By Kurt R. Karst –

For several years now we have been following instances in which FDA designated, and later approved, a drug (including a biological product) as an “orphan drug” on the basis that it is not the “same drug” as a previously approved product containing the same active moiety (or, in the case of macromolecules, containing the same principal molecular structural features) for the same orphan condition because the subsequent product is “clinically superior” to the prior product.  In those instances, the subsequent product can be approved notwithstanding an unexpired period of 7-year orphan drug exclusivity for another product that is otherwise the same orphan drug, and/or the subsequent product can earn a period of orphan drug exclusivity. 

Unfortunately, there is no FDA database that compiles the various drug products approved on the basis of a clinical superiority determination. FDA’s Orphan Drug Designations and Approvals Database, although it sometimes provides a hint as to whether or not a product was designated or approved on some clinical superiority basis, is generally opaque on the issue.  That means to find precedents folks generally have to sift through approval documents, submit FOIA requests to FDA, or otherwise look for “magic language” in company press releases announcing FDA’s grant of an orphan drug designation (or orphan drug approval).

We’ve tried to lift the veil of darkness by posting on clinical superiority precedents as we come across them, for example, here, here, here, and here.  With our recent discovery of yet another clinical superiority precedent – yet again involving the so-called Major Contribution to Patient Care (“MC-to-PC”) basis for demonstrating that an orphan drug is clinical superiority to another drug that is otherwise the same drug – we thought it was high time to put together a list of precedents.  But before we get to that list and the precedent we recently found, some background is in order, particularly for those folks new to the orphan drug space. . . .

FDA’s orphan drug regulations (21 C.F.R. Part 316) define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;

(2) greater safety in a substantial portion of the target population; or

(3) demonstration that the drug makes a major contribution to patient care.

To support a claim of “clinical superiority” based on greater effectiveness, generally the same kind of evidence is needed as that required to support a comparative effectiveness claim for two different drugs. That is, the second drug must demonstrate an improvement as assessed by “effect on a clinically meaningful endpoint in adequate and well-controlled clinical trials.”  FDA’s regulations also provide that, “in most cases, direct comparative clinical trials would be necessary” to demonstrate greater effectiveness. 

To support a claim of “clinical superiority” based on superior safety, the second product must provide “[g]reater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects.” FDA’s regulations also state that “[i]n some cases, direct comparative clinical trials will be necessary.”

With respect to a MC-to-PC “clinical superiority” claim, FDA states in the Agency’s regulations that it make such determinations only in “unusual circumstances.” While MC-to-PC determinations are made on a case-by-case basis, in the preamble to FDA’s final 1992 orphan drug regulations, the Agency commented that “convenient treatment location; duration of treatment; patient comfort; improvements in drug efficiency; advances in the ease and comfort of drug administration; longer periods between doses; and potential for self administration . . . when applicable to severe or life threatening diseases, might sometimes be legitimately considered to bear on whether a drug makes a major contribution to patient care.”

Although MC-to-PC clinical superiority decisions are supposed to be unusual, of the three clinical superiority bases FDA lays out in the Agency’s orphan drug regulations, it appears that it is the most common basis accepted by FDA’s Office of Orphan Products Development (“OOPD”) (at least in recent years). A precedent that recently came to our attention involves Sotalol Hydrochloride Injection, which FDA approved on July 2, 2009 under NDA 022306 for use as a substitute for oral sotalol in patients who are unable to take sotalol orally.  (Oral sotalol is indicated for maintenance of normal sinus rhythm in patients with history of highly symptomatic atrial fibrillation/flutter, and for treatment of documented life-threatening ventricular arrhythmias.)  The approved indication really says it all insofar as FDA’s clinical superiority basis is concerned; however, additional detail on the determination is provided in OOPD’s Orphan Drug Designation Review Memorandum.

Precedents for each of the three clinical superiority bases are grouped below. Each precedent concerns an approved product for which clinical superiority was determined by FDA to be necessary to break another sponsor’s orphan drug exclusivity, and/or for a sponsor to qualify for orphan drug exclusivity.  Other clinical superiority precedents exist, but they have either not yet come to fruition (e.g., because a product was merely designated based on a plausible hypothesis of clinical superiority and the product has not progressed to the FDA approval stage where FDA has to more closely examine the issue of clinical superiority), or a company’s bid for orphan drug exclusivity was unsuccessful (e.g., because the product for which designation was granted based on a plausible hypothesis of clinical superiority was approved for a use broader than the designated use, or because the sponsor failed to demonstrate clinical superiority . . . an issue that has been litigated in recent years – see here).  For example, we understand that EPANED (enalapril) for Oral Solution (NDA 204308), although designated for the treatment of hypertension in pediatric patients, failed to demonstrate clinical superiority; and SOTOLYZE (sotalol hydrochloride) Oral Solution (NDA 205108) was approved for a use broader than the orphan drug-designated use: for the treatment of documented life-threatening ventricular arrhythmias and the maintenance of normal sinus rhythm in pediatric and adults patients with history of highly symptomatic atrial fibrillation/flutter.  To the extent FDA Law Blog readers are aware of additional clinical superiority approval precedents, we’re all ears.

Greater Effectiveness Clinical Superiority Determinations

• In 2002, FDA determined (here and here) that Serono’s REBIF (interferon beta-1a) (BLA 103780) was “clinically superior” to Biogen’s AVONEX (interferon beta-1a) (BLA 103628) for the treatment of relapsing-remitting multiple sclerosis based on data from a head-to-head clinical trial demonstrating improved efficacy of REBIF over AVONEX in the frequency of multiple sclerosis exacerbations.  The effect of FDA’s approval of REBIF is that it broke AVONEX’s orphan drug exclusivity with respect to the marketing of REBIF only. 

Greater Safety Clinical Superiority Determinations

• In 1992, FDA determined that Armour’s MONONINE (coagulation factor IX) (BLA 103597) was clinically superior to Alpha Therapeutic’s ALPHANINE (coagulation factor IX) (BLA 103249).  This determination was based on manufacturing data in the MONONINE BLA that allowed FDA to conclude that the viral inactivation process used in manufacturing MONONINE “may result in a product less likely to transmit hepatitis C infection than . . . AlphaNine,” and further, that the prospect of improved viral safety allowed FDA to conclude that MONONINE was “probably a safer drug,” and thus approval of MONONINE was not blocked by ALPHANINE’s orphan drug exclusivity. 
• In 1996, FDA determined that Biogen’s AVONEX (interferon beta-1a) (BLA 103628) was clinically superior to Berlex’s BETASERON (interferon beta-1b) (BLA 103471) based on a reduced risk in AVONEX of one adverse event (injection site necrosis) associated with BETASERON.  FDA made its clinical superiority determination by comparing the labeled reports for BETASERON versus the injection site reaction attack rate and severity in the AVONEX pivotal study. 
• In 1997, FDA determined that Genetics Institute’s BENEFIX (coagulation factor IX) (BLA 103677) was clinically superior to MONONINE and ALPHANINE based on the fact that “BeneFix™ is inherently less likely to transmit human blood-born viruses and other infectious agents, and is also less likely to transmit animal-derived zoonotic agents.” 
• In 1997, FDA determined that Fujisawa’s AMBISOME (amphotericin B) (NDA 050740) was clinically superior to Enzon’s ABELCET (amphotericin B) (NDA 050724) based on the fact that “AmBisome appears to have a reduced frequency of the typical amphotericin B infusion reactions as compared to Abelcet, particularly with respect to hypotension and tachycardia, dyspnea, hypoxia or ‘severe asthma.’” 
• In 2010, FDA determined that United Therapeutics Corp.’s TYVASO (treprostinil) Solution for Inhalation (NDA 022387) was clinically superior to the company’s REMODULIN (treprostinil) Injection (NDA 021272), thus granting the company a second period of ODE for a second generation drug product.  Specifically, FDA determined that TYVASO, as an inhaled prostacyclin analogue, represents an important safety gain compared to prostacyclin analogues that had to be given subcutaneously or via a central venous line.  The widespread and severe nature of the pain associated with subcutaneous treprostinil and the risks of sepsis and death from the intravenous administration of treprostinil via indwelling venous catheter made the inhaled product clinically superior. 

