By Jeffrey K. Shapiro –

A determination of “intended use” is fundamental to FDA’s regulation of drugs and medical devices.  It is a primary basis for determining if an article is regulated by FDA at all, and if so, what regulatory requirements apply.

The intended use of an article for FDA regulatory purposes is not based upon the manufacturer’s subjective intent.  Rather, the determinant is “objective intent” based upon product labeling and advertising claims, i.e., the message about the recommended use of a drug or device that is communicated to the public.  E.g., Action on Smoking and Health v. Harris, 655 F.2d 236, 239 (D.C. Cir. 1980).

This regulatory framework is embodied in the parallel drug and device regulatory definitions of intended use (21 C.F.R. §§ 201.128 (drugs), 801.4 (devices)).  The definition provides:

The intent is determined by [a manufacturer’s] expressions or may be shown by the circumstances surrounding the distribution of the article.  This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by [a manufacturer] or [its] representatives.

This approach allows drug and device manufacturers to influence the regulatory requirements applicable to their products based upon their own public statements.  But FDA has also claimed the authority to regulate based upon the actual uses of an article even if such uses are not claimed in labeling or advertising.  The agency gave itself this authority in another part of the same regulation as quoted above.  This sentence states:

But if a manufacturer knows, or has knowledge of facts that would give him notice, that a [drug or device] introduced into interstate commerce . . . is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug/device which accords with such other uses to which the article is to be put.

This “knowledge” provision for many years has hung like the Sword of Damocles over the heads of manufacturers who have any knowledge of off‑label uses of their products.  The possibility was always present that FDA could deem such knowledge to create a new intended use.  If so, a manufacturer could find itself in trouble for failing to provide adequate directions for this imputed intended use.  FDA also could deem the intended use an unapproved use outside the scope of the existing clearance or approval, opening the manufacturer up to criminal and civil liability for past sales and the burden of developing a new marketing application to bring the imputed use on‑label.

One effect of the “knowledge” sentence has been to inhibit manufacturers from presenting on‑label information to physicians whose prescribing or use of a drug or device is known to be off‑label.  Such interaction has been perceived to heighten the risk that FDA would deem the off‑label use to be the manufacturer’s intended use.

It is true that the “knowledge” sentence has been rarely enforced.  But it has remained on the books and available for FDA’s use.  In May 2010, for example, FDA cited it in a warning letter to DexCom, Inc.  FDA warned Dexcom that the firm “has knowledge . . . that your device . . . is being used for conditions, purposes, and uses other than ones for which it is offered.”  Therefore:  “Under 21 CFR 801.4 you are required to provide labeling for such a device which accords with such other uses.”  FDA stated that the off‑label uses “require action from you in accordance with this regulation.”

So it was welcome news last month that FDA published a proposed rule, 80 Fed. Reg. 57756 (Sept. 25, 2015), proposing to delete the “knowledge” sentence from the intended use regulations.  The preamble to the proposal states that FDA “would not regard a firm as intending an unapproved new use for an approved or cleared medical product based solely on the firm’s knowledge that such product was being prescribed or used by doctors for such use.”  Id. at 57,757.  (FDA cites for this proposition a brief it filed in a court case in January 2010 – five months before the Dexcom warning letter.)

The qualifier “solely” in the preamble statement just quoted could be read to imply that FDA will continue to consider such conduct if it occurs as part of a larger scheme of off‑label promotion.  It is difficult, however, to imagine how lawful conduct could be cited to enhance the unlawful nature of a particular promotional scheme.  Either FDA has evidence of off label promotion or it does not, and a manufacturer’s lawful dissemination of information should not (and likely would not) be permitted to enter into the equation in an enforcement action.

It is also remarkable that FDA provides almost no explanation for the proposed revision to the intended use regulations, considering that it is a fairly significant alteration to regulations that have been on the books for decades.  FDA says only that the revision to the intended use regulations is a “clarifying change,” 80 Fed. Reg. 57761, that will “conform them to how the Agency currently applies these regulations.”  Id. at 57756.

The agency’s unspoken motivation may be to reinforce the position it has taken in recent First Amendment litigation.  As noted above, the “knowledge” sentence has deterred manufacturers from presenting on‑label information in off-label settings.  That chilling effect was part of Par Pharmaceutical’s First Amendment challenge to FDA’s application of the intended use regulation.  We wrote about this aspect of the Par case here and here. 

FDA’s tactical response in the Par lawsuit was to assert that it would never bring an enforcement action solely based upon the presentation of on‑label information in an off‑label setting, so that Par had no legitimate fear of legal jeopardy.  Specifically, the government asserted that “nothing in § 201.128 suggests that disseminating information about a drug’s approved use in settings where the drug is prescribed off- label is sufficient, without more, to establish that the off label use is an intended one. And the government does not construe the regulation to establish any such rule.” The “knowledge” sentence, however, inconveniently undercuts this position, since it appears to provide FDA with legal authority that would support just such an enforcement action.  Although the Par case settled, FDA may be attempting to ward off future challenges by conforming its intended use regulations to its litigation position.

Bottom line: it will now be undisputedly lawful to disseminate on‑label information (e.g., cleared or approved labeling) and/or otherwise promote an on‑label use to physicians, regardless of whether they may prescribe or use the product off‑label.  The mere fact that a manufacturer’s representatives call on physicians knowing that such physicians will use the product off-label will no longer be sufficient, if it ever was, as a basis for FDA to conclude that the off-label use is intended by the manufacturer.  In the Par case, FDA took the position that that such activity would not be deemed to create a new intended use.  The proposed rule will make certain that the intended use regulations no longer support any other position.

By Jennifer M. Thomas & Michelle L. Butler –

The U.S. District Court for the District of Columbia ruled decidedly in favor of PhRMA and against the government earlier this week in PhRMA v. HHS, No. 14-1685 (Oct. 14, 2015), potentially concluding a protracted fight between the Health Resources and Services Administration (“HRSA”) and PhRMA over the meaning of the so-called “orphan drug exclusion,” a provision of the Affordable Care Act (“ACA”) that excludes orphan drugs from the definition of a covered outpatient drug for certain categories of 340B Covered Entities under the 340B drug discount program (42 U.S.C. § 256b).  

We have followed this dispute as it proceeded before the District Court – not once, but twice (see our previous blog posts here, here, and here) – so we will not belabor the background here.  In brief, the Public Health Service Act (“PHSA”) was amended in 2010 pursuant to the ACA to (1) add additional categories of health care facilities to the categories of 340B Covered Entities eligible to purchase drugs at discounted prices pursuant to the 340B program, and (2) exclude “drug[s] designated . . . for a rare disease or condition” from the 340B program with respect to those new categories (with the exception of free-standing children’s hospitals) (the “orphan drug exclusion”). 

At issue in the present iteration of this case before the District Court was an “interpretive rule” under which HRSA stated that it would apply the exclusionary phrase “drug designated . . . for a rare disease or condition” narrowly, such that the exclusion would only apply to orphan drugs when used for their orphan indication, and not for any other use.  (See our previous blog post about the interpretive rule here.)  Pharmaceutical manufacturers that failed to make orphan drugs available to eligible 340B Covered Entities for non-orphan uses would be deemed in violation of the PHSA and could be subject to statutory penalties, refunds of overcharges, or termination of their Pharmaceutical Pricing Agreements.  PhRMA brought suit challenging HRSA’s interpretation, arguing that the orphan drug exclusion must apply to orphan drugs regardless of the particular use.  On cross motions for summary judgment, the District Court ruled that:

1. HRSA’s “interpretive rule” was final agency action subject to judicial review under the Administrative Procedure Act;
2. the Agency’s statutory interpretation did not deserve deference beyond its ability to persuade; and 
3. the Agency’s interpretation of the orphan drug exclusion conflicted with the plain language of the statute.

The Court focused a great deal of attention on the question of finality, and its extensive discussion of the Circuit case law on pre-enforcement review of agency interpretations would merit reading the opinion in full even apart from the underlying substance of the case.  The most salient facts (among the “constellation of factors”) weighing in favor of finality in this case were the significant practical and legal ramifications stemming from HRSA’s interpretive rule, even prior to any actual enforcement action by the Agency.  Slip. Op. at 21-27.

The Court also took the relatively unusual step of stating that the Agency’s interpretation deserved no deference, because HRSA lacks authority to issue regulations carrying the force of law in this context (see our discussion of the Court’s prior ruling on that point).  This statement, while consistent with the Court’s previous opinion, is nevertheless surprising because the Court arguably did not need to reach the issue of deference in light of its finding that the statutory language clearly and unambiguously forecloses the HRSA interpretation.

Specifically, the Court found that, while HRSA’s interpretation appears “plausible at first glance” when confined to the orphan drug exclusion provision alone, it “runs counter to the way Congress has used the phrase ‘a drug designated . . . for a rare disease or condition’” elsewhere throughout the U.S. Code.  Slip. Op. at 30.   The Court noted repeated instances in which Congress had used that phrase, or something similar, and then had gone on to specify that it only intended to include (or exclude, as the case may be) the particular orphan-designated indications of an orphan drug, rather than the orphan drug in general.  See Slip. Op. at 30-33 (citing 42 U.S.C. § 1395l(t)(6)(A)(i); 21 U.S.C. § 379h(a)(1)(F); 26 U.S.C. § 45C(b)(2)(B)).  According to the Court, if the phrase “a drug designated . . . for a rare disease or condition” had the narrow meaning ascribed to it by the HRSA interpretive rule, all these specifying phrases elsewhere in the Code would be rendered superfluous, contrary to basic principles of statutory construction.

Addressing policy concerns raised by the government and amici, the Court was dismissive.  It recognized the fact that excluding orphan drugs altogether from application of the 340B program could make the program less attractive for the newly covered 340B Covered Entities, but noted that “it is simply ‘not for [this Court] to rewrite the statute.’”  Slip. Op. at 37 (quoting Hall v. United States, 132 S. Ct. 1882, 1893 (2012)).  The Court addressed in a footnote the government’s argument that a broad reading of the orphan drug exclusion could create perverse incentives for pharmaceutical manufacturers to seek orphan drug designations for their best-selling drugs, but dismissed it as an unfounded fear.  Slip. Op. at 37 n. 20.

The government has 60 days to notice an appeal of the District Court’s ruling.  Given the history of this case and the importance of the issue, we would be surprised if the government does not pursue an appeal.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to announce that Jenifer R. Stach and Dr. Charlene Cho have joined the firm as associates.

Ms. Stach works as a general practice associate and provides counsel on regulatory matters related to foods, over-the-counter drugs, medical devices, cosmetics, and veterinary food and medicine.  Ms. Stach also assists with pharmaceutical compliance, label reviews, corporate compliance matters, and due diligence for mergers and acquisitions.     

