect to cough/cold drug products, such as those at issue in the Sovereign Warning Letter, FDA has discussed and elaborated on in preambles and policy statements OTC drug product combinations with conflicting directions.  For example, FDA has stated:

The agency has also identified conflicts in that portion of the directions that deal with the lower age limits of use for children’s dosages for some of the combinations identified in § 341.40.  For example, the directions for an OTC antihistamine advises that a doctor be consulted for use in children under 6 years of age, while OTC analgesic-antipyretic ingredients may be given to a child as young as 2 years of age without consulting a doctor.  The agency is concerned that when a combination product containing analgesic-antipyretic and cough-cold ingredients is labeled for use in children of a particular age group that each individual ingredient be generally recognized as safe for use in that particular age group.  Therefore, the agency is proposing that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.  Thus, in the above example, the product can be labeled only for use in children 6 years of age and over. [(53 Fed. Reg. 30,522, 30,554 (Aug. 12, 1988))]

. . . and

The agency believes that an OTC drug product containing diphenhydramine citrate or diphenhydramine hydrochloride that is labeled both as an antitussive and an antihistamine should conform to the same labeling restrictions that apply to combination drug products containing a different antitussive and antihistamine ingredient.  In the tentative final monograph for OTC cough-cold combination drug products, the agency proposed that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph (53 FR 30522 at 30554).  Therefore, when diphenhydramine citrate or diphenhydramine hydrochloride is labeled for both antitussive and antihistamine use, the limiting factor for directions for use for both the dosage amount and dosing interval for OTC labeling is the antitussive dosage in Sec. 341.74(d)(1)(iv) and (d)(I)(v).  However, the limiting factor for directions for use for professional labeling is the antihistamine dosage in Sec. 341.90(j) and (k) (21 CFR 341.90(j) and (k), respectively.  As noted above, the Panel believed that the interests of consumers are best served by exposing the user of OTC drug products to the smallest number of ingredients possible at the lowest possible dosage consistent with a satisfactory level of effectiveness. [(60 Fed. Reg. at 10,286, 10,290 (Feb. 23,1995))]

. . . and

The antitussive directions are 5 to 10 mg every hour as needed, while the anesthetic/analgesic directions are 2 to 20 mg every 2 hours.  The agency’s policy is that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for a combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph (53 FR 30522 at 30554).  This policy also applies when an ingredient is being labeled for dual use in a single product.  Under this rationale, the every 2 hours directions for anesthetic/analgesic use would be controlling.  The problem arises, however, that amounts of menthol from 2 mg up to 5 mg are not monograph dosages for menthol for antitussive use.  Therefore, the agency has determined that appropriate directions for menthol when labeled for both uses in a product is 5 to 10 mg every 2 hours.  [(67 Fed. Reg. 78,158, 78,162 (Dec. 23, 2002))]

Given all of this history, why then would FDA tell Sovereign that there is no way to write adequate directions for use for the combination cough/cold OTC drug products it contract manufacturers that would meet the dosing direction and dosage limit requirements for each individual active ingredient under the monograph?  That’s the truly perplexing part of this story.  Perhaps FDA made the statements in error and has not yet acted to correct them.  If that’s the case, then the uncorrected Warning Letter sends the wrong – indeed, incorrect – message to the OTC drug industry.  Or perhaps there’s more to the story and something is brewing at FDA.  But if that were the case, then one might have expected to see more on the topic over the past 8 months.  So we’re left scratching our heads.