MC-to-PC Clinical Superiority Determinations

• In 1998, FDA determined that Novartis’ reformulated SANDOSTATIN LAR (octreotide) (NDA 021008) was clinically superior to a previously approved subcutaneous dosage form of SANDOSTATIN (NDA 019667), because “patients can be managed with one injection per month instead of sixty to ninety injections.” 
• In 2007, FDA determined that Indevus’s histrelin acetate implant drug product, SUPPRELIN LA (NDA 022058), was clinically superior to SUPPRELIN (NDA 019836) on the basis that “a single histrelin subcutaneous implant could provide therapeutic blood levels for a period of 1 year versus 365 daily injections of Supprelin.” 
• In 2008, FDA determined that Antisoma’s Fludarabine Phosphate 10 mg Tablets for Oral Use (NDA 022273) was clinically superior to FLUDARA (fludarabine phosphate) for Injection (NDA 020038) because of a change in dosage form from injection to oral (a change identified by FDA as constituting a major contribution in the preamble to the Agency’s orphan drug regulations).
• In 2009, FDA determined that Academic Pharmaceuticals’s Sotalol Hydrochloride Injection (NDA 022306) was clinically superior to BETAPACE (sotalol HCl) Tablets (NDA 021151 and NDA 019865) because of a change in dosage form from oral to injectable and for patients unable to use the oral dosage form of the drug (e.g., because of surgery, intubation, acute illness, etc.).
• In 2011, FDA determined that Arbor's NYMALIZE (nimodipine) Oral Solution, 60 mg/20 mL (NDA 203340), was clinically superior to Bayer’s NIMOTOP (nimodipine) Capsules (NDA 018869) on the basis that the oral formulation “represents a major safety initiative that [FDA has] undertaken to eliminate a rare, but persistent error that may be, and has been, fatal.”  Specifically, it addressed the concern arising from health care providers extracting the capsule contents with a syringe and administering it intravenously. 
• In 2013, FDA determined that Raptor’s PROCYSBI (cysteamine bitartrate) Delayed-release Capsules (NDA 203389) was clinically superior to Mylan’s CYSTAGON (cysteamine bitartrate) Capsules (NDA 020392) based on a new dosing regimen.  According to FDA, “[s]ince it is recognized that cysteamine must be dosed at a strict q6h regimen to achieve its maximum benefit in cystinosis patients and that it is documented that many patients with cystinosis are unable to follow a strict q6h regimen throughout their lifetime, a q12h cysteamine product that can maintain cystine at the [white blood cell] levels to achieve maximum benefit can provide a MC to PC over a q6h cysteamine product.” 
• In 2015, FDA determined that Eagle’s RYANODEX (dantrolene sodium) for Injectable Suspension (NDA 205579) was clinically superior to DANTRIUM IV (dantrolene sodium for injection) (NDA 018264) on the basis that “the ability of the anesthesiologist to reconstitute and administer Ryanodex within one minute allowed the anesthesiologist to concentrate on continued supportive care and treatment of the patient with malignant hyperthermia compared to treatment with the previously approved dantrolene product that required up to one hour to reconstitute and administer, which would not allow the anesthesiologist to fully concentrate on the other aspects of treatment and support of the patient.” 

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By Kurt R. Karst –

Ever since FDA Commissioner Dr. Robert M. Califf's February 2016 call for a sweeping review of FDA policies concerning opioids (in response to growing pressure from Congress), the Agency has been on a tear to meet that call with new policies and requirements.  There's the recent announcement that the Agency will require class-wide safety labeling changes for immediate-release opioid pain medications (as well as a related citizen petition response – Docket No. FDA-2014-P-0205).  And now FDA is tackling generic opioids. 

On March 24, 2016, FDA announced (Docket No. FDA-2016-D-0785) the availability of a highly-anticipated draft guidance document concerning abuse-deterrent Solid Oral Dosage Form (“SODF”) generic opioids: “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drugs.”  Publication of the draft guidance is now one of the items we can check off of the Calendar Year 2016 Guidance Agenda FDA published in January 2016. (This blogger is still sitting on the edge of his seat watining for other guidances identified in the “Generics” category of the Guidance Agenda, including “180 Day Exclusivity: Guidance for Industry;” “Three-Year Exclusivity Determinations for Drug Products;” “Submission of ANDAs for Certain Highly Purified Synthetic Peptide Drug Products;” and “Determining Whether to Submit an Application Under 505(b)(2) or 505(j).”)

The draft guidance, which is a nice complement to the brand-side guidance – “Abuse-Deterrent Opioids: Evaluation and Labeling” (see our previous post here) – lays out the principles for ANDA applicants to evaluate the abuse-deterrence of a proposed generic version of a brand-name Reference Listed Drug (“RLD”) with labeling that describes properties that are expected to deter misuse or abuse. We’ve seen things here and there over the past few years giving us some vague sense of FDA’s thinking on how an ANDA applicant might demonstrate that a generic SODF opioid drug product is no less abuse-deterrent than the RLD with respect to potential routes of abuse. . . but nothing solid . . . just bread crumbs. Consider, for example, FDA’s Draft Bioequivalence Guidance for generic EMBEDA (morphine sulfate/naloxone) Extended-release Capsules (NDA 022321), which recommends a “fasting, crushed drug product” study to allow “for the assessment of Naltrexone bioequivalence in a potential abuse situation.”

For now, the draft guidance provides testing recommendations for four of the seven categories of abuse-deterrent technologies described in FDA’s “Abuse-Deterrent Opioids: Evaluation and Labeling” guidance: solid oral opioid drug products formulated to incorporate physical or chemical barriers, agonist/antagonists, aversive agents, or combinations of two or more of these technologies (but not products in the delivery system, NME/prodrug, or novel approaches categories). For these technologies, and where the RLD labeling describes abuse-deterrent properties, FDA recommends that ANDA applicants conduct a comparative evaluation of the abuse potential of the proposed generic test product (“T product”) to the RLD product (“R product”) – sometimes including a control product (“C product”) – taking into consideration all potential routes of abuse (i.e., injection, ingestion, insufflation, and smoking) according to the following five principles:

• Tier-based approach to testing. FDA recommends that potential ANDA applicants follow a tier-based approach to efficiently compare a T product to its R product and limit the number of tests required for evaluating the abuse deterrence of T product. This tier-based approach allows for hierarchical testing, starting with simple and gentle manipulations of the product in in vitro studies (Tier 1) and progressing to more destructive mechanical and chemical manipulations until R product’s abuse deterrence is defeated or compromised, or T product is shown to be less abuse-deterrent than R product.
• Evaluation of Abuse Deterrence. The evaluation of the abuse deterrence of the T product should be based on its performance relative to R product. The proposed generic product need not have the same formulation design as the R product. In order to adequately compare R and T products, a potential ANDA applicant should identify the R product’s abuse deterrence for all routes of abuse using the tier-based approach described in this guidance. If R product has not been found by the potential applicant to have any abuse deterrence for a particular route of abuse, the potential applicant should summarize the studies conducted and the results to support the applicant’s assessment that the RLD has no abuse deterrence with respect to that route and explain why there is no need to test its T product in comparative in vitro or other studies for that route. The evaluation of the abuse deterrence of T product should be based on the potential applicant’s best understanding of the abuse deterrence of R product, the potential routes of abuse, and specific measures meaningful to the evaluation of abuse by those routes. . . .
• Use of control.  Manipulation of an opioid product is a function of several factors including, but not limited to, tampering skills, time, and tampering resources available. The abuse-deterrent properties of currently approved drug products are not absolute, and can eventually be compromised or defeated. Therefore, it is important to identify appropriate discriminatory study conditions to compare R and T products. For certain comparative studies (e.g., extractability studies), such discriminatory study conditions should be identified by including a [C product] and comparing it to R product in order to identify the abuse deterrence of R product. Potential ANDA applicants should select an appropriate C product for their proposed T product. When available, C product should be a non-abuse-deterrent version of the opioid R product that contains the same active pharmaceutical ingredient (API) as the R product.
• Identification of discriminatory study conditions. The parameters for the discriminatory study conditions should lie within the range specified in this guidance for different routes of abuse (Appendices 2-5). In order to determine the abuse deterrence of T product by, for example, the injection route, a potential ANDA applicant should first identify the in vitro discriminatory study conditions under which the % extraction of opioid from R product is statistically less than the % extraction of opioid from C product, i.e., the conditions under which R product is statistically superior to C product. The potential applicants should then compare the % extraction of opioid of T product to R product under the same discriminatory study conditions.
• Comparison of R and T products. Once the in vitro discriminatory study conditions have been identified, a potential ANDA applicant should perform the recommended statistical comparisons for each of the different routes of abuse as recommended [elsewhere in the draft guidance].