Before joining HP&M, Ms. Stach worked at FDA for almost five years.  During her time at FDA, Ms. Stach worked in the Office of Operations as a liaison to CDRH and CFSAN, CDER as a Regulatory Health Project Manager in the Office of Regulatory Policy, and CFSAN in the Office of Regulations, Policy, and Social Sciences as a Regulatory Counsel.  Ms. Stach graduated cum laude from The Catholic University of America Columbus School of Law, and earned a Bachelor of Business Administration in marketing from the University of Notre Dame. 

Dr. Cho advises clients about regulatory strategies, compliance matters, and the FDA approval process.  With a doctorate in Neurobiology, Pharmacology & Physiology and over five years of experience working at FDA on regulatory policies and procedures, she is well positioned to provide technical advice and counseling on regulatory matters related to biologics, devices, and drugs.

Prior to joining HP&M, Dr. Cho worked as Regulatory Counsel at FDA’s CBER.  While there, she worked on a variety of policy and classification issues relating to human cells, tissues, or cellular or tissue-based products (HCT/Ps).  She also went on detail to the CDRH, where she worked on jurisdictional matters for medical devices and combination products.   Dr. Cho graduated from the Vanderbilt University Law School, and earned her Ph.D. at the University of Chicago.  She has a Bachelor of Arts from Smith College.

By Jenifer R. Stach* – 

There have been a number of recent battles between Attorneys General (AG)in various states and dietary supplement manufacturers.  These battles have generally been triggered by AG letters which have alleged that manufacturers have marketed supplements that contain drug-like ingredients in violation of deceptive trade practice state laws.  The letters have resulted in some settlements (see press releases from the New York State Office of the Attorney General, Oregon Department of Justice, and Vermont Office of the Attorney General).  We will see if the recent decision by the 5^th Circuit may discourage state Attorneys General from sending similar warning letters to dietary supplement manufacturers.  We will also see if this ruling provides a legal path for dietary supplement manufacturers to pursue legal claims against a state, state agency, or state official upon receiving a warning letter. 

NiGen is a Utah-based manufacturer and distributor of the dietary supplements, Isodrene and The HCG Solution.  In December 2011, NiGen brought suit against the Texas Attorney General (AG) Ken Paxton after the AG sent warning letters to NiGen, and retailers CVS, Walgreens, and Wal-Mart.  The Texas AG determined that use of the term “hCG” was “false, misleading, or deceptive” in violation of the Texas Deceptive Trade Practices Act because, “the claim is trying to mimic claims that FDA considers off-label for the prescription drug.”  (As stated in the 5th Circuit opinion, discussed below, “hCG is an acronym for human chorionic gonadotropin hormone, a protein found in pregnant women that is an ingredient in prescription drugs sold under the brand names Novarel, Ovidrel, and Pregnyl.”)  Retailers removed the products from the shelves allegedly resulting in millions of dollars in lost revenue for NiGen.

NiGen filed suit under 42 U.S.C. § 1983 alleging violations of its rights under the First Amendment, Fourteenth Amendment Due Process and Equal Protection Clauses, the Commerce Clause, the Supremacy Clause, and state law claims of tortious interference with business relations.  According to the 5th Circuit opinion, “NiGen sought 1) a declaration that its labeling did not violate federal law and that it was entitled to use “HCG” on its labels; 2) preliminary and permanent injunctive relief; 3) money damages; and 4) costs and attorneys' fees.”  After motions by the AG for dismissal and an unexplained two-year delay, the District Court for the Northern District of Texas dismissed the case based on state sovereign immunity.   

NiGen timely appealed and in the case of NiGen Biotech, L.L.C. v. Paxton, No. 14-10923, 2015 WL 5749618 (5th Cir. Sept. 30, 2015), the court reversed in part in favor of NiGen.  The 5th Circuit ruled that NiGen’s claims are not barred from federal jurisdiction on the basis of Ex Parte Young, that federal jurisdiction exists over most of the claims pled, and that NiGen has standing to sue.  In its opinion, the 5th Circuit addressed State Sovereign Immunity, Federal Question Jurisdiction, and Standing.  

State Sovereign Immunity

State sovereign immunity is based on the premise that Federal Courts do not have jurisdiction over suits against a state, state agency, and officials acting in their official capacity, unless the state has waived its immunity or Congress has abrogated it.  According to the 5th Circuit opinion, “[u]nder the doctrine articulated in Ex parte Young, 209 U.S. 123 (1908), a state official attempting to enforce an unconstitutional law ‘is stripped of his official clothing and becomes a private person subject to suit.’”  Under Ex parte Young, a plaintiff must seek relief from a state actor acting in his official capacity, for alleged ongoing violations of federal law (and not merely that the state actor has violated federal law in the past), and that the relief sought must be injunctive in nature and prospective in effect.  The court concluded that NiGen’s allegations of the AG's continuous refusal to justify the warning letters were sufficient to meet the Ex parte Young standard.  The AG’s action was allegedly an ongoing violation of federal law, which could be remedied with injunctive relief which would allow NiGen to sell their products.   

Federal Question Jurisdiction

The AG contended that NiGen’s claims were anticipatory defenses to threatened enforcement action, and were therefore barred from Federal Jurisdiction.  The 5^th Circuit disagreed with the AG and stated that a plaintiff who seeks both declaratory and injunctive relief based on the unconstitutionality of a state statute may raise this as a claim, even if the claim might also be used as a defense to state enforcement action. 

Standing

The AG challenged NiGen’s standing by contending that, “To have standing to sue, the plaintiff must demonstrate injury in fact that is fairly traceable to the defendant's conduct and that would be redressed by a favorable judicial decision. Lujan v. Defenders of Wildlife, 504 U.S. 555, 560, 112 S.Ct. 2130, 2136 (1992).”  In Lujan, standing was denied in part because the only entities that could redress the plaintiff’s alleged injury were nonparties that would be bound to the judgment.  The AG points to the claim by NiGen that the warning letters to the retailers cost NiGen millions of dollars in lost revenue.  In response, the 5th Circuit pointed out that the warning letters were directed at NiGen itself, and concluded that a favorable court decision would allow NiGen to sell its products in Texas, whether directly or through its retailers, and could again conduct business as usual.  

In conclusion, the 5th Circuit affirmed the District Court’s dismissal of NiGen’s claims for money damages, state law violations, retrospective relief, and declaratory relief against a threatened enforcement action, reversed the dismissal of NiGen’s constitutional law claims, and remanded the case for further proceeding.  We will keep you posted as to how the District Court rules in light of the 5th Circuit analysis if NiGen decides to pursue its Constitutional claims against the Texas AG.

*Admitted only in Maryland. Work supervised by the Firm while D.C. Bar application is pending.

By Larry K. Houck –

The Centers for Disease Control and Prevention (“CDC”), the nation’s premier agency focusing on public health and safety through disease prevention and control, and a component within the U.S. Department of Health and Human Services, is developing guidelines “to provide recommendations for the prescribing of opioid pain medication for patients 18 and older in primary care settings” that focus on treating chronic pain outside end-of-life care.  Draft CDC Guideline for Prescribing Opioids for Chronic Pain.  The CDC observes on its website that existing opioid guidelines vary and that primary care providers do not receive sufficient opioid prescribing training.  Id.  The CDC further notes that its guidelines will address determining initiation or continuing opioid therapy; opioid selection, dosage, duration, follow-up and continuation; and assessing associated risk and harm.  Id.

The CDC provided limited public access to the draft guidelines during a webinar on September 16th but is providing no further access or participation in their development.  The independent online chronic pain and pain management news source Pain News Network, reported that CDC anticipates finalizing the guidelines next month, and submitting them to the Department of Health and Human Services for publication in January 2016.  Pat Anson, CDC: Opioids Not ‘Preferred’ Treatment for Chronic Pain, Pain New Network, (Sept. 16, 2015).  It is unclear what form the publication of the guidelines will take.

The CDC is not making the guidelines available, but the Pain News Network lists the dozen guidelines provided during the webinar as follows:

1. Non-pharmacological therapy and non-opioid pharmacological therapy are preferred for chronic pain.  Providers should only consider adding opioid therapy if expected benefits for both pain and function are anticipated to outweigh risks.
2. Before starting long term opioid therapy, providers should establish treatment goals with all patients, including realistic goals for pain and function.  Providers should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety.
3. Before starting and periodically during opioid therapy, providers should discuss with patients risks and realistic benefits of opioid therapy and patient and provider responsibilities for managing therapy.
4. When starting opioid therapy, providers should prescribe short-acting opioids instead of extended-release/long acting opioids.
5. When opioids are started, providers should prescribe the lowest possible effective dosage.  Providers should implement additional precautions when increasing dosage to 50 or greater milligrams per day in morphine equivalents and should avoid increasing dosages to 90 or greater milligrams per day in morphine equivalents.
6. Long-term opioid use often begins with treatment of acute pain.  When opioids are used for acute pain, providers should prescribe the lowest effective dose of short-acting opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids.  Three or fewer days will usually be sufficient for non-traumatic pain not related to major surgery.
7. Providers should evaluate patients within 1 to 4 weeks of starting long-term opioid therapy or of dose escalation to assess benefits and harms of continued opioid therapy.  Providers should evaluate patients receiving long-term opioid therapy every 3 months or more frequently for benefits and harms of continued opioid therapy.  If benefits do not outweigh harms of continued opioid therapy, providers should work with patients to reduce opioid dosage and to discontinue opioids when possible.
8. Before starting and periodically during continuation of opioid therapy, providers should evaluate risk factors for opioid-related harms.  Providers should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid-related harms are present.
9. Providers should review the patient’s history of controlled substance prescriptions using state Prescription Drug Monitoring Program data to determine whether the patient is receiving excessive opioid dosages or dangerous combinations that put him/her at high risk for overdose.  Providers should review Prescription Monitoring Program data when starting opioid therapy and periodically during long-term opioid therapy (ranging from every prescription to every 3 months).
10. Providers should use urine drug testing before starting opioids for chronic pain and consider urine drug testing at least annually for all patients on long-term opioid therapy to assess for prescribed medications as well as other controlled substances and illicit drugs.
11. Providers should avoid prescribing of opioid pain medication and benzodiazepines concurrently whenever possible.
12. Providers should offer or arrange evidence-based treatment (usually opioid agonist treatment in combination with behavioral therapies) for patients with opioid use disorder.  Id.

