By Jennifer D. Newberger –

On August 14, 2014, FDA issued a draft guidance titled, “De Novo Classification Process (Evaluation of Automatic Class III Designation)” (draft guidance). 

The de novo review process, formally known as Evaluation of Automatic Class III Designation, is established by section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act (FDC Act), as amended.  This process was added to the FDC Act by the Food and Drug Administration Modernization Act of 1997 (FDAMA) to address novel devices that lack a predicate device but pose only a low to moderate risk, making them ill suited to the PMA process. 

Under FDAMA, before a device could utilize the de novo process, a device first had to be found not substantially equivalent (NSE) to a predicate device through the 510(k) process, even if the submitter and FDA agreed no appropriate predicate existed.  Due to the burdensome, time consuming nature of the de novo process, it was under utilized.

In September 2011, FDA issued a draft guidance document attempting to streamline the de novo process.  We discussed this draft guidance here.  Under that draft guidance, a person could submit a 510(k) and de novo petition simultaneously, and FDA could begin review of the de novo petition immediately upon issuance of the NSE letter. 

In July 2012, Congress amended section 513(f)(2) through passage of the Food and Drug Administration Safety and Innovation Act (FDASIA).  Under section 607 of FDASIA, a finding of NSE is not required before submitting a de novo petition.  Instead, if a person believes the device is low to moderate risk but no appropriate predicate exists, the person may submit a de novo without previously submitting a 510(k).  With the passage of FDASIA, the draft guidance issued in September 2011 was essentially mooted. 

The latest draft guidance describes the process of submitting a de novo petition under FDASIA, focusing primarily on the information to include in a de novo petition or a request for a Pre-Submission meeting prior to submitting a de novo request.  The information to include in a de novo petition includes the following: 

• a recommendation whether the device should be regulated as Class I or Class II;
• whether the device should be subject to 510(k) requirements;
• if a Class II device subject to 510(k), the petition should include a proposed special controls document, describing the intended use, risks, and risk mitigation strategy for the device;
• supporting protocols and data;
• a summary of benefits and known and potential risks; and 
• risk and mitigation information. 

In addition, the submission must include a “classification summary” demonstrating that the submitter has thoroughly researched legally marketed devices and concluded that no appropriate predicate exists.  To demonstrate that the submitter conducted such a search, the de novo submission should include:

• a description of the databases searched and terms used to establish no predicate exists; 
• regulations, PMAs, and/or product codes that may relate to or are potentially similar to the subject device; and 
• a rationale for why the subject device does not fit within or is different from the identified regulations, PMAs, and/or product codes. 

The draft guidance states that if a submission fails to include this information, it will be put on hold.

While it seems appropriate for a submitter to demonstrate that it has conducted a reasonable search and concluded that no appropriate predicate exists, there is a potential for overly burdensome implementation of these search requirements by FDA.  If FDA places a de novo submission on hold after concluding that insufficient information has been provided, FDA should help guide the submitter in searching for or identifying information FDA believes may be relevant.

The de novo process has long been in need of remediation.  FDASIA provided the basis for that remediation, and the guidance should help industry take advantage of this process.  Hopefully this more streamlined process will allow innovative, moderate risk devices to more easily enter the marketplace.

By Kurt R. Karst –       

We were beginning to wonder whether FDA would ever issue a letter decision addressing the novel issues raised in the Agency’s January 15, 2014 “Dear NDA/ANDA Applicant” letter (Docket No. FDA-2014-N-0087) concerning approval of generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection, 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials.  The days turned into weeks, and the weeks into months.  But earlier today, FDA finally issued the highly anticipated decision. [UPDATE – Subsequent to posting we learned of a lawsuit filed early on August 19, 2014 challenging the FDA Letter Descision.  Links to the papers in that case are provided below.]  And the decision was probably surprising to many.  Instead of addressing head-on the novel generic drug labeling “carve-in” and patent use code issues FDA initially raised in the Agency’s “Dear NDA/ANDA Applicant” letter – and that were the subject of numerous comments – FDA instead ruled that generic dexmedetomidine is a straight-on labeling carve-out case, similar to that faced by the Agency when it initially considered approving generic versions of PRANDIN (repaglinide) Tablets (prior to the change in patent use code issue that was ultimately ruled on by the U.S. Supreme Court in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012)).  That treatment of the case is immediately apparent in the second paragraph of FDA’s August 18, 2014 Letter Decision:

Today’s letter reflects FDA’s determinations with respect to permissibility of labeling carve outs for ANDAs referencing Precedex.  For the reasons set forth below, FDA concludes that regardless of whether the original use code or the revised use code applies, the agency can approve an ANDA that submits a “section viii” statement and omits labeling that discloses the protected use (as identified by Hospira).  FDA further concludes that such omissions do not render the drug less safe or effective for the remaining non-protected conditions of use.

For much of the backgound on this case, we refer you to our previous post; however, here are a few key facts to keep in mind:

• PRECEDEX is currently approved in three strengths and for two indications: (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting; and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures. 
• FDA’s Orange Book currently lists one unexpired patent for the 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials strength at issue: U.S. Patent No. 6,716,867 (“the ‘867 patent”), which expires on March 31, 2019, but is subject to a period of pediatric exclusivity that expires on October 1, 2019. 
• The ‘867 patent is listed in the Orange Book as a method-of-use patent with a “U-1472” patent use code, which is defined in an Orange Book addendum as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”
• The ‘867 patent was previously listed with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”

The general question FDA initially had to address was whether FDA could, in light of the the original and clarified patent use code narratives, approve an ANDA for a generic version of PRECEDEX containing a “section viii” statement to omit information protected by the ‘867 patent, or whether the omission of such information would preclude a carve-out and ANDA approval.  Or, as FDA explains it in the Agency’s Letter Decision:

Hospira asserts that both its original and its revised use code overlap not only with the first indication for Precedex but also with the second indication for that drug because there is a subset of non-intubated patients that may receive Precedex for procedural sedation (the second indication) in the ICU setting.  Hospira argues that because its use code(s) for the ‘867 patent fully cover the first indication and may overlap with the second indication, an applicant with a section viii statement to the ‘867 patent must carve out both the first and the second indications in their entirety, thereby precluding approval of any ANDAs with carved out labeling.