The tier-based approach to testing is illustrated in a decision tree for evaluation of the extractability of opioid from an intact product for ingestion:

Although in vitro (mechanical and chemical manipulation) studies are the default studies FDA expects ANDA applicants to conduct, the Agency recognizes that in some instances there may not be a reliable in vitro testing methodology. In those cases, FDA recommends pharmacokinetic studies (subject to FDA’s review of a protocol). Other types of studies are not recommended except in cases involving an excipient. For example, writes FDA, “in comparing the abuse deterrence potential of an excipient that functions as an aversive agent, FDA may recommend that applicants conduct pharmacodynamics studies with drug liking as a comparative endpoint between the R and the T product to permit FDA to evaluate formulation equivalence.” As new technologies emerge, FDA will use an adaptive approach and revise recommendations and develop new ones as needed.

By Ricardo Carvajal –

That’s our take-away from FDA’s recent public meeting on the implementation of FSMA’s import provisions and the associated regulations (FSVP, VQIP, and Accredited Third Party Certification).  Several comments made at the meeting suggest that many importers may still be unaware of the advent of FSMA’s import-related requirements – perhaps not surprising, given that importers as a class are a new constituency for FDA. 

Although the compliance date for the FSVP regulation is still over a year away, importers should already be digesting that regulation and considering its implications for their operations.  FDA is scheduling public meetings to help that process along, and this first meeting is expected to be followed by others in different geographic locations.  During the meeting, FDA staff presented on the basic requirements of the regulations, the status of the agency’s implementation activities, and an overview of international outreach efforts.  Among the many issues discussed during the Q&A sessions were these:

• FDA will issue a guidance document on the FSVP regulation that purportedly will provide much more information than what is provided in the regulation.  Thus, it might make sense to postpone the execution of a detailed compliance strategy pending publication of the guidance, but in our view, any postponement should be subject to re-evaluation if publication of the guidance is significantly delayed.
• Third party schemes such as GSFI should be useful in ensuring supplier compliance with applicable U.S. requirements, but can’t be relied on without more because they are not identical to those requirements. 
• There is no exemption from FSVP requirements for an importer whose supplier is owned by the same entity; however, that circumstance could factor into the importer’s determination of appropriate supplier approval and verification activities.
• Food imported for consumption at trade shows will not be exempt from FSVP requirements.
• Food contact substances are not exempt from the FSVP requirements, and do not qualify for the VQIP.  Furthermore, such substances are not covered by existing equivalency agreements (currently executed only with New Zealand).

Copies of the presentations delivered at the meeting are available on the web page linked above, and if the past is any guide, a full transcript of the meeting should eventually be made available as well.

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

On March 31, 2016, from 10:00 AM – 12:30 PM, the American University Washington College of Law (Washington, D.C.) will hold a symposium to discuss recent developments in off-label promotion, including the recent Amarin case (see our previous post here).   The symposium, titled “Drug Promotion in the 21st Century: Off-label Marketing and First Amendment Concerns,” will be moderated by Lewis A. Grossman J.D., Ph.D., Professor of Law at American University’s Washington College of Law, and includes a stellar cast of panelists. 

Here’s a description of the symposium from the event flyer:

Although FDA approves drugs for specific medical purposes, many treatments approved for one use are also effective for other diseases and conditions.  The FDA has traditionally prohibited the promotion of medical products for uses other than those approved by the agency and reflected in the labeling.  This restriction, however, has recently been weakened by successful legal challenges based on the First Amendment guarantee of freedom of speech.  This event will provide an overview of these issues and assess recent legal developments, including several important cases decided in the past few months.  The panelists will also consider the implications of this expanding right to off‑label promotion for the FDA, the drug industry, and medical practice.

Registration for the symposium is free but required.  You can register here.  Lunch will be served.

By Alexander J. Varond –

FDA’s breakthrough therapy designation (BTD) program has been, by all accounts, a popular program. Sponsors, looking to gain extra support from the Agency, shorten review times, and signal to investors that FDA views their preliminary clinical evidence favorably, have submitted over 330 breakthrough therapy designation requests (BTDRs) in just under 4 years.  Perhaps responding to the program’s popularity, FDA has begun implementing a new procedure, dubbed the “Preliminary BTDR Advice” Request.  The new Preliminary BTDR Advice Form is available here. 

FDA’s Preliminary BTDR Advice Form states that it is to be used “as a basis for the Division to comment on whether a [BTDR] is appropriate, at this time, may be too preliminary, or does not currently meet the BTD criteria.” Preliminary BTDR Advice Requests must not exceed 2 pages and must be submitted to the IND. 

FDA advises further that:

• The Division’s preliminary advice is nonbinding and will not preclude [Sponsors] from submitting an official BTDR in the future.
• Even if [Sponsors] request preliminary BTDR advice, the Division may not have enough information to determine if a BTDR is appropriate at this time. An official BTDR may be required to make a determination.
• The Division will schedule a 15 minute telecon to discuss [the request].
• No written documentation of the advice provided by the Division or minutes of the telecon will be issued to the Sponsor.

The four categories of information requested in the Preliminary BTDR Advice Form are:

• Whether the indication is serious and life-threatening;
• The drug’s mechanism of action and the drug’s relation to existing therapy(ies);
• Available therapies; and
• Preliminary clinical evidence, including trial design, trial endpoints, treatment groups, and number of subjects enrolled.

FDA is often asked by Sponsors whether the Agency agrees that the therapy should be designated as a breakthrough therapy. The Preliminary BTDR Advice Request appears to be a way to formalize these inquiries and encourage Sponsors to open a dialogue about BTD eligibility before submitting an official BTDR.

In practice, drafting an official BTDR is fairly straightforward and does not require extensive resources. So, it is unclear that Sponsors will use the Preliminary BTDR Advice Request since they are able to get an actual determination on an official BTDR with fairly limited effort, within 60 days of FDA’s receipt of the request.

On the other hand, FDA has often discussed the burdens that the BTD program puts on the Agency. BTRDs are first handled by the Division and then sent to CDER’s Medical Policy Council, which is staffed by senior FDA officials.  The Division is tasked with making a recommendation on BTD eligibility to the MPC, and the MPC makes the final call on whether to grant BTD.  Given this multilevel review process, it is not hard to understand that the BTD process is comparatively much more burdensome for FDA than for Sponsors. What’s more, Sponsors may resubmit BTDRs that were initially denied or withdrawn.

FDA had previously responded to this asymmetric resource requirement by educating Sponsors on BTD requirements (see FDA’s presentation from 2015) and requesting that Sponsors discuss the viability of a breakthrough therapy designation request prior to actual submission of a request.

By Mark I. Schwartz –

One of the pre-eminent rules in QSR and cGMP compliance is to document one’s activities. In the eyes of FDA, the “failure to document” is often equated with the failure to perform the underlying regulated activity. FDA takes this position principally because the failure to document denies the firm, and hence FDA, of the evidence needed to determine the adequacy of the underlying activity. The requirement to document one’s activities is repeated over and over again throughout the QSR and the cGMP regulations.

A case in point is 21 CFR 820.100, which outlines the requirements for corrective and preventive actions, or CAPAs, in the medical device regulations. In 21 CFR 820.100(a)(1) through (a)(7), there are a wide range of requirements, including investigating the cause of a non‑conformity, identifying the actions needed to correct and prevent recurrence, verifying or validating the effectiveness of the corrective actions and ensuring that they do not adversely affect the finished device. Importantly, arching over all of these requirements is subsection (b) of 21 CFR 820.100, which states that “[a]ll activities required under this section, and their results, shall be documented” (emphasis added). Thus, CAPA documentation is itself a regulatory requirement.

In discussing the evidentiary basis of this documentation requirement, we are reminded of a soliloquy from the movie, A Few Good Men, when Lieutenant Daniel Kaffee chastises Lieutenant Commander JoAnne Galloway, by saying: “You and Dawson, you both live in the same dreamworld. It doesn’t matter what you believe. It only matters what I can prove! So please, don’t tell me what I know, or don’t know; I know the LAW.”

In other words, if you have not documented the QSR or cGMP compliant steps that you have taken at your facility, it is as though the QSR or cGMP compliant activity itself has not taken place. There is no better example of this observation than a recent 483 issued to a device manufacturer, where virtually all the observational comments by the investigator reference the firm’s lack of documentation of various QSR activities, rather than the lack of performance of the underlying QSR activities themselves.

Interestingly, even some trade press confounded the 483 observations involving “failures to document” as “failures to investigate”: “[t]he post-inspection finding for [the firm] concluded that the devicemaker did not adequately investigate reported product variances and did not fully investigate multiple complaints about product failings.” International Devices & Diagnostics Monitor, March 4th, 2016, “Form 483 Hits the SweetSpot for Alleged Follow-Up Issues” (emphasis added).

According to Observation #1 in the 483, three of the nineteen CAPAs that the investigator reviewed had allegedly failed to include some type of documentation relating to the investigation into the cause of the nonconformities.