The guidelines provided during the webinar are reasonable and public health benefits could result from clarifying opioid prescribing.  However, we question CDC’s process for developing the guidelines.  The Pain News Network noted that the Food and Drug Administration (“FDA”), not CDC, normally sets prescription drug guidelines, and that an FDA official responsible for opioid issues was unaware that CDC was drafting the opioid prescribing guidelines.  Id.  Knowledgeable and responsible FDA officials are not providing meaningful input to the guidelines. 

Secondly, the guidelines have ramifications for activities in which many stakeholders hold strong interests-healthcare professionals including prescribers and pharmacists, regulators and especially patients.  How will the American Medical Association and state medical boards react to the final guidelines?  Will the Drug Enforcement Administration take enforcement action against practitioners who it believes issued opioid prescriptions for other than legitimate medical purpose because they did not following the guidelines?  Or, in the alternative, will following the guidelines strengthen a practitioner’s defense that the opioid prescriptions they issued were legitimate?

CDC should not draft the guidelines in isolation until finalized, but instead make them available for public comment prior to their becoming final.  We agree with Edith Rosato, CEO of the Academy of Managed Care Pharmacy, who in a letter to CDC Director Tom Frieden, “strongly urges the CDC to formally release the draft guidelines and provide for a sufficient public comment period to ensure the perspective of all parties, including those of managed care pharmacy, are taken into consideration.”  Letter from Edith A. Rosato, RPh, Academy of Managed Care Pharmacy, to Tom Frieden, CDC, (Sept. 18, 2015).

By Karla L. Palmer –

The U.S. Government Accountability Office (GAO) recently published a Report concerning animal drug compounding, titled “FDA Could Improve Oversight with Better Information and Guidance.”  The Report is a result of a Congressional request for GAO to review issued related to animal drug compounding and FDA’s oversight thereof.  GAO conducted its audit from June 2014 to September 2015.  The Report examines: (1) the benefits and risks of animal drug compounding; (2) the extent animal drug compounding occurs; and (3) FDA’s approach to regulating compounded animal drugs.  The Report comes on the heels of Congress’  reenactment of FDCA Section 503A addressing compounding of human drug products for individually identified patients and the enactment of Section 503B (Title I of the Drug Quality and Security Act, blogged about extensively here, in November 2013).  

The GAO undertook, among other activities, an analysis of relevant federal law, regulations, and animal compounding guidance documents (withdrawn in May of 2015; FDA simultaneously issued draft guidance, with comments now due November 19, 2015; see our previous post here).  GAO also reviewed FDA’s Foods and Veterinary Medicine Program Strategic Plan (2012-16), FDA’s activities concerning animal drug compounding over the past decade, and the Office of Management and Budget’s instructions for drafting appropriate regulatory guidance.  In addition, GAO interviewed FDA officials and reviewed regulatory oversight in four states – Florida, California, Kentucky, and Texas.  GAO selected these states because they vary in their regulation of animal drug compounding, and two of the states (Florida and Kentucky) have been the site of adverse events related to compounded drugs over the past six years.  For the four states, GAO also reviewed relevant state statutes and regulations, because states traditionally have provided oversight of animal drug compounding. 

The Report provides a historical background into animal drug compounding from both approved animal drugs and bulk substances and describes the benefits and risks of the same. (Report at 6-11).  It cites the benefits of compounding to include, among other factors, the lower costs of compounded animal drugs (especially given the high cost of approved drugs and the lack of insurance coverage for most drugs for animals), and the life-saving benefits associated with compounding when no suitable FDA-approved drugs exist.  The Report does differentiate compounding drugs for food-producing versus non-food producing animals, however – the latter of which typically presents less risk to the public health. 

The GAO stated that there is incomplete information concerning the extent to which compounded drugs have caused or may be linked to adverse events given the voluntary nature of reporting from veterinarians, pet owners, and pharmacies, unlike reporting required by manufacturers of approved animal drugs.  (Report at 12-14). The lack of reporting makes it difficult for FDA to determine whether the drug involved in an adverse event was compounded, and the frequency of adverse events.

The GAO also found that FDA does not have guidance concerning compounded animal drugs, and it has not documented consistently the bases for its enforcement and other decisions.  However, FDA in fact did issue guidance animal drug compounding (CPG 608.400) back in 2003, which FDA withdrew in the wake of its publication of its new draft guidance in July 2015 (mentioned above).  GAO noted the prior guidance contained several “limitations” and vague definitions (Report at 14-16). 

FDA explained to GAO that it did not routinely inspect pharmacies that compounded animal drugs because: (1) FDA does not have a comprehensive list of pharmacies that compound animal drugs because they do not need to register with FDA; (2) FDA lacks resources to routinely inspect the thousands of animal drug compounding pharmacies; and, (3) states regulate pharmacy practice and drug compounding.  Notwithstanding these limitations, FDA noted it has sought enforcement action against pharmacies that compound animal drugs on several occasions (including warning letters and voluntary recalls). 

However, FDA has not pursued a legal action to stop a pharmacy from illegally compounding animal drugs since 2010 (referring generally to the Franck’s Lab Inc. matter in the United States District Court for the Middle District of Florida, which decision favorable to the compounder was vacated as moot by agreement when the compounder stopped compounding animal drugs from bulk substances.)  With respect to its enforcement actions generally and FDA’s inconsistent documentation, GAO noted the significant inconsistencies with FDA’s follow-up concerning allegedly violative activities  – ranging from no apparent follow-up to follow-up occurring from 9 months to 6 years after identifying potential violations.  (Report at 20-21).  GAO found FDA was also inconsistent with its handling of adverse event reporting. (Report at 21).  GAO was also unable to determine how FDA handles complaints about illegal compounding because FDA does not track or collect such information. 

GAO provided the following recommendations for FDA:

• Modify the voluntary reporting form FDA uses to obtain information on adverse events to ask whether drugs involved in adverse events were compounded
• Develop policy or guidance for agency staff that specifies circumstances under which FDA will or will not enforce compounding regulations for animals and clearly define key terms.
• Consistently document the bases for FDA’s decisions about how or whether it followed up on warning letters, adverse event reports, and complaints about drug compounding for animals. 

FDA stated in response to GAO’s Report that it generally agreed with the Report’s recommendations, and that it has made substantial progress addressing animal drug compounding.  However, to date, the FDA’s draft guidance is still awaiting industry comments and must be finalized, and there is no effective federal regulatory structure – for better or worse – addressing compounded animal drugs. 

By Ricardo Carvajal –

The Center for Science in the Public Interested (CSPI) filed suit in the D.C. District Court to compel FDA to respond to CSPI’s 2005 citizen petition (Docket No. FDA-2005-P-0196) asking FDA to revoke the GRAS status of salt, require reduced levels of salt in processed foods, and require “health messages” on retail salt packages.  The complaint alleges that FDA’s failure to act violates the Administrative Procedure Act (APA), and asks the court to order FDA to respond within 30 days of the court’s finding of an APA violation. 

CSPI’s complaint is similar in substance to the complaint filed by Dr. Fred Kummerow in 2013 alleging that FDA violated the APA when it failed to respond to his citizen petition seeking a ban on partially hydrogenated oils (PHOs).  FDA framed its recent declaratory order revoking the GRAS status of PHOs as a partial response to Dr. Kummerow’s citizen petition (see our previous post here).  There has been no indication that FDA intends to take such an action with respect to salt.  However, FDA has indicated its intent to seek gradual reduction of added sodium in the food supply.  We’ll therefore be keeping a close eye on developments in this area.

By James E. Valentine* – 

In recent years there has been an increasing focus on patient engagement, centering on new opportunities for FDA to incorporate the patient perspective into its regulatory decision making.  These discussions have resulted in Congress and FDA establishing new policies and programs (see our previous posts on these efforts here, here, here, here, and here).  However, the public dialogue has largely left out the opportunities for meaningful engagement between patients and research sponsors (academia and the medical product developers).  That changed in 2014, when Clinical Trials Transformation Initiative (CTTI) initiated the Patient Groups & Clinical Trials (PGCT) Project.  

CTTI is a public-private partnership established to identify and promote practices that will increase the quality and efficiency of clinical trials.  Government partners included FDA, NIH, CMS, OHRP, AHRQ, CDC, and the Department of Veterans Affairs.  For those of you that may not be familiar with CTTI or its work, information about its membership, project methodology, projects, and published resources can be found here. 

The PGCT Project was established to find evidence-driven, actionable solutions to a number of questions:  How and when should patient groups be engaged in the research and development continuum? How do patient groups and sponsors of research best assess each other’s interests, expertise, and assets to increase the chances of successful clinical trials and therapy development? 

Today, CTTI is releasing the culmination of that effort at the BIO Patient and Health Advocacy Summit (view the slides presented at this session here).  CTTI’s PGCT Project official recommendations identify best practices for engaging with patient groups, as well as provide case examples and tools.

The PGCT Project

Key sectors of the research community had identified a gap in the knowledge and understanding about how and when to best interact with patient groups and clinical trials.  There was a dearth of empirical evidence and no guidelines or best practices existed.  As a result, CTTI identified a need for actionable recommendations and metrics, which was the foundation for establishing the PGCT Project. 

To work towards the goal of establishing guidelines and best practices, the PGCT Project first sought to identify gaps and barriers to effective engagement between patient groups and research sponsors.  The project then took that information to experts to analyze and interpret, and subsequently inform the development recommendations.  The PGCT Project consisted of a series of activities:

• Literature Review and Survey – a joint CTTI/Drug Information Association (DIA) survey elicited feedback from 244 respondents and examined current practices and perceptions among the different stakeholders about the value of, and barriers to, successful patient group engagement in clinical trials;
• Semi-structured interviews – a qualitative scientist conducted 32 semi-structured interviews with 10 leaders of patient groups, 12 industry sponsors, and 10 academic investigators to follow up on findings from the survey; and
• Expert Meeting – presentations and discussions from diverse stakeholders during a January 2015 expert meeting examined the findings of the survey and semi-structured interviews.  Meeting participants also explored the diverse capabilities and assets that many patient groups are assembling, as well as examples of how and when research sponsors and patient groups are engaging to build effective partnerships.  Based on these experiences, participants were asked challenging questions about overcoming barriers and developing best practices.  FDA was well represented at the meeting, with presentations and/or participation by Janet Woodcock and Theresa Mullin from CDER, Richard Klein and Steve Morin from the Office of Health and Constituent Affairs, and Kathryn O’Callaghan and Annie Saha from CDRH, among others.

Through this process, CTTI was able to characterize the range of “best practices” that respondents reported are producing positive results, which are intended to serve as guideposts for patient groups and research sponsors alike.