By Kurt R. Karst –    

If you wait around long enough, almost any scenario feasible under the FDC Act with respect to Hatch-Waxman exclusivity is bound to happen.  Nearly six years after the September 2007 enactment of the FDA Amendments Act (“FDAAA”), one company’s drug product has finally qualified for the election at FDC Act § 505(u), and the company elected for its drug product to be treated as a “new active ingredient” and was granted 5-year New Chemical Entity (“NCE”) exclusivity.  Specifically, we’re talking about FETZIMA (levomilnacipran) Extended-release Capsules, 20 mg, 40 mg, 80 mg and 120 mg, which FDA approved on July 25, 2013 under NDA No. 204168 for Major Depressive Disorder (“MDD”).  Levomilnacipran is a stereoisomer – an enantiomer – of the previously approved racemate, milnacipran HCl.  FDA approved milnacipran as SAVELLA Tablets, 12.5 mg, 25 mg, 50 mg, and 100 mg, under NDA No. 022256 on January 14, 2009.  SAVELLA is approved for the management of fibromyalgia.

By way of background, a molecule may exist in two “mirror image” forms.  The two forms of such molecules are called “enantiomers.”  A “racemate” is a mixture of two enantiomers in equal amounts.   For some drugs, one enantiomer may have markedly different pharmacological effects than the other.  (For more on stereoisomers, see FDA’s 1992 policy statement, Development of New Stereoisomeric Drugs.)  In promulgating rules implenenting the Hatch-Waxman Amendments, FDA had initially taken the position that the Agency would not grant NCE exclusivity for an enantiomer when the racemate had previously been approved.  See 59 Fed. Reg. 50,338, 50,359 (Oct. 3, 1994).  In January 1997, FDA announced in a Federal Register notice that the Agency was reconsidering that position and requested comments.  Years went by, however, and FDA remained mum on where things stood with the potential reconsideration.

When FDA did not act, Congress in the 2007 FDAAA passed a change in the law, reauthorized in the 2012 FDA Safety and Innovation Act, that permits sponsors of enantiomers to elect to claim “new active ingredient” status and be awarded 5-year NCE exclusivity when new indications are developed for the enantiomers.  Specifically, Congress amended the statute to add FDC Act § 505(u), titled “Certain Drugs Containing Single Enantiomers.”  There are several limitations that come with such an election.  The enantiomer drug cannot rely on studies of the racemate, and approval must be based on full reports of new clinical investigations.  In addition, the sponsor agrees not to seek, for 10 years, approval of the enantiomer for a use in a “therapeutic category” for which the racemate is approved, or for a use for which any other enantiomer of the racemate is approved.  For purposes of determining the “therapeutic category” of a drug, the statute references a list developed by the United States Pharmacopeia and as in effect on September 27, 2007.  A copy of that list is available here.  (Although subsequent versions of the list provide more granularity in terms of therapeutic categories, and could, therefore, lead to a greater likelihood of exclusivity-qualifying enantiomers, the list, unless amended by FDA by regulation, is static under the statute.)  Finally, the labeling of the enantiomer drug for which “new active ingredient” status is elected must “include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”

When FDA posted on its website in July the approval letter and labeling for FETZIMA, we had an inkling that the approval might be precedent setting with respect to NCE exclusivity.  After all, the labeling includes the following in the “Indications and Usage” section:

FETZIMA, a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD).  The efficacy of FETZIMA was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD [see Clinical Studies (14)].

Limitation of Use: FETZIMA is not approved for the management of fibromyalgia.  The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established.

Now that the Orange Book has been updated with the latest Cumulative Supplement, our suspicion has been confirmed: 5-year NCE exclusivity was granted.  (The July Orange Book Cumulative Supplement took a little longer than usual to get posted this month because of some glitches in new software that is being used by FDA.)  The exclusivity is identified as “NCE*”, which is defined in an Orange Book addendum to mean: “NEW CHEMICAL ENTITY (AN ENANTIOMER OF PREVIOUSLY APPROVED RACEMIC MIXTURE. SEE SECTION 505(U) OF THE FEDERAL FOOD AND DRUG COSMETIC ACT).” 

How long it might be until FDC Act § 505(u) gets used again remains to be seen.  As noted above, the static nature of the therapeutic category list may be an obstacle.  Sponsor interest is another factor.  A 2012 report from the Government Accountability Office says that FDA has received very few inquiries regarding FDC Act § 505(u) (see our previous post here).