For example, at some point the firm allegedly determined that the release of a version of their Diabetes Data Management System had resulted in certain customers not being able to use the device, presumably leading to this CAPA. However, the firm allegedly failed to document certain portions of the investigation into this nonconformity, specifically documentation into the investigation relating to the failure of the system to produce PDF reports, as well as documentation into the root cause of the failure. Despite these alleged inadequacies, the firm allegedly closed the CAPA, and signed it as having been reviewed and approved.

In the world of FDA, if a warning letter were to be issued regarding this Observation, it would be cited as a violation of 21 CFR 820.100(b) relating to the requirement to document, not as a violation of 21 CFR 820.100(a)(2), relating to the underlying requirement of “…investigating the cause of nonconformities relating to product, processes, and the quality system….”

Next, the investigator noted that the firm allegedly had not documented verification and/or validation of the corrective actions to ensure that such actions were effective and had not negatively affected the finished device, in accordance with both their internal SOPs and 21 CFR 820.100(a)(4). One of the examples cited in this regard relates to the same CAPA referenced above, and was stated as follows:

CAPA – 30 – Your firm identified corrective actions including release of …Diabetes Data Management System, r152, backwards compatibility testing for future releases and creation of a test plan for automated and manual tests. Your firm did not document verification by examination and provision of objective evidence [that] these corrective actions were effective. Your firm closed this CAPA on [September 2, 2014] and signed this CAPA as reviewed and approved on [December 14, 2015]…. (emphasis added).

According to Observation #2, the investigator claimed that for two of the 16 complaints reviewed during the inspection, the firm allegedly did not document the complaint investigation into possible failures of the firm’s devices. For example, Complaint #379 was created on July 29, 2015 to address a report of a customer receiving blank and erroneous data on reports generated by the firm’s device. The customer identified an upload which contained numerous readings of mostly out-of-normal range values, and these values were dated prior to the patient in question having received the device.

Among other things, the investigator alleges that the firm closed the complaint ticket and signed the complaint as having been reviewed and approved, allegedly without the firm documenting the investigation into the possible report of erroneous data.

So to summarize, if one is required to perform some task under the QSR/cGMP regulations, absent specific regulatory language to the contrary, FDA generally expects the documentation of steps taken in the performance of that task. (We will leave for another day the issue as to whether FDA’s broad expectation in this regard is supported by the relevant statutory and regulatory provisions.) Failure to do so effectively negates the underlying QSR or cGMP compliant activity that has been taken, at least in the eyes of FDA.

For those in the drug or medical device industry who are bold enough to ignore this admonition, another quote from A Few Good Men comes to mind, when Colonel Jessep excoriates Lieutenant Kaffee with the following diatribe: “I run my unit how I run my unit. You want to investigate me, roll the dice and take your chances. I eat breakfast 300 yards from 4000 Cubans who are trained to kill me, so don’t think for one second that you can come down here, flash a badge, and make me nervous.”

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By David C. Gibbons & Jeffrey N. Wasserstein –

On March 16, 2016, the Feinstein Institute for Medical Research, located in Manhasset, New York, (“Feinstein”) entered into an agreement with the U.S. Department of Health and Human Services Office for Civil Rights (“OCR”) to pay $3.9 million to settle potential violations of the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) Privacy and Security Rules. Resolution Agreement, (Mar. 16, 2016). In addition to the payment, Feinstein agreed to undertake a comprehensive corrective action plan to remediate alleged deficiencies that led to a breach and disclosure of protected health information (“PHI”) This agreement stems from an incident that occurred on September 2, 2012, when a Feinstein laptop containing unencrypted, electronic PHI was stolen from a Feinstein employee’s car.  The laptop contained information on approximately 13,000 Feinstein patients and research participants, including names, dates of birth, addresses, social security numbers, diagnoses, laboratory results, medications, and other medical information regarding subjects’ participation in a research study.  HHS, Press Release, Improper disclosure of research participants’ protected health information results in $3.9 million HIPAA settlement (Mar. 17, 2016).

Pursuant to HIPAA regulations, covered entities, such as Feinstein, must:

1. Ensure the confidentiality, integrity, and availability of all electronic protected health information the covered entity or business associate creates, receives, maintains, or transmits;
2. Protect against any reasonably anticipated threats or hazards to the security or integrity of such information;
3. Protect against any reasonably anticipated uses or disclosures of such information that are not permitted or required under [the regulations]; and
4. Ensure compliance with [the regulations] by its workforce. 45 C.F.R. §164.306(a).

Feinstein reported the breach to OCR on September 14, 2012, and OCR initiated an investigation later that year. According to the Resolution Agreement that followed, the investigation found that the individuals’ PHI was “impermissibly disclosed” when an unsecured laptop was taken from the employee’s car.  The investigation also found that Feinstein failed to: (i) conduct a proper risk analysis identifying the risks and vulnerabilities to the confidentiality, integrity, and availability of PHI, (ii) implement policies and procedures governing employee access to PHI as well as the use of hardware and electronic media containing PHI, (iii) implement appropriate physical safeguards on laptops to restrict access to PHI, and (iv) implement appropriate electronic safeguards against disclosure of PHI.

This case is notable for the fact that, unlike many of the earlier enforcement actions relating to HIPAA, the disclosure of PHI was unintentional and not made for personal gain. It is also notable given it occurred in a clinical research, as opposed to a healthcare, setting.  OCR Director, Jocelyn Samuels, was quoted as saying that “[r]esearch institutions subject to HIPAA must be held to the same compliance standards as all other HIPAA-covered entities.”  HHS Press Release.  The case is a pointed reminder that the HIPAA Privacy and Security Rules have teeth and can result in large penalties when violated.

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By Larry K. Houck –

The Centers for Disease Control and Prevention (“CDC”) has released its final guidelines for prescribing opioids for chronic pain. CDC Guideline for Prescribing Opioids for Chronic Pain-United States, 2016, Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, Mar. 15, 2016. We blogged on the draft guidelines on October 12, 2015 and December 16, 2015. The guidelines represent the CDC’s contribution to the ongoing debate about the appropriate treatment of pain and, while the guidelines are voluntary, they will be very influential on opioid therapy for chronic pain.

The guidelines are intended for primary care clinicians (e.g., family physicians and internists) and provide recommendations for prescribing opioid pain medication for chronic pain (pain conditions that typically last longer than three months or past the time of normal tissue healing) in outpatient settings. The guidelines apply to patients eighteen years of age or older with chronic pain unrelated to active cancer treatment, and outside of palliative and end-of-life care. The CDC states that the guidelines are “intended to ensure that clinicians and patients consider safer and more effective treatment, improve patient outcomes such as reduced pain and improved function, and reduce the number of persons who develop opioid use disorder, overdose, or experience other adverse events related to these drugs.” CDC Guideline, 2.

CDC has organized the guidelines into three general areas: (1) when to initiate or continue opioids for chronic pain; (2) opioid selection, dosage, duration, follow-up, and discontinuation; and (3) assessing risk and addressing harms of opioid use. The final guidelines are with slight variation, the same as the draft guidelines published in December 2015. The final guidelines are:

Determining When to Initiate or Continue Opioids for Chronic Pain

1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate.
2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians 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, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy.

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation

4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long acting (ER/LA) opioids.
5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥ 50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥ 90 MME/day or carefully justify a decision to titrate dosage to ≥ 90 MME/day.
6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed.
7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids.

Assessing Risk and Addressing Harms of Opioid Use

8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥ 50 MME/day), or concurrent benzodiazepine use, are present.
9. Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months.
10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.
11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.
12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder.

Id. at 16.

As we noted previously, the guidelines are reasonable and the recommendations are commonsensical, constitute good medical practice, and apply to the prescribing of any medication, not just opioids or controlled substances. Primary clinicians in the field should familiarize themselves with the guidelines and detailed explanation for each. The guidelines will further the public discussion on appropriate pain treatment. The guidelines will have a significant impact on practitioners and patients so it was appropriate that in addition to seeking input from a “Core Expert Group” that the CDC provided stakeholders and the public with an opportunity to comment on the guidelines. The CDC received more than 4,350 comments from patients, clinicians, families who lost loved ones to overdose, medical associations, professional organizations, academic institutions, state and local governments and industry. Id. at 7. We wonder about the extent of the CDC’s review and incorporation of the public comments into the final guidelines because they are so similar to the draft guidelines.