The PGCT Recommendations

The PGCT recommendations document organizes its best practices into three categories: (1) recommendations for all stakeholders, (2) recommendations for research sponsors—industry and academia, and (3) recommendations for patient groups.

Several of the recommendations emphasize the importance of engaging early and often.  CTTI developed an infographic (see below) that provides a fairly comprehensive list of opportunities for patient groups to engage during clinical trials.

At whatever point engagement begins, from the start it is recommended that the research sponsor and patient group clarify the roles of the partnership and set expectations.  For example, the document emphasizes the importance of patient groups to understand that:

[W]hile [their] input may be taken into account when determining the objectives of a clinical program or development of a protocol, research sponsors must balance that input with scientific understanding as well as business and regulatory needs. These multiple influences reflect the reality of the environment that will drive the program, and PGs should understand that research sponsors reserve the right to make final decisions about study design.

In addition to establishing roles and responsibilities, the recommendations call for all stakeholders to be open, transparent, and honor the commitments they have agreed upon (including Confidentiality Agreements).  CTTI recommends that agreements are documented, and such documentation can be customized to fit the needs of each partnership (e.g., may include a Memorandum of Understanding or more formal contract). 

With respect to whom to engage with, CTTI recommends that patient groups should be involved with multiple research sponsors to maximize the potential pipeline of therapies in development.  Likewise, it is recommended that sponsors should engage with more than one patient group in a particular disease area to ensure that a representative patient perspective is reflected in the input obtained.

Finally, the recommendations note that while there are a number of FDA-related and other legal and regulatory issues surrounding sponsor engagement with patient groups, there is no explicit prohibition against early engagement with patient groups.  CTTI recommends that research sponsors clarify which kinds of interactions are permissible and which ones might violate FDA regulations or fraud, abuse, and other regulations.  This includes patient groups understanding these rules and taking appropriate steps.  For example, if establishing a partnership with a sponsor with trial recruitment (e.g., raising awareness, assisting with screening), patient groups should clearly characterize clinical studies as research, not misrepresent the investigational nature of the trial, and convey information about a trial as approved by the Institutional Review Board (IRB).

These recommendations discussed above cover those that apply to both research sponsors and patient groups, however, the CTTI’s document provides a number of more detailed best practices for both sets of stakeholders.  

Tools

In addition to its recommendations, embedded in the document, CTTI has provided a series of tools to assist research sponsors in engaging with patient groups.  

• The “Patient Group Organizational Expertise and Assets Evaluation Tool” can be used by research sponsors to analyze patient group skills and strengths and by patient groups to help define their values and document their assets. 
• The “Assessment of Patient Group Internal Aspects: Focus” and “Assessment of Patient Group External Relationships: Other Patient Groups” tools provide research sponsors with a way to assess patient group expertise, interests, organizational capacity, and relationships.  Using these will direct sponsors to learn about the patient group’s priorities, past and present programs, and strengths in policy, finance, and research.  The hope is that these tools will make it easier for sponsors to identify patient groups whose strengths match their needs.

Future Developments

While the PGCT Project helped reveal several modifiable barriers to successful relationships between research sponsors and patient groups, it also identified that further work needs to be done on metrics and models to assess the value and impact of such engagement.  The PGCT Project has established a Value Work Stream that is currently developing new conceptual models and methods to measure the benefit of partnerships captured in CTTI’s recommendations.

*James Valentine serves as a member of CTTI’s Patient Groups & Clinical Trials Project team.  He is admitted only in Maryland, and his work supervised by the Firm while D.C. application pending.

By Kurt R. Karst –

Hatch-Waxman controversies are often like trains barreling down railroad tracks.  They first appear in the distance as small objects, seemingly moving at a slow velocity.  But with each passing moment, the object grows larger and more distinct, and appears to pick up speed.  Finally, the train is upon you and we’re in the middle of litigation.  Take, for example, FDA’s February 2009 decision to invoke the Agency’s Application Integrity Policy (“AIP”) against Ranbaxy’s Paonta Sahib, India manufacturing facility, and the Consent Decree Ranbaxy entered into with FDA in January 2012.  The AIP affected several pending Ranbaxy ANDAs, and the Consent Decree identified some ANDAs for which Ranbaxy risked losing (forfeiting) eligibility for 180-day exclusivity.  At the time of the AIP in 2009, and later in 2012 with the Consent Decree, it seemed inevitable that FDA would be dragged into court over 180-day exclusivity for at least one Ranbaxy ANDA affected by the company’s compliance woes.  In fact, FDA was sued multiple times over several ANDAs (see our previous posts here, here, here, and here).  

Although we’re not yet (to our knowledge) at the point of litigation, FDA’s October 5, 2015 approval of Alkermes plc’s (“Alkermes”) 505(b)(2) NDA 207533 for ARISTADA (aripiprazole lauroxil) Extended-elease Injectable Suspension, a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole), for the treatment of schizophrenia may very well end up in court.  Accompanying the approval of ARISTADA is FDA’s 31-page denial of a July 13, 2015 Citizen Petition (Docket No. FDA-2015-P-2482) submitted on behalf of Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceuticals Co., Ltd. (collectively “Otsuka”) that primarily concerns the scope of 3-year exclusivity. 

Otsuka is the sponsor of several NDAs for aripiprazole drug products marketed under the proprietary name ABILIFY.  The Orange Book lists three unexpired periods of non-patent exclusivity for ABILIFY Tablets, ABILIFY Oral Solution, ABILIFY DISCMELT Orally Disintegrating Tablets, and ABILIFY Injection, which expire on December 12, 2021 (orphan drug exclusivity), December 12, 2017 (concerning treatment of pediatric patients with Tourette’s Disorder), and June 9, 2017 (concerning labeling revisions relative to a study in pediatric patient with irritability associated with autistic disorder).  Another ABILIFY product, ABILIFY MAINTENA, is listed in the Orange Book with two unexpired periods of 3-year exclusivity expiring on February 28, 2016 (new dosage form) and December 5, 2017 (identified in an Orange Book addendum as “addition of the results of a controlled clinical study treating adult patients with schizophrenia experiencing an acute relapse”). 

Otsuka has already shown a willingness to protect the ABILIFY estate in court with a lawsuit – ultimately unsuccessful – filed against FDA earlier this year after the Agency approved ANDAs for generic aripiprazole drug products notwithstanding unexpired periods of exclusivity for ABILIFY (see our previous post here).  For the past several months we’ve watched the volley of comments from Otsuka and Alkermes as they debated the scope of ABILIFY’s 3-year exclusivity vis-à-vis ARISTADA.  Of course, the recent decision from the U.S. District Court for the District of Columbia in Veloxis Pharmaceuticals, Inc. v. FDA, No. 14-cv-2126, 2015 U.S. Dist. LEXIS 77559 (D.D.C. June 12, 2015), concerning the scope of 3-year exclusivity (see our previous post here) has played a central role in the debate.  As in the Veloxis case, the ARISTADA 505(b)(2) NDA does not cite as a listed drug the particular drug product covered by 3-year exclusivity and the scope of which is alleged to extend to  a second-in-time 505(b)(2) NDA (rather, the ARISTADA 505(b)(2) cites a different Otsuka aripiprazole drug product as its listed drug).  Other FDA letter decisions related to the Veloxis decision and an exclusivity decision we posted on this blog concerning FDA’s rationale for granting exclusivity for abuse-deterrent OXYCONTIN (see our previous post here) have also popped up in comments to Otsuka’s Citizen Petition.

Otsuka’s July 2015 Citizen Petiton requests that FDA delay or withhold final approval of NDA 207533 for ARISTADA “at least until Otsuka’s 3-year exclusivity for the conditions of approval of aripiprazole expires on December 5, 2017.”  Otsuka also requests that FDA refuse to approve NDA 207533 in its entirety because it “does not satisfy the substantial evidence of effectiveness requirement prescribed in section 505(b)(1)(A)” of the FDC Act insofar as the ARISTADA NDA “is supported with only one adequate and well-controlled clinical trial . . . of the drug (aripiprazole lauroxil) for which Alkermes seeks approval.”   This second request was the subject of a September 9, 2014 Otsuka Citizen Petition (Docket No. FDA-2014-P-1354) that FDA denied without comment in February 2015. 

Before delving into the issues raised in Otsuka’s Citizen Petition, FDA first provides a rather detailed (and helpful) analysis of ARISTADA and the eligibility of the 505(b)(2) NDA drugh product for New Chemical Entity (“NCE”) exclusivity.  According to FDA:

Aripiprazole lauroxil is an ester ofN-hydroxymethyl aripiprazole, and not an ester of aripiprazole.  N-hydroxymethyl aripiprazole differs from aripiprazole because of the addition of a hydroxymethyl group, connected by a covalent C-N bond.  Because the Agency excludes the ester-bonded portion of the drug substance for the active moiety determination, the active moiety of aripiprazole lauroxil is N-hydroxymethyl aripiprazole.  Under FDA's “structure-based” approach for determining the active moiety, because of the covalent, non-ester C-N bond, FDA includes the hydroxymethyl group in determining the active moiety of aripiprazole lauroxil, even though that bond is eventually hydrolyzed in the body to yield aripiprazole.  Therefore, N-hydroxymethyl aripiprazole is the active moiety of aripiprazole lauroxil.  Furthermore, N-hydroxymethyl aripiprazole has not been approved by FDA in any other application submitted under section 505(b) of the FD&C Act.  Therefore, Aristada contains an NCE entitled to 5-year NCE exclusivity, which will expire in 2020.

With that, FDA moves to the primary question raised in Otsuka’s Citizen Petition: whether the periods of 3-year exclusivity for ABILIFY MAINTENA block the approval of the 505(b)(2) NDA for ARISTADA “(1) even though the NDAs are for different active ingredients (aripiprazole versus aripiprazole lauroxil) and different active moieties (aripiprazole versus N-hydroxymethyl aripiprazole) and (2) even though Aristada includes an NCE and has earned its own period of 5-year NCE exclusivity.”  Otsuka contends that the conditions of approval for which ABILIFY MAINTENA received 3-year exclusivity overlap with the conditions of approval sought for ARISTADA, and asserts that the scope of 3-year exclusivity for ABILIFY MAINTENA is for “long-acting, monthly injectable formulations of aripiprazole for the treatment of schizophrenia with conditions of approval for both maintenance and acutely relapsing patients,” thereby blocking approval of the NCE exclusivity-qualifying ARISTADA NDA.