There has been increased enforcement against physicians for failing to adhere to their primary responsibility to ensure that prescriptions must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice. See, e.g., Henri Wetselaar, M.D.; Decision and Order, 77 Fed. Reg. 57,126 (Sept. 17, 2012). And there has been action against pharmacies that have failed in their corresponding responsibility to ensure that the prescriptions they dispense are for a legitimate medical purpose. See, e.g., The Medicine Shoppe; Decision and Order, 79 Fed. Reg. 59,504 (Oct. 2, 2014). The CDC guidelines help clarify these standards for physicians, pharmacies and regulators. However, there may be occasions when legitimate medical treatment conflicts with strict adherence to the guidelines. For example there may be instances when opioid therapy is required for more than seven days or a patient requires more than 50 or 90 morphine milligram equivalents per day. The CDC recognizes that the recommendations in the guidelines are “voluntary, rather than prescriptive standards” and cautions clinicians to “consider the circumstances and unique needs of each patient when providing care.” Id. at 2. But we again question whether the Drug Enforcement Administration will take enforcement action against practitioners who it believes prescribed opioids for other than legitimate medical purpose if they did not follow the CDC guidelines?

The CDC plans to follow-up by disseminating materials based on the guidelines to health systems, medical professional societies, insurers, public health departments, health information technology developers and clinicians. Id. at 33. In addition, the CDC plans to support clinician education on pain management options, opioid therapy and risk mitigation strategies. Id. at 34.

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By Kurt R. Karst –      

Earlier this week, the U.S. District Court for the District of Columbia (Judge Rudolph Contreras) issued a 33-page Memorandum Opinion in a case stemming from a Complaint filed in June 2015 by Ferring Pharmaceuticals Inc. (“Ferring”) against FDA challenging the Agency’s denial of 5-year New Chemical Entity (“NCE”) exclusivity for Ferring’s PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution, which the Agency approved on July 16, 2012 under NDA 202535 for cleansing of the colon as a preparation for colonoscopy in adults. In an Order granting in part and denying in part FDA’s Motion for Summary Judgment, and denying Ferring’s Motion for Summary Judgment, (other responsive briefs are available here and here) Judge Contreras, while deferring to FDA’s interpretation of the FDC Act’s NCE exclusivity provisions that led the Agency to deny Ferring NCE Exclusivity in 2012, directed FDA and Ferring to file renewed Motions for Summary Judgment on the issue of the retroactivity of a decision FDA reached in October 2014 that would have resulted in NCE exclusivity for PREPOPIK had the interpretation been in effect in 2012. 

As we previously reported, a lot of events led up to FDA’s denial of NCE exclusivity for PREPOPIK, and to Ferring’s lawsuit against FDA. While readers can refer to our previous post for all of the background, a couple of facts are critical.  First, on October 10, 2014, FDA released on the Agency’s website a final guidance document (see our previous post here) reinterpreting the statutory NCE exclusivity provisions to award NCE exclusivity for a newly approved Fixed-Dose Combination (“FDC”) drug product containing an NCE and a previously approved drug.  As summarized by Judge Contreras:

[P]rior to 2014, the FDA interpreted the five-year exclusivity provision to provide that only drug products containing no previously approved drug substances were eligible for exclusivity. Once eligible, however, the FDA interpreted the bar clause to bar all ANDAs and 505(b)(2) applications referencing that drug product or any later-approved products containing the product’s drug substances, in order to preserve the innovator’s exclusivity to the greatest extent possible. [(Emphasis in original)]

Also on October 10, 2014, FDA denied Petitions for Reconsideration and a separate Citizen Petition submitted to the Agency by Ferring and other companies requesting that FDA interpret the law to award NCE exclusivity for several previously approved FDC drugs, including PREPOPIK (Docket No. FDA-2013-P-0119).  In those petition denials, FDA refused to apply the Agency’s new interpretation to NDAs for FDCs approved prior to October 2014.

In its Complaint, Ferring alleges that FDA’s actions violate the Administrative Procedure Act, the FDC Act, and the Agency’s regulations. Specifically:

First, Ferring contends that the FDA’s prior interpretation, under which PREPOPIK was denied five-year exclusivity, contravened the plain language of the FDCA. Second, Ferring argues that, even if the language of the FDCA is ambiguous, the FDA’s interpretive choice to read “drug” in the eligibility clause to mean “drug product” was an unreasonable reading of the statute or was arbitrary and capricious because it treated similarly situated parties differently.  Finally, Ferring claims that, even if the FDA’s prior interpretation was permissible, its decision not to apply the new interpretation retroactively was arbitrary and capricious.

Reviewing the case under the familiar Chevron analysis, Judge Contreras considered the term “drug” in the FDC Act’s NCE exclusivity provisions to be ambiguous, thus requiring an evaluation of FDA’s pre-2014 interpretation of the statute under Step Two of the Chevron inquiry.  The bottom line, says Judge Contreras, is that FDA’s interpretation is reasonable:

As a result of the statute’s ambiguity, the FDA was left to determine at what level of specificity to define “drug”: at the “drug product” level, and in reference to all of the product’s “drug substances,” or at the “drug substance” level. Although scientific and policy considerations may have now persuaded the FDA to modify its interpretation, given the statutory ambiguity and the considerations discussed above, it was neither unreasonable nor arbitrary and capricious for the FDA to define “drug,” in the “eligibility clause” as “drug product,” and to thereafter ensure the greatest benefit for pharmaceutical manufacturers who are provided with exclusivity by interpreting “drug” in the “bar clause” as “drug substance.”  Therefore, Ferring’s Chevron Step Two argument fails.

That decision left remaining Ferring’s argument that FDA acted arbitrarily and capriciously when the Agency decided not to apply the Agency’s October 2014 reinterpretation retroactively, and only prospectively, thereby denying NCE exclusivity for PREPOPIK. On that issue, Judge Contreras says that he needs more from the parties:

[N]either party cites a case considering an agency’s decision to apply a new interpretation retroactively (or not) under that framework [(i.e., whether FDA acted arbitrarily and capriciously in not applying its new interpretation retroactively)]. Overall, the parties’ arguments on this issue are thin on legal citations. 

Despite FDA’s citation to one decision – Retail Wholesale & Department Store Union v. NLRB, 466 F.2d 380 (D.C. Cir. 1972) – that the Agency believes supports the Agency’s position against retroactivity, and that the The DC Circuit has described as “provid[ing] the framework for evaluating retroactive applications of rules announced in agency adjudications,” Judge Contreras says that neither FDA nor Ferring “grapple with that case and its progeny nor explain, alternatively, why it is inapplicable.” As a result, writes Judge Contreras, “[t]he parties’ limited reliance on case law is also a hindrance to the Court’s analysis of the retroactivity question.  And because the Court has held that the FDA’s prior interpretation passes muster under Chevron, the retroactivity issue will be dispositive of Ferring’s claims.”  Accordingly, Judge Contreras directed FDA and Ferring to file renewed Motions for Summary Judgment “that more fully address the retroactivity issue. . . .”

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By Ricardo Carvajal & JP Ellison –

In a decision of significance in the realm of food additive regulation, the U.S. District Court for the Northern District of California dismissed a lawsuit targeting coffee-creamer products containing partially hydrogenated oil (PHO) on preemption grounds.  The complaint – one of several similar complaints targeting PHO-containing products – asserted nine causes of action under California law, some of which challenged the use of PHOs (the use-based causes of action), and others of which challenged a “0g Trans Fat” label declaration (the label-based causes of action).  The court found the use-based causes of action preempted based on conflict preemption and the label-based causes of action expressly preempted.
 
With respect to the use-based causes of action, the Court noted that FDA had set a 3-year compliance date in its declaratory order revoking the GRAS status of PHOs (see our prior post here).  That declaratory order cited a number factors in support of that compliance date, including the need to minimize market disruption, and to allow time for submission and review of food additive petitions, adjustments by small businesses, and development of supply chains for alternative oils.  The Court also noted that the recently enacted Consolidated Appropriations Act included language stating that no food that contains a PHO shall be deemed adulterated by virtue of containing that PHO until the compliance date established by FDA.  The  Court held that Plaintiff’s claims “would impose an immediate prohibition on the use of PHOs in all foods under all circumstances” and thereby “’stand[ ] as an obstacle’ to the fulfillment of the FDA’s objectives, as embodied in its regulatory scheme setting a three-year compliance period, and conflict with Congress’s decision not to deem PHOs unsafe, or the food containing them adulterated” pending the compliance date.
 
With respect to the label-based causes of action, the Court found that the challenged trans fat claim was authorized by FDA regulations.  Because Plaintiff’s claims “would impose a requirement that is not identical to the requirements imposed by those regulations,” the Court held that those claims are expressly preempted.  This is the latest of several decisions finding preemption with respect to “0g trans fat” claims, but as noted by this Court, “no trans fat claims” have not fared as well.

In any future revocations of GRAS status, we expect this decision to be cited in defense of products marketed during any compliance period established by FDA.  The Court’s rationale for finding conflict preemption, together with its observation that Congress “essentially ratified FDA’s Final Determination,” suggests that FDA compliance dates should be read to preempt claims of unlawfulness prior to such dates even in the absence of accompanying federal legislation.

By Melisa M. Moonan –

On March 4, 2016, FDA published a Federal Register Notification titled “Refurbishing, Reconditioning, Rebuilding, Remarketing, Remanufacturing, and Servicing of Medical Devices Performed by Third-Party Entities and Original Equipment Manufacturers; Request for Comments” (March 2016 notification).  This notification announces the establishment of a docket to receive comments “concerning the service, maintenance, refurbishment, and alteration of medical devices, including endoscopes (Ref. 3), by third-party entities” and to learn “more about the challenges third-party entities face in maintaining or restoring devices to their original or current specifications.”  FDA is also asking for assistance in defining certain relevant terms.  Despite the specific mention of endoscopes and reference to an Advisory Panel meeting on reprocessing issues, FDA does not intend the docket to address device reprocessing.

After a number of historical initiatives in this area, and essentially no regulation of activities short of remanufacturing since 1998, FDA appears to be going back to the drawing board.  The agency states this action was prompted by stakeholder concerns about the quality, safety, and continued effectiveness of medical devices that have been subject to one or more of these activities, whether by original equipment manufacturers (OEMs) or by third parties, including health care establishments and humanitarian organizations.  In particular, FDA has heard concerns that some third parties may use unqualified persons to perform this work and that the work may not be adequately documented.  FDA states that potential public health issues resulting from the named activities may include disabled device safety features, improper or unexpected device operation, and ineffective recalls. 

While the concerns focus primarily on third party activities, FDA is also interested in determining whether there are any risks associated with the specified activities when performed by OEMs. FDA also notes that OEMs have requested clarification regarding their responsibilities when third parties have altered their devices, although FDA does not appear to be seeking feedback on this particular issue.  

Historical Background

FDA has focused attention on these activities a number of times in the past.  In the 1980s, FDA issued Compliance Policy Guide (CPG) 7124.28 on reconditioners and rebuilders (defined as firms that acquire ownership of a used device and restore or refurbish them to their original or current specifications, or new specifications, for purposes of resale).  The CPG subjected such activities to most of the general medical device controls of the Food, Drug and Cosmetic Act (FDC Act), including registration and listing, 510(k) notification, good manufacturing practices (GMPs), medical device reporting (MDR), labeling (including requiring the device to be labeled as reconditioned or rebuilt), and for such firms that handled Class II or III devices, inspection.

In the 1990s, FDA considered the issue again when promulgating the Quality System Regulation (QSR), which describes current good manufacturing practices (CGMPs) for medical devices.  In 21 C.F.R. § 820.200, FDA required manufacturers to establish and maintain servicing instructions for certain devices and to maintain service records. However, in the preamble to the final rule, the agency explained that although it believed servicers and refurbishers met the definition of a manufacturer, it had decided not to include servicers or refurbishers who were outside the control of the OEM under the definition of “manufacturer[s]” who would be regulated under the QSR.  FDA’s reasons included that the agency’s GMP Advisory Committee had “sharply divided views” on the issue.  See 61 Fed. Reg. 52602, 52610 (Oct. 7, 1996).  Instead, the agency determined that remanufacturers, who were defined in the QSR as “any person who processes, conditions, renovates, repackages, restores, or does any other act to a finished device that significantly changes the finished device's performance or safety specifications, or intended use,” would be subject to the QSR as manufacturers, and that servicing and refurbishing would be addressed in a later rulemaking. 

In December 1997, FDA issued an advanced notice of proposed rulemaking (1997 ANPR) seeking input on how to define and regulate servicers, refurbishers, and “as is” remarketers.  FDA sought comments on proposed definitions for such persons/activities, and whether some or all of the general controls of the FDC Act should apply or be voluntary.  The ANPR was never finalized.  In December 1998, FDA revoked CPG 7124.28, stating that the CPG no longer represented agency thinking.

The revocation of the CPG and the failure to finalize the 1997 proposed rule left refurbishing, servicing, and similar activities essentially unregulated.  FDA’s registration and listing website clearly indicates that refurbishers are not required to register or list with FDA.  In addition, FDA’s compliance program guidance manual (CPGM) pertaining to inspection of medical device manufacturers states:  “Third party refurbishers, reconditioners, servicers and ‘as is’ resellers of used devices are currently not subject to the requirements of the Quality System regulation.”  See CPGM 7382.845 at 17.  Manufacturers and third parties have been left with uncertainty in terms of the controls, processing, and labeling necessary to remarket used devices.

Definitions, Questions, and Next Steps

Like the 1997 ANPR, the March 2016 notification again seeks comments on suggested definitions (here for the terms recondition, service, repair, refurbish, remanufacture, and remarket).  Reconditioning is now defined in a more limited manner (at most it now may involve refurbishing a device to current specifications), and rebuilding is not defined.  Servicing is defined similarly to the 1997 ANPR, i.e., maintenance or repair to return a device to the OEM safety and performance specifications, without change to intended use.  The refurbishing definition has been updated since the 1997 ANPR to include the concept of restoring the device to a like new condition and to specifically cover hardware and software updates “that do not change the intended use of the original device.”  Remarket is defined as “facilitating the transfer of a previously owned device” by various means; “as is” remarketing is not included in the definitions.  Remanufacture is defined as in the QSR.

Unlike the 1997 ANPR, FDA makes no statements regarding potential regulatory approaches.  Instead, FDA asks seven questions geared to gathering risk/benefit information, and requests specific examples of issues related to the benefits, risks, and challenges associated with each type of activity when performed by different entities (OEMs and third parties, including hospitals and humanitarian organizations).  The questions also address the types of information third parties need to perform these activities properly, and request specific examples of actual problems experienced by users of devices subjected to these activities.  None of the questions request information on international government or industry policies and initiatives in this area and any potential for harmonization.

Comments are due May 3, 2016 to Docket FDA-2016-N-0436.  [UPDATE: The comment period on the subject notification has been extended  to June 3, 2016 “due to the unanticipated high-level of interest.”]  FDA also plans to hold a public meeting in 2016 on this topic, and states that the comments will inform the agenda.  There is sure to be high interest, and stakeholders should take this opportunity to comment and help shape the agenda as this new initiative to clarify an old and controversial issue moves forward to the public meeting.

By James C. Shehan & Kurt R. Karst –

On March 10, 2016, FDA released a draft guidance interpreting the “deemed to be a license” provision of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  This provision, at BPCIA § 7002(e)(4), is one of a broader series of transition provisions in BPCIA § 7002(e), and, as FDA notes in the draft guidance, is “[t]he linchpin of the transition scheme described in section 7002(e).”  The “deemed to be a license” provision, which FDA notes Congress was silent on implementation when it passed the BPCIA, transitions certain products that FDA has historically regulated as drugs into biologics on March 23, 2020.  (Shortly thereafter, FDA archly quotes a Supreme Court opinion for the proposition that the Affordable Care Act – of which the BPCIA is part – “contains more than a few examples of inartful drafting.”)  Specifically, BPCIA § 7002(e) states:

(e) PRODUCTS PREVIOUSLY APPROVED UNDER SECTION 505.—

(1) REQUIREMENT TO FOLLOW SECTION 351.—Except as provided in paragraph (2), an application for a biological product shall be submitted under [PHS Act § 351] (as amended by this Act).

(2) EXCEPTION.—An application for a biological product may be submitted under section [FDC Act § 505] —

(A) such biological product is in a product class for which a biological product in such product class is the subject of an application approved under such section 505 not later than the date of enactment of this Act; and

(B) such application—

(i) has been submitted to the Secretary of Health and Human Services (referred to in this subtitle as the “Secretary”) before the date of enactment of this Act; or

(ii) is submitted to the Secretary not later than the date that is 10 years after the date of enactment of this Act.

(3) LIMITATION.—Notwithstanding paragraph (2), an application for a biological product may not be submitted under [FDC Act § 505] if there is another biological product approved under [PHS Act § 351(a)] that could be a reference product with respect to such application (within the meaning of such section 351) if such application were submitted under [PHS Act § 351(k)].

(4) DEEMED APPROVED UNDER SECTION 351.—An approved application for a biological product under [FDC Act § 505] shall be deemed to be a license for the biological product under such section 351 on the date that is 10 years after the date of enactment of this Act.