The answer to the question above is simple, says FDA: the ARISTADA approval cannot be blocked by 3-year exclusivity applicable to ABILIFY because the drug products contain different active moieties.  According to FDA:

In general, if Abilify Maintena and Aristada contained the same active moiety, FDA would begin its analysis, as the Agency did in the Veloxis Letter, with the nature of the innovation in the Abilify Maintena NDA and supplement and would determine which clinical studies were the new clinical investigations essential to approval of the NDA or supplement with exclusivity.  However, because the scope of the 3-year exclusivities for Abilify Maintena, like the scope of any 3-year exclusivity, is tied to the active moiety of Abilify Maintena and because Aristada contains a different active moiety than Abilify Maintena, FDA concludes that approval of the Aristada NDA is not blocked.  To determine whether approval of Aristada is blocked, the Agency need not examine the other details of the new clinical investigations essential to the approval of Abilify Maintena; nor does it need to determine the extent to which Abilify Maintena’s exclusivities would block a different product that contains aripiprazole as an active moiety.   

FDA goes on to explain why the Agency believes its decision on the scope of ABILIFY’s 3-year exclusivity is consistent with the Agency’s interpretation of the statutory phrase “conditions of approval of such drug in the approved subsection (b) application” concerning 3-year exclusivity, as articulated in the Veloxis Letter Decision and elsewhere.  “If FDA were to take the position that 3-year exclusivity described in section 505(c)(3)(E)(iii) or 505(c)(3)(E)(iv) of the FD&C Act could block approval not only of drugs containing the same  active moiety as the product with exclusivity but also of drugs containing a different active moiety, the scope of 3-year exclusivity would be broader than the scope of 5-year NCE exclusivity in section 505(c)(3)(E)(ii),” writes FDA.  “Thus, the 3-year exclusivity for Abilify Maintena could block approval of Aristada, whereas the 5-year NCE exclusivity of an Abilify product could not block approval of Aristada.”  That result would be inconsistent with FDA precedent and the Hatch-waxman Amendments, explains FDA:

Under the result for Aristada urged by Otsuka, the 3-year exclusivity granted to any drug in a 505(b) NDA could potentially block the approval of any other later-in-time 505(b)(2) NDA as long as the two products shared certain conditions of approval.  The two products would not need to share an active moiety or even be in the same chemical class of compounds.  FDA rejects this approach because, among other things, it would extend the scope of 3-year exclusivity in a manner that would upset the balance Congress intended.  Such an outcome could hinder the availability of therapeutic alternatives and discourage or delay the development of innovative new drugs.

FDA also explains why the Agency is hesitant to go down the rabbit hole of evaluating “end metabolites” for exclusivity purposes.  “Assuming that FDA were to limit the inquiry for determining possible blocking exclusivities to products that share active metabolites, this inquiry would also pose difficult and potentially insurmountable challenges from a regulatory and scientific standpoint,” writes FDA. 

Metabolites are formed after a drug product is ingested, and frequently different metabolites are formed at different stages of bioconversion. . . .  In some cases, such as that of aripiprazole lauroxil, one or more of the metabolites (e.g., N-hydroxymethyl aripiprazole) is further converted into a different metabolite (e.g., aripiprazole).  In still other instances, many metabolites are formed after a drug product is ingested.  This raises the complex question of which metabolite would be relevant for exclusivity purposes (e.g., those created after the first stage of bioconversion, those created after subsequent stages of bioconversion, or all metabolites).  Furthermore, in many cases, it may not be possible from a scientific perspective to identify all of the metabolites and their relative activity at the time of drug approval. . . .  FDA has adopted an approach focusing on the drug’s chemical structure that can be applied consistently with scientific rigor across drug products.

Moving on to Otsuka’s argument that FDA cannot approve a 505(b)(2) NDA for an NCE that is supported by a single adequate and well-controlled clinical trial and that relies on the Agency’s findings of safety and effectiveness for a listed drug, FDA says that this argument is without merit.  “[A] 505(b )(2) NDA, like a stand-alone NDA, is approved under [FDC Act § 505(c)] and must meet the ‘full reports’ requirement in section 505(b)(1)(A).  The difference between a 505(b)(2) NDA and a stand-alone NDA is the source of information relied on for approval,” writes FDA.  “Alkermes conducted a single adequate and well-controlled clinical trial and bridged to the findings of safety and effectiveness for Abilify (aripiprazole) Tablets (NDA 021436) to support approval of its 505(b)(2) NDA for Aristada.  FDA has determined that Alkermes has provided substantial evidence that Aristada is effective under the conditions of use prescribed, recommended, or suggested in the drug’s labeling.”  Indeed, as FDA points out in the petition decision, there are several instances where FDA has approved 505(b)(2) NDAs for NCEs that rely on the Agency’s findings of safety and effectiveness for a previously approved drug.

We’ll be closely watching the various court dockets over the next few days to see if the the Hatch-Waxman train once again barrels into court, this time with a challenge to FDA’s ARISTADA approval and Citizen Petition decisions.  As always, we’ll keep you updated. 

By Jennifer M. Thomas –

As we indicated in our post last week, the District Court’s opinion in United States v. Bayer, unsealed on October 1, 2015, reads as a serious loss for the government.  It is certainly a clear victory for Bayer. The Court’s opinion also has the potential to affect the industry as a whole, although perhaps not as much as it might seem at first blush.  We will discuss the case’s likely effects.  But first, a brief summary:

Bayer’s Consent Decree with the FTC and DOJ, issued by the United States District Court for the District of New Jersey in 2007, prohibits the company from representing that any of its products “can or will cure, treat, or prevent any disease; or have any effect on the structure or function of the human body” or making any representation, express or implied “about the benefits, performance, or efficacy of any dietary supplement it markets or sells,” unless, at the time the representation is made, Bayer “possesses and relies upon competent and reliable scientific evidence that substantiates the representation.”  United States v. Bayer Corp., No. 0701, slip op. at 3 (D.N.J. Sept. 24, 2015) (citing Consent Decree §§ III.A-B, ECF No. 2). 

In 2011, the FTC began investigating whether Bayer had violated the Consent Decree in advertising for its Phillip’s Colon Health (PCH) probiotic dietary supplement that contained claims relating to constipation, diarrhea, gas, and bloating.  After receiving a significant volume of substantiating evidence from Bayer in 2011 and 2012, including (1) the results of a literature search and a medical Point of View memorandum, and (2) nearly 100 studies on the species of bacteria contained in PCH, the FTC nevertheless referred the case to DOJ.  In September 2014, the government moved for an Order to Show Cause why Bayer should not be held in civil contempt for violating the 2007 Consent Decree.

The government argued that, based on the opinion of its expert, Dr. Loren Laine, Bayer needed one or more randomized controlled trials (RCTs) on the specific product at issue to satisfy the Consent Decree’s “competent and reliable scientific evidence” standard for the claims at issue.  Because the company did not possess or rely on such data, the government contended that Bayer had failed to meet the substantiation standard set out in the Consent Decree. 

However, Bayer put forth two reputable experts in the probiotics field to contradict Dr. Laine’s interpretation of the FTC’s “competent and reliable scientific evidence” substantiation standard.  Those two experts (who had actually read the FTC’s substantiation guidance, unlike Dr. Laine) opined that Bayer’s evidence was more than sufficient to support its claims. 

The Court overwhelmingly accepted the arguments asserted by Bayer, and rejected those of the government. 

First, the Court determined that Bayer’s claims for PCH (namely, “To Promote Overall Digestive Health,” and “Helps Defend Against Occasional Constipation, Diarrhea, Gas and Bloating”) were not “disease” claims, a determination that found support in the testimony of the government’s own investigator.  See Bayer,slip op. at 9, 26.  The Court relied on the fact that Bayer characterized the claims as structure-function claims and included the Dietary Supplement Health and Education Act of 1994 (DSHEA) disclaimer (disclaiming any intent to treat, cure, or prevent disease).  The Court also flatly rejected the government’s suggestion that Bayer’s advertisements contained implied claims to treat, cure, or prevent disease, since (1) the government had failed to present clear and convincing evidence (in the form of consumer surveys, for example) that Bayer’s advertising implied disease prevention or treatment, and (2) the FTC had made no agency findings of implied claims.   The Court indicated the government’s argument that Bayer made implied disease claims was based on nothing more than “arguments of counsel.”  Bayer, slip op. at 11.

Second, the Court discounted the opinions of the government’s expert as to what level of substantiation was necessary under the “competent and reliable scientific evidence” standard.  The Court noted specifically that Dr. Laine’s opinion made no distinction between the level of substantiation that would be required for a drug, versus a dietary supplement, and indicated that such a distinction was necessary in light of DSHEA, as well as recent court rulings in Garden of Life and Basic Research.  To that point, the Court noted that Dr. Laine had no knowledge of the FTC’s guidance regarding claim substantiation for dietary supplements, or of the DSHEA statutory framework.  The Court was so dismissive of Dr. Laine’s opinions that we feel compelled to note that Dr. Laine did, in fact, survive a motion to exclude his testimony in this case.  In contrast, the Court recognized that Bayer’s experts, Drs. Merenstein and Fennerty, had specialized experience in the area of probiotics research, and credited their arguments that most experts in the field would disagree with Dr. Laine’s conclusion that RCTs were required.  

The Court also rejected the government’s argument that Bayer did not have adequate substantiation for its claims because it had not printed out the studies it had relied on.  The Court ruled that the “Consent Decree does not require Bayer to make records or copy studies,” but could instead rely on studies that were otherwise in the public domain.  Bayer, slip op. at 35-37.

The Court was presented with a clear legal issue; namely, did the 2007 Consent Decree provide adequate prior notice to Bayer that the company was legally required to have RCTs in order to meet the Consent Decree’s “competent and reliable scientific evidence” standard?  As an initial matter, the Court ruled that to be found in civil contempt of court, an entity must be shown to have violated a clear and unambiguous provision of the Consent Decree, and that the requirements must be set forth in the four corners of the Consent Decree.  It was undisputed that the Consent Decree did not explicitly require RCTs.  The Court noted that FTC hadimposed such a requirement in Orders issued to other advertisers, but failed to do so with respect to Bayer.  Thus, instead of citing clear wording in the Consent Decree itself, the government relied on Dr. Laine for the proposition that the dietary supplement claims at issue required RCTs under the Consent Decree.  The Court concluded that the government failed to demonstrate that Bayer had any notice that its claims would require substantiation in the form of RCTs, stating that the “[g]overnment cannot seek contempt on the basis of a lone expert who proposes a standard that was not disclosed to industry until the day the government filed its contempt motion.”  Bayer, slip op. at 28.   