The draft guidance deals with four major topics: (1) what happens to approved applications for such transitional products on March 23, 2020; (2) what happens to pending applications on that date; (3) how sponsors of pending applications should prepare for the effects of the transition; and (4) how exclusivity will be affected by the transition. FDA’s position on the last topic is sure to generate the most commentary and controversy, because FDA proposes to interpret the law such that transitional products get less exclusivity than either traditional drugs or biologics.   

Some background on these transition products and the BPCIA is necessary to understand the guidance.  Although most products that fit the statutory definition of “biologic” have been licensed and regulated by FDA under Section 351 of the Public Health Service Act (“PHS Act”), some protein products historically have been approved and regulated as drugs under FDC Act § 505.  The draft guidance provides examples of such products, including insulins, hyaluronidases, thyrotropin alfas and human growth hormones.  Although such products seem to fit the pre-enactment definition of biologic, the BPCIA removed any doubt, amending the definition of “biologic” in the PHS Act to include “protein[s] (except any chemically synthesized polypeptide).”  The BPCIA also requires, with certain exceptions, that a marketing application for a biologic be submitted as a BLA and not as an NDA.  And lastly, BPCIA § 7002(e)(4) provides that, on March 23, 2020, a marketing application for a biologic that has been approved as an NDA shall be “deemed to be a license” for a biologic under PHS Act § 351; that is, NDAs for transitional products become BLAs. 

Regarding approved applications, FDA simply states that, on March 23, 2020, applications for biologics approved under FDC Act § 505 “will no longer exist” as NDAs or ANDAs and “will be replaced by approved” Section 351(a) “full” BLAs or Section 351(k) “abbreviated” BLAs (“ABLAs”), “as appropriate.”  In a footnote, FDA states that the Agency intends to provide further guidance on the issue of which transitional products will become Section 351(a) full BLAs and which will become Section 351(k) ABLAs.  This further guidance will also address issues such as user fees and BLA numbers.  FDA also states that these products will be removed from the Orange Book, but the Agency is silent as to whether they will then appear in one of the two lists that comprise the Purple Book.

Regarding pending applications, the draft guidance interprets the statute rather strictly.  FDA states that the BPCIA “does not provide a mechanism to transition an approved application under section 505 to an approved BLA under the PHS Act prior to March 23, 2020, or after March 23, 2020.  Therefore, FDA “will not approve” any pending or tentatively approved application for a transitional product.  FDA recommends that such an application be “withdrawn and resubmitted under section 351(a) or 351(k).”

Recognizing the potential “significant impact” of such a policy on development programs, FDA later in the guidance offers sponsors more detailed advice.  The soundest and most basic piece of advice is that sponsors developing transitional products should evaluate whether a planned 505 submission would allow adequate time for approval of an NDA or ANDA prior to March 23, 2020, considering, among other things, “whether the submission may require a second cycle of review and, for certain types of applications, whether unexpired patents or exclusivity may delay final approval.”  FDA recommends that sponsors of full NDAs consider submitting a full BLA instead.  Noting that the PHS Act has no analogy to a Section 505(b)(2) NDA, FDA recommends that sponsors of these applications for transitional products consider submitting them as full BLAs or treat them as biosimilars and submit ABLAs.

Regarding the existing exclusivity of transitional products, FDA, with very little preamble, states that “any unexpired period of exclusivity” for a transitional product, “e.g., 5-year exclusivity, 3-year exclusivity, or pediatric exclusivity … would cease to have any effect, and any patents listed in the Orange Book would no longer be relevant for purposes of determining the timing of approval of a 505(b)(2) application (or ANDA).”  A single sentence provides the rationale for this decision: “the exclusivity provisions of the FD&C Act serve to limit the submission or approval of applications under section 505 of the FD&C Act, but not under section 351 of the PHS Act.”  FDA makes one crucial exception: because orphan drug exclusivity is available to both drugs and biologics, “any unexpired period of orphan drug exclusivity would continue to apply to the drug for the protected use after March 23, 2020.”  FDA is silent with respect to the applicability of previously earned pediatric exclusivity to extend a period of orphan drug exclusivity for a transitioned product, but it would seem to make sense to apply pediatric exclusivity for such a product given that the BPCIA, at Section 7002(m), attaches pediatric exclusivity to orphan drug exclusivity.

Turning to the question of whether transitional products will be eligible for biologics exclusivity come March 23, 2020,  FDA explains that the BPCIA grants such exclusivity to products “first licensed under” PHS Act § 351(a).  Because transitional products are only “deemed” to be licensed under Section 351(a), FDA does not regard them as eligible for exclusivity.  In support of this determination, FDA states that “[n]othing in the [BPCIA] suggests that Congress intended to grant biological products approved under [FDC Act § 505] – some of which were approved decades ago – a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032.”  

FDA’s statement implies that the Agency’s only option was to grant all transitional products 12 years of exclusivity starting on March 23, 2020.  But it seems that same statutory language relied upon by the Agency could support a number of alternative positions on transitional product exclusivity, including awarding a 12 year period from the date of FDC Act § 505 approval.  It remains to be seen whether interested parties, perhaps including Congress, will support those alternatives.  In 2015, Congress did express some interest in the BPCIA’s transition provisions.  Specifically, the “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015” (H.R. 1576) would have the Government Accountability Office study some of the unique challenges presented by FDA’s evaluation of generic versions of complex drug products in the context of BPCIA § 7002(e) (see our previous post here).

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By David C. Gibbons & Alan M. Kirschenbaum –

On March 8, 2016, CMS issued a proposed rule to test new models for payment of drugs and biologicals under Medicare Part B (“Proposed Rule”). Medicare Part B covers limited categories of drugs, including (1) those provided incident to a physician’s services that are usually not self-administered (e.g., injectables); (2) those administered in conjunction with an item of durable medical equipment covered under Part B (e.g., infusion pumps or nebulizers); and (3) specific types of drugs enumerated in the statute. The preamble explains that, while payments for drugs account for a relatively small proportion of total Part B expenditures, CMS made approximately $22 billion in payments for separately reimbursed drugs in 2015, a figure that is about double what was paid in 2007. Id. at 8.  

The statutory payment methodology for most drugs under Medicare Part B is the Average Sales Price (“ASP”) reported by the manufacturer plus six percent. The six percent add-on generates more revenue for more expensive products, and therefore, in CMS’s view, may incentivize the use of such products. Id. at 10. CMS proposes to test whether alternative drug payment designs will reduce Medicare drug expenditures while preserving or enhancing quality of care. Id. at 9. The proposed five-year pilot would be conducted under authority of Section 1115A of the Social Security Act, which authorizes CMS’s Center for Medicare and Medicaid Innovation to test innovative payment models to reduce program expenditures.

The Model includes two phases. In phase I, which would begin 60 days after publication of the final rule, all providers and suppliers in certain, randomly-selected geographic areas (primary care service areas, or PCSAs) would receive Part B drug payments under the current ASP + 6% methodology (the control group), while all providers and suppliers in other selected PCSAs would receive payment under an alternative methodology of ASP + 2.5% plus a flat fee of $16.80.   Id. at 43. The reduction in the add-on percentage would reduce the revenue benefit of more expensive drugs, while the flat fee would provide proportionately greater revenue for less expensive drugs. A CMS Fact Sheet provides the following example:   

Phase II, which would begin no earlier than January 1, 2017, would test the effect of four value-based pricing (“VBP”) methods: 

1. Reference pricing, which sets a standard payment rate for a given drug based on a benchmark rate that has been set for a group of drugs. The benchmark rate would be set based on the average price for drugs in a group of either therapeutically-similar drugs, the most clinically effective drug in a group, or some other pricing threshold. Id. at 50-51.
2. Indications-based pricing, which may be used when a drug is used for more than one indication, but where its effectiveness varies by indication. Such a drug would be reimbursed at a higher rate for indications for which it has demonstrated greater effectiveness and a lower rate for indications for which it is less effective. Id. at 52. Indication-based pricing would be used “where appropriately supported by published studies and reviews or evidence-based clinical practice guidelines . . .” Id.
3. Outcomes-based risk-sharing agreements between CMS and manufacturers, under which the final price of a drug would be tied to clinical outcome targets among specific patients. Should a product not meet its agreed-upon outcomes targets, manufactures would be required to provide rebates, refunds, or other price adjustments. Id. Manufacturers themselves would provide outcome targets based on “competent and reliable scientific evidence.” Id. at 53.
4. The reduction or elimination of patient cost-sharing obligations to provide incentives for the use of products determined to be of high-value. Id. at 54-55.

CMS also proposes to develop, for implementation in phase II, clinical decision support (CDS) tools consisting of “timely clinical information at the point of care” so that healthcare providers can access up-to-date scientific and medical evidence to inform treatment decisions, and claims data reports to provide feedback to providers and suppliers on their prescribing patterns. Id. at 58, 60-61.  