In sum, the contest between the government and Bayer was largely the battle of experts that we expected.  While the government’s case failed in several respects, perhaps the most important of those failings was with respect to the selection and preparation of the government’s expert, Dr. Loren Laine (whose name may be forever linked with “Laine-Level substantiation,” the shorthand phrase used liberally by the District Court).  And Bayer’s success was largely attributable to its own experts – both its two consulting experts, and its internal medical staff who testified about the data in Bayer’s possession at the time it began making the claims for PCH.

So what can industry take away from this case?  While it is a significant victory for Bayer, this decision is not necessarily a significant (1) set-back for the FTC, or (2) boon to the dietary supplement industry, for a few key reasons.  

First, it is important to note that the government can still appeal this decision within 60 days.  If appealed, it is far from certain that the Third Circuit would uphold the District Court’s decision on appeal.  After all, the government succeeded in its appeal of Lane Labs before the Third Circuit in 2010.  In that case, another District Court Judge in New Jersey refused to find Lane Labs in contempt of court for its dietary supplement claims, finding that Lane Labs was in substantial compliance with a prior court injunction.  The Third Circuit reversed, holding that the District Court failed to provide adequate findings and had misapplied the “substantial compliance” standard for holding someone in contempt of court.  However, the lower court’s findings in Bayer are very different from those in Lane Labs:  The Bayer Court did not conclude broadly that the company was in substantial compliance, but instead found other legal and factual errors in the government’s position.

Second, as the District Court correctly points out, the government knows how to impose a more specific substantiation standard in a consent decree or litigated order.  See our series of posts on POM Wonderful LLC v. FTC; see also In the Matter of Nestlé HealthCare Nutrition, Inc., (No. 92-3087), 2010 WL 2811203 (F.T.C. July 14, 2010); Stipulated Final J. and Order for Permanent Inj. And Other Equitable Relief, FTC v. Iovate Health Sciences USA, Inc., (W.D.N.Y. July 29, 2010) (No. 10-cv-587); Consent Decree, United States v. Jason Pharms, Inc., (D.C. Cir. 2012) (No. 12-1476), ECF No. 3.  Thus, in response to the Bayer decision (following the Garden of Life, POM Wonderful, and Basic Research decisions we’ve blogged about here, here, and here), the FTC could be expected to simply (1) pursue specific substantiation provisions regarding RCTs even more doggedly in Consent Order negotiations and litigated orders, and/or (2) revise its substantiation guidance to explicitly require “Laine-Level” substantiation as “competent and reliable evidence” for certain categories of claims (thereby putting industry on notice of the requirement).

Third, Bayer did ultimately produce a large quantity of data and significant analysis in support of its structure function claims – undoubtedly at significant expense to the company.  If this level of substantiation is viewed by the government in the future as a “floor” for “competent and reliable scientific evidence” to support structure function claims, it is still a relatively high bar. 

One lesson for all companies regulated by FDA and the FTC is the Court’s analysis of Bayer’s good faith efforts to comply with the Consent Decree.  The Court noted that Bayer sought to ensure its compliance with the Consent Decree by following an extensive process that Bayer called its “Legal, Medical, Regulatory (LMR) review.”  Bayer,slip op. at 11.  That review and approval was required for every single piece of promotional material leaving Bayer.  Id.  Other companies would be well advised to establish and/or continue to have such reviews whether or not they are under a Consent Decree.

By James E. Valentine* & David C. Clissold –

On September 8, the U.S. Department of Health and Human Services (HHS) and fifteen other Federal departments and agencies announced a Notice of Proposed Rulemaking (NPRM) to revise the Federal Policy for the Protection of Human Subjects, known as the “Common Rule.”  This 1991 set of regulations created a uniform set of human subject protections which are codified in each department or agency’s title or chapter of the Code of Federal Regulations (CFR) based on HHS’ regulations at 45 CFR part 45, subpart A. 

The NPRM applies the same fundamental principles that underlie the Common Rule—respect for persons, beneficence, and justice—to the new contexts in which research is conducted in the 21st Century.  The proposal is intended, among other things, to account for the change in volume and landscape of research involving human subjects, as well as the greater scale and more diverse nature of such research.  The NPRM is also meant support efforts at HHS to harmonize human subjects policies between the HHS Office of Human Research Protection (OHRP) and FDA (e.g., see our previous post on FDA’s draft guidance on “Use of Electronic Informed Consent in Clinical Investigations,” which was developed as part of these efforts). 

Below are some of the major proposed changes set forth in the NPRM.

Reforming the Informed Consent Process

Tightening Informed Consent Documents

In an attempt to focus the informed consent document on the information critical to a prospective subject’s decision about whether or not to participate in a research study, and reduce the document’s length and complexity, the NRPM would:

• Add new language to strengthen the informed consent requirements to make sure the most appropriate information is presented to prospective subjects in a sufficient detail and in a format that is tied to understandability;
• Add new language that would clarify that, when a HIPAA authorization is combined with consent, the HIPAA authorization elements must be part of the core elements of consent.
• State wehther indentifiers will be removed from data and data then provided to other investigators for future use without additional informed consent, or that it will not be used or distributed for further research.
• If appropriate, inform the subject: (1) that the subject’s biospecimens may be used for commercial profit and whether the subject will or will not share in this commercial profit; (2) whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions; and (3) an option to consent, or refuse to consent, to investigators re-contacting the subject to seek additional information or biospecimens or to discuss participation in another research study.

Increasing Transparency

The NPRM would also require that, for clinical trials conducted or supported by a Common Rule department or agency, a copy of the final version of a consent form to posted on a publicly available federal website within 60 days after the trial is closed for recruitment.

Creating Information Privacy Protections

Under the NPRM, HHS would create a list of specific measures that the institution or investigator can use that will be deemed to satisfy the requirement for “reasonable and appropriate safeguards” for the protection of identifiable private information and biospecimens.  The regulations would also add limitations for the use and disclosure of identifiable private information and biospecimens.

Regulating Research Use of Identifiable Private Information & Biospecimens

The NPRM would now generally require informed consent for the use of identifiable private information and biospecimens in secondary research (e.g., information or biospecimens originally collected for clinical purposes or for use in research other than the proposed research).  This new requirement would be accomplished by changing the definition of “human subject.”  However, the consent would not need to be obtained for each specific subsequent study using the biospecimen, but could instead be obtained through “broad consent” for future unspecified research.  This requirement would be only apply prospectively to research involving biospecimens that are collected in the future, with implementation delayed until three years after publication of the final rule.

HHS must publish a “template” for the broad consent and, unless such broad consent is altered, no IRB review is required.  The proposal would only allow IRBs to waive the requirement for informed consent under a set of strict requirements so that waivers will only occur in rare circumstances.

Recalibrating the Review Process: Exclusions and Exemptions

The NPRM attempts to make the level of review more proportional to the seriousness of the harm or danger to be avoided.   Some studies that currently require IRB approval would now become exempt, and others that are currently exempt would specifically become excluded. 

An “exclusions” section would be created that would specify eleven types of activities that would be outside of the scope of the Common Rule (and would not be subject to any level of review):  

Activities Deemed Not to be Research

1. Program improvement activities (e.g., a survey of hospital patients to evaluate and improve the quality of meals delivered to hospital patients);
2. Oral history, journalism, biography, and historical scholarship activities that focus on the specific individuals about whom the information is collected;
3. Criminal justice activities (i.e., collection and analysis of data, biospecimens, or records by or for a criminal justice agency for activities authorized by law or court order solely for criminal justice or criminal investigative purposes);
4. Quality assurance and quality improvement activities (e.g., evaluation of the implementation of an accepted practice, such as education, training, and procedures related to care or services);
5. Public health surveillance activities (pursuant to or by a public health authority, limited to those necessary to fulfill its legal mandate);
6. Intelligence surveillance activities (conducted by a defense, national security, or homeland security authority solely for authorized purposes).

Activities that are Low-Risk and Already Subject to Independent Controls

1. Educational tests, survey procedures, interview procedures, or observation of public behavior (not including research activities where nay sort of intervention is used);
2. Research involving the collection or study of information that has or will be collected (current Common Rule exemption category 4);
3. Research conducted by a government agency using government-generated or government-collected data (if the information is collected and maintained in compliance with other certain Federal statutes);
4. Certain activities subject to the HIPAA Privacy Rule whose risks relate only to privacy and confidentiality;

Activities that Do Not Meaningfully Diminish Subject Autonomy

1. The secondary research use of non-identified biospecimens that are designed only to generate information about the individual that is already known (e.g., research to develop a diagnostic test for a condition using specimens from individuals known to have the condition and those known not to have the condition).

The NPRM also adds a number of “exemptions” to those currently set forth in the Common Rule, largely for categories of social and behavioral research.  To assist in determining when a study is exempt, a web-based “decision tool” will be created, which can be relied upon by investigators as a “safe harbor” for this determination.

Mandating Single IRBs

With the goal of streamlining the review process by reducing inefficiencies, the NPRM would require all U.S. institutions engaged in a cooperative study to reply upon a single IRB for that study, with some exceptions (e.g., where more than single IRB review is required by law, such as FDA-regulated medical devices).  In addition, the proposal extends regulatory requirements to IRBs that are not affiliated with an institution that is subject to the Common Rule if it reviews research covered by the Common Rule.

Changes to IRB Operational Requirements

The NPRM proposes a number of changes to the criteria for IRB approval of research, as well as IRB operations, functions, and membership, including:

• Eliminating the need for continuing review of research that has progressed to the data analysis or follow-up phase using data from procedures subjects would undergo as part of standard of care;
• Authorizing more limited IRB review of activities related to the storage or maintenance of biospecimens and identifiable private information for the purposes of doing secondary research;
• Have IRBs considering the equitable selection of subjects focus on issues related to coercion or undue influence in research with vulnerable populations;
• Allowing IRBs to consider both disabled persons and economically or educationally disadvantaged persons when determining that the selection of subjects is equitable and that they may be vulnerable to coercion or undue influence, as well as when considering IRB membership expertise;
• Making the default position that there is no need for additional IRB review of a research study’s privacy and security protections;
• Having IRBS, where a protocol calls for returning research results, determine whether the plan is appropriate; and
• Removing the provision regarding IRBs avoiding membership that consists entirely of individuals of one gender or profession since the requirements that IRB membership reflect members of varying backgrounds and diversity would accomplish the same goal.

Extending the Scope of the Regulations

Finally, one of the most significant proposals in the NPRM is with respect to the scope of clinical trials that are subject to the Common Rule.  Currently, the Common Rule applies to all research involving human subjects that is conducted or supported by a Federal department or agency that has adopted the policy.  The NPRM proposes an extension that would include clinical trials conducted at an institution in the United States that receives federal support for non-exempt and non-excluded human subjects research, regardless of the funding of the specific clinical trial.  Because the intent of this proposal is to ensure that clinical trials that would not otherwise be covered by federal research ethics regulations are covered, research subjects to FDA regulation would not be included in this expansion.  However, there might continue to be research that would be subject to both sets of regulations involving federal funding of research concerning an FDA-regulated product.

Questions to the Public

While the NPRM calls for input on each of its specific proposals, the notice calls out two overarching issues for which it is seeking comment:

1. Will the proposed changes decrease the administrative burden, delay, and ambiguity for investigators, institutions, and IRBs?
2. Will the proposed changes strengthen, modernize, and make the regulations more effective for protecting research subjects?

In addition, since FDA-regulated research remains exempt from the Common Rule under the NPRM, the notice considers whether there is the need for updates to FDA regulations where there is overlapping scope. 

As noted in the title of this post, the NPRM lays out 88 questions it would like comments on with respect to these proposals.  Comments are being accepted through December 7, 2015 here.  To assist stakeholders in reviewing the NPRM, OHRP has just released a 6-part webinar series available here.  

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.

By Jennifer M. Thomas –

On October 1, 2015, the U.S. District Court for the District of New Jersey unsealed its opinion in United States v. Bayer Corp., No. 07-cv-00001 (D.N.J. Sept. 24, 2015), confirming a significant defeat for the government, and a clear victory for Bayer.  Whether the decision represents a victory for the dietary supplement industry as a whole remains to be seen, depending on the government’s response to the case with respect to its enforcement efforts going forward and whether the government will appeal this ruling.

We have previously blogged about the Bayer case here and here, and those postings include links to key documents including the underlying 2007 consent decree, the government’s motion for an Order to Show Cause, Bayer’s response to that motion, the Council for Responsible Nutrition’s and Natural Products Association’s requests to participate as amici, and the Court’s Order granting the government’s motion for an Order to Show Cause.

We will post a more detailed analysis of the Bayer case and its potential effects in the coming days. 

By Kurt R. Karst –

On September 30, 2015, Judge Randolph D. Moss of the U.S. District Court for the District of Columbia issued his highly-anticipated decision in a lawsuit lodged by Eisai Inc. (“Eisai”) last August challenging FDA's April 2014 denial of a Citizen Petition (Docket No. FDA-2013-P-0884) requesting that the Agency conclude that the 5-year New Chemical Entity (“NCE”) exclusivity start dates for Eisai's BELVIQ (lorcaserin HCl) Tablets (NDA 022529; approved on June 27, 2012) and FYCOMPA (perampanel) Tablets (NDA 202834; approved on October 22, 2012) are triggered only when FDA-approved labeling incorporating the final DEA Controlled Substances Act (“CSA”) scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  In granting FDA's Motion for Summary Judgment and denying Eisai's Motion for Summary Judgment, Judge Moss concluded that despite some good arguments put forth by Eisai, FDA's interpretation of the Agency's own controlling regulation defining the term “date of approval” is not plainly erroneous or inconsistent with that regulation.  “This case . . . turns on the meaning, not the wisdom, of an FDA regulation implementing the Hatch-Waxman Amendments,” writes Judge Moss.  “Under that regulation—the validity of which Eisai does not challenge—the exclusivity period for a new drug begins when the FDA issues its letter approving the drug, even if the drug’s manufacturer must await DEA’s scheduling determination before it can bring the drug to market.  The regulation does provide for an exception under limited circumstances.  But the FDA has interpreted that exception narrowly, and the Court is bound to defer to the agency’s reasonable interpretation of its own regulation.  Because Eisai’s drugs do not qualify for the exception under the FDA’s interpretation of its regulation, the FDA and its co-Defendants are entitled to summary judgment.”

There's a lot of background to Eisai's case against FDA, which we've reported on in previous posts (here, here, and here) and that we won't repeat here.  (Eisai even unsuccessfully challenged DEA in court before challenging FDA – see our previous post here.)  The regulation at issue in the case is in 21 C.F.R. § 314.108(a), which defines the term “date of approval” to mean:

the date on the letter from FDA stating that the new drug application is approved, whether or not final printed labeling or other materials must yet be submitted as long as approval of such labeling or materials is not expressly required. “Date of approval” refers only to a final approval and not to a tentative approval that may become effective at a later date. [(Emphasis added)]

Eisai alleged in its Complaint that FDA violated the FDC Act and the Administrative Procedure Act (“APA”) in multiple respects by using the BELVIQ and FYCOMPA NDA approval dates as the triggering events to start the NCE exclusivity periods, thereby possibly accelerating the timing of future generic competition for BELVIQ and FYCOMPA.  According to Eisai:

[C]onsistent with FDA’s regulation—21 C.F.R. §314.108(a)—the governing statute, and clear congressional intent, market exclusivity for BELVIQ® and FYCOMPA® should have been triggered when labeling incorporating the final CSA schedule permitted legal marketing of the products.  FDA’s letters approving the products as safe and effective reinforce this requirement.  FDA’s letters make clear that the products’ labeling would need further revisions once CSA scheduling was complete. . . .  Thus, after CSA scheduling, a revision to the labeling was expressly required before the product could be legally marketed.  Therefore, the date of the approval letters cannot be considered the triggering date for market exclusivity purposes.

As to Eisai's argument that the company should prevail because the FDA letters approving BELVIQ and FYCOMPA contained language that should have brought the drugs within the exception to 21 C.F.R. § 314.108(a) (highlighted above), thereby delaying the official approval date, it was a close call for the court.  “The question here is whether the NDA approval letters themselves 'expressly required' that approval.”  If so, wrote Judge Moss, “then the drugs should have fallen within the exception in § 314.108(a), even as the FDA construes the regulation, and should have received an official approval date that reflected that later approval. This is a close question on the facts.”  

As the court read FDA's BELVIQ and FYCOMPA approval letters, “both expressly require Eisai to revise the labels, but neither expressly requires that the FDA approve those edits.  It is true that the letters require the sort of label revision that the FDA must presumptively approve under its regulations. But only an express requirement of FDA “approval” triggers the exception in 21 C.F.R. § 314.108(a), at least as the FDA construes that exception, and the letters say nothing about approval” (emphasis in original; citation omitted).  This is a fine, but not insignificant distinction, as noted by Judge Moss. “Because those letters did not facially contain an 'express[] require[ment]' that the FDA approve of additional labeling requirements and because Eisai understood that, in fact, the FDA would not need to approve of any additional labeling requirements before the company could take the drugs to market, the Court concludes that the FDA’s decision to consider the date of approval for both Belviq and Fycompa as the date found on their NDA approval letters was not arbitrary or capricious.” 

Judge Moss then turned to whether or not FDA reasonably construed the exception to its regulation defining “date of approval.”

[I]n run-of-the-mill cases, the date of approval is simply the “date on the letter from the FDA stating that the new drug application is approved.”  There is little room for the agency to interpret this clear rule, and its interpretation is not at issue here.  There is room, however, to interpret the exception to the general rule, which applies when “approval of [final printed] labeling or other materials” is “expressly required.”   The regulation is entirely silent as to who must “expressly require[ ]” labeling approval, where that requirement must appear, or even what constitutes an “express require[ment].”  [(Emphasis in original)]

But after analyzing the text of 21 C.F.R. § 314.108(a), FDA's intent behind the regulation, and the statutory purpose of NCE exclusivity, Judge Moss decided that FDA had a reasonable interpretation of its regulation:

Although the extent to which the current regulatory scheme comports with the incentive structure that the Hatch-Waxman Amendments put in place raises difficult issues, the question presented here is a narrow one: Is the FDA’s interpretation of the exception to its “date of approval” regulation “plainly erroneous or inconsistent with the regulation.”  The answer to that question is relatively straightforward.  The FDA has reasonably construed the exception to mean that the requirement for further FDA approval must appear in the letter itself.  

Before turning to prior FDA practice and some other miscellaneous arguments Eisai raised, Judge Moss addressed a lingering “interpretive question”: “What rational basis might plausibly exist to confer different effective periods of exclusivity on new drugs based on whether a requirement for further FDA approval of labeling or other materials is expressly mentioned in the approval letter itself or simply mandated by statute or regulation.” The answer, said Judge Moss,

is that the approval letters signify completion of the FDA’s process for reviewing and approving a manufacturer’s NDA. . . .  Some requirements that may remain after the FDA sends such a letter are ministerial and do not affect the finality of that approval. In those circumstances—including when the manufacturer will have to finalize a label to reflect DEA scheduling—the FDA does not need to consider further any aspect of the NDA and so it treats its “approval” as final.  In other cases, however, the requirements that remain are substantial and will require further substantive review and approval.  In those cases, the agency expressly requires further action in its approval letter as a signal that the FDA has concluded that its process is not yet completed.  Although not the only method that the FDA might use to differentiate applications that require no further substantive review from those that still demand some significant approval, the approach the FDA has adopted is a reasonable one.  The operative statute makes it necessary for th e FDA uniformly to define the “date of approval,” and the agency drew that line in a reasonable place. The Court, accordingly, concludes that the FDA’s interpretation of 21 C.F.R. § 314.108(a) is not “plainly erroneous or inconsistent with the regulation,” and it thus defers to that interpretation.  [(Emphasis in original; citation omitted)

Finally, Judge Moss addressed a precedent Eisai raised concerning FDA's decision to reset the NDA approval and NCE exclusivity dates of RAZADYNE ER (galantamine hydrobromide) Extended-release Capsules (NDA 021615).  Eisai argued that FDA's decision on RAZADYNE ER is inconsistent with FDA's construction of 21 C.F.R. § 314.108(a) as applied to BELVIQ and FYCOMPA.  (The RAZADYNE ER precedent was also raised by another company in a citizen petition – see here – that FDA later denied – see here.)  But Judge Moss found instead that the RAZADYNE ER precedent helps to define the contours of the exception under § 314.108(a):

The Razadyne letter thus reveals where the FDA draws the line for the § 314.108 exception.  Its interpretation is strict enough that merely mentioning regulatory obligations that, in turn, give rise to a requirement to obtain approval of a label change is insufficient to trigger the exception.  But it is accommodating enough that language expressly referring to an obligation to submit labeling-related materials for “review” qualifies for the exception.  The agency did not need to draw the line in this place—it could have adopted an interpretation of the exception under which both Eisai and the sponsor of Razadyne qualified, and it likely could have adopted an interpretation under which neither qualified.  The conclusion it actually reached, however, reasonably relies on a real—even if modest—textual difference in the letters the FDA issued, and it warrants deference. 

There's more in Judge Moss' decision as to additional arguments Eisai raised in the litigation against FDA.  But it's getting late in the night, so we'll leave it to you to peruse the remainder of the decision (pages 28-31).