In order to robustly test the elements of the Model described above, CMS proposes to require the participation of all Part B providers and suppliers in every state except Maryland. Id. at 34-35. Geographic areas will be assigned to control or test arms of the Model according to Primary Care Service Area (“PCSA”). The 7,048 PCSAs in the U.S. (excluding Maryland) would be randomly assigned to one of four randomized groups that would test elements of phase I (ASP+6% versus ASP+2.5%+flat fee) and phase II (No VBP tools versus VBP tools) simultaneously. Id. at 15, 35.

In addition to comments regarding the proposed revised payment methodology, VBP strategies, and use of CDS tools, CMS is specifically soliciting comments on three other approaches: value-based purchasing agreements, reviving the Part B drug competitive acquisition program (which was discontinued in 2009), and episode-based or bundled pricing for Part B drugs. Comments are due no later than 5:00 p.m. on May 9, 2016.

By Jenifer R. Stach & Wes Siegner –

If you weren’t aware that the Department of Justice (DOJ) has unsafe dietary supplements on its list of enforcement priorities, you should take notice.

On Tuesday March 8th, 2016 as part of National Consumer Protection Week, United States Attorney General Loretta E. Lynch delivered a message in a recorded video emphasizing DOJ’s efforts to protect consumers from unsafe dietary supplements. Given the thousands of consumer products regulated by several branches of the federal government; including the Food and Drug Administration, Federal Trade Commission, Consumer Product Safety Commission, and the National Highway Traffic Safety Administration, it is worthy of notice whenever the Attorney General chooses to focus on any particular category of products.      

Attorney General Lynch’s message reinforces the November 2015 announcement that after a year-long effort, DOJ had engaged in over 100 criminal and civil cases against dietary supplement manufacturers and marketers. Since Congress passed the Dietary Supplement Health and Education Act of 1994 ("DSHEA"), FDA has been criticized for its loose regulation of unsafe, and in certain cases allegedly dangerous ingredients found in dietary supplements.  Attorney General Lynch acknowledges that, “[w]hat many Americans don’t know is that dietary supplements are not subject to testing by the Food and Drug Administration before they reach store shelves – meaning that every day, millions of Americans are ingesting substances whose safety and efficacy are not guaranteed.”  In the video message, she discusses products that purport to provide results they can’t possibly deliver, which is an abuse of consumer trust.  She also discusses dietary supplements that contain harmful ingredients.  Under the FDCA, the basis for such enforcement action is that the products are adulterated, misbranded, or both.   

In one example, Attorney General Lynch highlights recent criminal charges brought against USPlabs executives.  In concluding the video, Attorney General Lynch states that, “bad actors” will be held accountable for their actions.  This is consistent with the September 2015 “Yates memo” (see our blog post here) in which DOJ announced that they intended to hold individuals liable for misdemeanor and felony situations. While Attorney General Lynch emphasizes the importance of DOJ enforcement action, she also sends the message that consumers must take steps to protect themselves.  She directs consumers to consult with a health care provider, check the FDA and FTC websites for dietary supplement information, and use tools developed by the Department of Defense and the U.S. Anti-Doping Agency, including a smartphone app to make informed decisions before taking dietary supplements.   

If the Yates memo was a preview, it has become evident that DOJ is taking action on this policy in the realm of the dietary supplement as well as the food industry (see our blog post here). As we note future DOJ enforcement action, we will be certain to keep you posted. 

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By James C. Shehan –

More than one commentator predicted that the Federal Circuit’s decision in Amgen v. Sandoz interpreting the patent dance provisions of the Biologics Price Competition Innovation Act ("BPCIA") would be a fertile source of new litigation rather than a definitive decision laying out clear rules for industry to follow.  But to our knowledge no one predicted that Amgen and Sandoz would themselves engage in multiple additional patent dance lawsuits, which is exactly what is occurring now after Amgen filed two suits against Sandoz on February 26th (complaint here) and March 4th (complaint here). 

The first case involves an etanercept biosimilar to Amgen’s Enbrel and the second a pegfilgrastim biosimilar to Amgen’s Neulasta. Of perhaps great significance is that the first case is a patent infringement case and the second is not – it solely asks the court to interpret the BPCIA.  The second case may therefore result in a court ruling on a point contested by Amgen and Sandoz – whether a decision by a reference product sponsor such as Amgen to not bring a patent infringement lawsuit within 30 days of a breakdown in patent dance proceedings will trigger 35 U.S.C. § 271(e)(6)(B) and therefore limit the reference product sponsor to the sole and exclusive remedy of a reasonable royalty in case of a later finding of infringement.

In the Enbrel case, Amgen alleges infringement of five patents covering the active ingredient, its method of manufacture, and certain therapeutic uses.  According to the Amgen complaint, in October 2015, Sandoz gave Amgen its ABLA and information about the manufacturing processes for its Enbrel biosimilar.  In December, Amgen provided Sandoz with a list of patents for which it believes that infringement claims could reasonably be asserted. At this point, Sandoz apparently decided to exit the dance floor.  On January 27th, Sandoz sent Amgen an 86 page letter in which Sandoz agreed with the Amgen patent list and provided more information about its manufacturing processes for its biosimilar.  But Amgen states that Sandoz also declared in that letter that it was “waiving” its right to receive the next documents in the patent dance, a detailed statement from Amgen under 42 U.S.C. § 262(l)(3)(C) of the grounds for infringement.  Sandoz also informed Amgen that further “negotiations were unnecessary” and that Amgen under 42 U.S.C. § 262(l)(6) should file a patent infringement suit within 30 days.

Amgen protested by letter Sandoz’s exit from the dance and invoked its right under 42 U.S.C. § 262(l)(9) to seek a declaratory judgment of infringement. According to Amgen, Sandoz replied by confirming its refusal to further negotiate and stating that it “wished for patent litigation to begin as soon as possible."  The eagerness exhibited in this “see you in court” statement may hearken back to Sandoz’s attempt a couple of years ago to get a judicial declaration of invalidity for two of the patents that Amgen is now asserting, an attempt that ended with the Federal Circuit dismissing the case as premature (see our post here and the decision here) In contrast to the Enbrel case, Amgen’s lawsuit against Sandoz over the Neulasta biosimilar does not allege patent infringement.  Rather, it asks the court to declare that Sandoz failed to comply with the mandatory patent dance information exchanges, declare that this failure means that there can be no “immediate patent infringement action” under 42 U.S.C. § 262(l)(6), and declare that Amgen may get injunctive relief and lost profits damages in case infringement is later found, 

The interactions between the parties leading up to the Neulasta lawsuit are quite similar to those in the Enbrel lawsuit. In November 2015, Sandoz gave Amgen its ABLA and information about the manufacturing processes for its Neulasta biosimilar.  In January 2016, Amgen provided Sandoz with a list of two patents that Amgen believed Sandoz’s biosimilar would infringe.  Then on February 2, 2016, Sandoz told Amgen why the two patents were invalid, unenforceable and/or not infringed, and also told Amgen that it would no longer follow the patent dance. 

As in the Enbrel case, Sandoz declared that it was waiving its right to receive Amgen’s detailed statement of the grounds for infringement, informed Amgen that further “negotiations were unnecessary” and admonished Amgen to file a patent infringement suit within 30 days.  Sandoz added that “[o]therwise, the penalty for an untimely suit—that the ‘sole and exclusive remedy’ for any infringement be limited to a ‘reasonable royalty’—applies.  See 35 U.S.C. § 271(e)(6)(B).”  Note that the reasonable royalty point does not appear in Amgen’s complaint in the Enbrel lawsuit, so it is unknown whether Sandoz asserted it there as well. 

What can be gleaned from these multiple battles? As for Sandoz, it may be that, at least in the case of older biologics lacking exclusivity, Sandoz has decided that beginning and then abandoning the patent dance is a good strategy.  As for Amgen, it seems committed to litigating to defend its biologics products but there is no indication of why it did not bring a patent infringement lawsuit over the Neulasta patents but did over the Enbrel patents.  In any event, a court ruling over whether reasonable royalties are the sole remedy if a patent infringement case is not brought is likely to be at least an unintended consequence of that decision.  And for both parties, it seems that there are many more turns ahead in their BPCIA patent dance saga. 

And finally we wonder whether, having been jilted three times now, does Amgen feel like a shy but determined teenager who keeps on pursuing the same potential partner despite multiple rejections, hopeful that one day he or she  will own the dance floor as completely as Tony Manero, Alex Owens or Ren McCormack?