We'll know in the coming weeks whether or not Eisai's bid to reset the NCE exclusivity start dates for BELVIQ and FYCOMPA will continue on with an appeal to the U.S. Court of Appeals for the District of Columbia Circuit.  In the meantime, we note that Congress is considering legislation – H.R. 639, the Improving Regulatory Transparency for New Medical Therapies Act – that would, among other things, amend the FDC Act to delay the effective date of approval (and therefore, delay the start of applicable exclusivity and other deadlines keyed to an approval date) of a drug, biological product, or animal drug for which FDA recommends scheduling under the CSA until the Department of Justice issues a final interim scheduling rule for the product. 

By Douglas B. Farquhar –

Industry newsletter The Pink Sheet reports that, at a conference Monday, FDA said that investigators performing FDA inspections will likely be divided into “subspecialties within the various product groups.”  Thanks for reporting that news, but we are not sure we agree with The Pink Sheet prediction that this development “surely will be welcomed by industry, because it could lead to smoother inspections.”

Notably, the announcement was made by FDA’s GDUFA (Generic Drug User Fee Act) staff director for the Office of Regulatory Affairs at FDA.  She has been a very busy woman: the number of Warning Letters issued to drug manufacturers has mushroomed in recent years, and most of those letters have been issued to foreign generic drug manufacturers, or to the facilities that manufacture Active Pharmaceutical Ingredients (many of which are used in generic drug manufacturing).  Indeed, we reviewed Warning Letters issued by FDA between July 1, 2013, and May 26, 2015, and of the 35 Warning Letters issued during that period to mainstream human drug manufacturers for cGMP violations (excluding compounding pharmacies), 30 were for facilities outside the United States and 22 were for data integrity/data integrity protection issues.  We haven’t performed a detailed analysis of Warning Letters posted in the last four months, but a quick review shows that the trend continues.

Reasons that there have been so many Warning Letters in this area include the increased number of foreign inspections, and the increasing specialization of the investigators performing these inspections.  One of the investigators who identified many of the deficiencies leading to the Warning Letters is Peter Baker, who is stationed in India, but has also performed inspections in China.  To his credit, Mr. Baker has proven to be especially gifted at tracking down laboratory testing (usually performed on High Performance Liquid Chromatography equipment, or moisture analysis equipment) that has not been properly analyzed, documented, or reported by laboratory personnel.  Another trend is that microbiological and sterile technique experts are being sent to inspect aseptic processing areas, enforcing very strict – some would say unreasonably strict – standards in sterile manufacturing technique, or environmental or personnel monitoring.

Such specialized investigators may be more adept and knowledgeable at identifying issues, making for undoubtedly “smoother inspections” instead of flailing around.  But just because an inspection may be smoother, it does not mean that there will be happier consequences for the affected facilities.

What’s a pharmaceutical manufacturer to do?  Ensure that all electronic testing equipment is Part 11 compliant, and perform regular audits of electronic data to make sure that testing is not being hidden, that data are not being destroyed, and that laboratory and manufacturing personnel are strictly following Good Documentation Practices.  Also, watch Warning Letters for trends in cited deficiencies, and do everything possible to ensure that when specialized investigators show up to perform an inspection, you are confident that you know what they will find.

As the experience of many companies has demonstrated, the expenditures required to identify and correct problems in advance of an FDA inspection are only a fraction of what is required if the specialized investigators identify the problem for you, and FDA imposes serious sanctions, such as import alerts. 

By Jamie K. Wolszon & Jeffrey N. Gibbs –

As kids around the country return to school, FDA also appears to be returning from a break—in this case a break from public enforcement-type activities related to laboratory-developed tests (LDTs)—with the issuance of a letter to Pathway Genomics.  FDA has a litany of concerns, including that the test appears to be marketed without requisite FDA approval, clearance, listing or adequate clinical validation and the test may hurt the public health.  Meanwhile, Congress is back in action—or what passes for action these days—and there is yet another proposed legislative alternative to the FDA Framework—this time from laboratory accrediting body the College of American Pathologists (CAP).  And while we are on the topic of LDTs, we also think it is worth noting that a significant number of comments submitted to the Framework draft guidance docket still have yet to be made available, and some critics have voiced suspicions that comments favorable to the proposal are more likely to be posted in a timely fashion, and unfavorable comments to remain unpublished.

FDA Letter to Pathway Genomics

As we have previously reported (here, here, and here), in October 2014, FDA issued its controversial two draft guidances that outlined its proposal to actively regulate LDTs.  Since that time, we are unaware of any public action by FDA against an LDT—until now.

On September 21, 2015, FDA sent a letter to Pathway Genomics stating that the CancerIntercept Detect, a non-invasive blood test intended for use as a screening tool for the early detection of up to 10 different cancer types in high-risk populations, appears to be an unapproved device that does not have a PMA, 510(k) or requisite listing.  Although it is not a Warning Letter, FDA posted the letter on its website, indicating that it believes it is important to communicate.  FDA stated that the Company was marketing the test under a “direct-to consumer type model.”  FDA continued: “Under this model, you ship blood collection tubes, a medical device, for use with CancerIntercept Detect.”  The use of the collection system provides the articulated jurisdictional hook for the agency.

The letter also states that the test lacks adequate clinical support for the claims it is making.  “We have also examined published literature and have not found any published evidence that this test or any similar test has been clinically validated as a screening tool for early detection of cancer in high-risk individuals. We have reviewed the information presented on your website in the white paper, entitled ‘Liquid Biopsy for the Detection and Monitoring of Cancer: Analysis of 96 Hotspot Mutations via Plasma Derived Circulating Tumor DNA,’ dated September 2015. It is unclear how the literature that you cited, addressing the presence of circulating tumor DNA (ctDNA) in already-diagnosed patients, is adequate to support the expansive claims of screening for early cancer detection using ctDNA in undiagnosed patients for up to 10 different cancers with the CancerIntercept Detect,” the letter states. 

FDA calls on the Company to discuss with the Agency “your offer of the CancerIntercept Detect and the associated blood specimen collection device, and any validation strategies you have undertaken beyond those reported in the publications cited in your white paper, including your determination of the test’s clinical sensitivity and specificity and the corresponding positive and negative predictive values for its claimed intended use.”  The letter requests a proposed timeline from the Company within 15 days. 

The letter states that the Agency “is committed to working with you as we strive to protect the public health without unnecessarily imposing regulatory burdens on the marketing of products of potential clinical importance.”  We do not recall seeing similar language in similar letters by FDA.  The inclusion of this language suggests that the Agency is sensitive to the current climate as the draft guidances are pending.

Pathway Genomics released a response on September 24, 2015, stating that it would respond to the FDA letter.  The Company did not take a conciliatory tack, contesting the assertion that it was offering a DTC model.   “We assure that there is physician involvement in the ordering, review and follow-up of CancerIntercept testing.  We believe that CancerIntercept Detect is a laboratory-developed test and, as a CLIA and CAP certified clinical laboratory, we are offering it as such.  While Pathway Genomics is involved in educating and marketing the tests to physicians and consumers, we do not believe this is a direct-to-consumer model.”  The Company also took issue with the statement that there was not adequate clinical support: “We believe we have performed appropriate validation of the test as a laboratory-developed test, and we are in the process of performing additional studies.”

This is not the first time that Pathway Genomics has been the subject of FDA scrutiny:  In May 2010, FDA sent a letter to Pathway Genomics objecting to its home-use saliva collection kit to analyze for predisposition for over 70 genetic conditions.

CAP Adds to Legislative Proposals that Would Serve as Substitute for Framework

The FDA letter comes on the heels of CAP unveiling what is now the third publicly proposed legislative alternative to FDA’s Framework.  As we previously reported, the Association of Molecular Pathology (AMP) announced in a press release that it has met with the Senate Health, Education, Labor and Pensions Committee to propose a legislative solution to modernize the Clinical Laboratory Improvement Amendments (CLIA), including premarket review by the Centers for Medicare & Medicaid (CMS) or its designated third parties, as a substitute to the FDA Framework.  We also previously reported that a group of labs and in vitro diagnostic kit companies called the Diagnostic Test Working Group have tried to craft their own legislative solution. 

The CAP proposal would amend the Federal Food, Drug, and Cosmetic Act to subject high-risk LDTs to existing FDA pre-market and post-market requirements.  The proposal also would modify CLIA to subject low and moderate-risk tests to CMS regulation; under the proposal, CMS or a third party would review moderate-risk tests.  Low-risk tests would not undergo premarket review.  In several respects, the CAP legislative proposal is similar to the AMP proposal.  For instance, both similarly define high-risk, moderate-risk and low-risk tests.  Both exempt low-risk tests from premarket review, would give CMS or third-party reviewers sole authority to review moderate-risk tests, and FDA would only get involved for high-risk tests (all high-risk tests under the CAP proposal and a subset of high-risk tests under the AMP proposal).  Both would exempt tests for rare disorders from premarket review.  However, the CAP proposal, unlike the AMP proposal, incorporates certain elements of the FDA Framework (with modifications), such as exceptions from premarket review for tests for unmet needs and “traditional LDTs,” and a separate requirement for notification to the Secretary (presumably through CMS but it is unclear) of tests.

The flurry of legislative proposals is enough to make even the most dedicated LDT-watchers lose track.  In an effort to provide some clarity about the competing proposals, we provide a chart comparing some of the key provisions of the AMP and CAP proposals, as described in publicly available documents.  We do not include the DTWG proposal in this chart as it has been reported that members of the group are working with the House Energy & Commerce Committee on a revised version; we fear that the DTWG proposal will change as soon as this blog is posted.  Of course, if any legislation is enacted, it is likely to look different from what is proposed.

Large Number of Comments to Framework Still have Yet to be Posted

We previously reported that, according to regulations.gov, FDA has received 236 comments on the draft “Framework” guidance; however, it has only posted 170 of those comments.  As of this writing, that number has not changed.  But some critics are suspicious that FDA is more likely to post a comment if the comment is favorable to the proposal than if the comment is negative.  One member of the laboratory community, which submitted comments that criticized the proposal well within the deadline for comments, said that FDA did not initially post their comments.  When they called to inquire, they were informed that it had been flagged for an inappropriate reason, and the comments were subsequently posted.  By contrast, according to the individual, one company submitted comments that were favorable to the proposal after the docket deadline, and those got posted within a few weeks.  Several weeks after that company submitted their comments late, additional comments were posted that had been submitted on time but were against the proposal.  Whatever the objective validity of their concerns, it speaks to a perception that FDA is not acting fairly.