Among other things, Hospira cited the Caraco decision in which the Court stated: “the FDA will not approve an ANDA if the generic’s proposed carve out label overlaps at all with the brand’s use code.”

After affirming FDA’s authority to determine permissible labeling carve-outs, the Agency, pointing to precedent labeling carve-out decisions involving generic repaglinide (Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411), tramadol HCl (FDA Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003), and oxandrolone (Docket No. FDA-2005-P-0368) rejected Hospira’s arguments.  According to FDA:

Both the original and the revised use codes are limited to “intensive care unit sedation.”  Although the revised use code includes additional language specifying some of the types of patients that Hospira claims are encompassed within the “intensive care unit sedation” use, i.e., non-intubated ICU patients prior to and/or during surgical and other procedures, it does not broaden the claimed method of use beyond “intensive care unit sedation.” . . .  Nor does the clarified use code and its explicit inclusion of a subset of patients that may undergo procedural sedation somehow expand the patented use to encompass and prevent approval for all patients who seek to use the drug for the separately delineated procedural sedation indication. . . .  FDA previously has determined that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.  The procedural indication and related information in the labeling do not impermissibly disclose the use of Precedex for procedures in the ICU (i.e., for the use covered by the use code).  ANDAs therefore may be approved for the second indication, consistent with how FDA has implemented use codes and allowed carve outs in other circumstances.

And:

Just as FDA concluded that a labeling carve out was proper for repaglinide before Novo broadened its use code to duplicate in its entirety the single approved indication, so, too, here ANDAs for Precedex may carve out the protected information (related to use for ICU sedation), and be approved for procedural sedation despite the fact that use for procedural sedation may at times occur in an intensive care setting.  Use in an intensive care setting is not expressly disclosed in any proposed ANDA labeling.  Hospira’s reliance on a single sentence about a different type of “overlap” at issue in Caraco does not control the outcome here.

From there it was relatively easy for FDA to conclude that “permitting ANDA sponsors to omit information from the labeling related to use for ICU sedation does not render the product less safe or effective for the remaining use of sedation of non-intubated patients prior to and/or during surgical and other procedures,” which is a finding that must be made in labeling carve-out cases pursuant to 21 C.F.R. § 314.127(a)(7).

Whether FDA’s side-stepping of several of the issues the Agency initially raised last January was a deliberate attempt to avoid having to address those thorny issues, or the result of an epiphany that this is, to the Agency at least, a “straight 8 case” is unclear.  Certainly one thing was clear all along: at least one party involved in the dispute would be disappointed with FDA’s result.  Now the question is: how disappointed?

UPDATES:

• Early on August 19, 2014, Hospira filed a Complaint and Motion for Temporary Restraining Order and/or Preliminary Injunction in the U.S. District Court for the District of Maryland to stay FDA's Letter Decision, rescind any ANDA approvals predicated upon that Letter Decision, order FDA to recall any product sold or distributed under such an ANDA approval, and enjoin FDA from granting any further or additional approvals predicated upon the Letter Decision.
• PAPERLESS ORDER (Entered: 08/19/2014)) scheduling an emergency hearing on the Motion for Temporary Restraining Order for Tuesday, August 19, 2014 at 3pm in Courtroom 2C. 
• ORDER directing that the decision of Defendant Food and Drug Administration (FDA), in Docket No. FDA-2014-N-0087 is STAYED; directing that this order is to remain in effect until September 2, 2014.  Temporary Restraining Order Granted.

By Kurt R. Karst –      

The folks in FDA’s Office of Generic Drugs (“OGD”) have been especially busy as of late preparing for the October 1, 2014 implementation of the review and performance metrics agreed to under the Generic Drug User Fee Amendments of 2012 (“GDUFA”).  The Office continues to make personnel changes in preparation for the big event (see here), and has been pumping out policy and guidance documents faster than we can keep up with them.

Earlier this month, OGD issued two important Manual of Policy and Procedures (“MAPPs”) documents for managing the ANDA review queue: (1) MAPP 5200.4, Criteria and Procedures for Managing the Review of Original ANDAs, Amendments and Supplements; and (2) MAPP 5240.3 (Rev. 1), Prioritization of the Review of Original ANDAs, Amendments, and Supplements.  The documents convey OGD’s reworked prioritization schedule for ANDAs in light of GDUFA.  Under the revised policy, ANDAs will be prioritized and considered for expedited review if they meet the specifics of one or more various categories:

1. Submissions containing patent certifications pursuant to 21 CFR 314.94(a)(12), including the following circumstances in which priority review may be granted:
• Potential first generic products for which there are no blocking patents or exclusivities on the reference listed drug may receive expedited review; 
• Submissions that contain a Paragraph IV certification, but become eligible for approval during the review period as a result of no blocking patents or exclusivities (including 180-day exclusivity) and no applicable stays; and 
• Submissions that contain a Paragraph IV certification, that are submitted on the first day that any valid Paragraph IV application for the drug in question is submitted, and that are received as substantially complete.
2. Submissions related to drug shortages
3. Submissions that are subject to special review programs such as the President’s Emergency Plan for AIDS Relief
4. Submissions related to public health emergencies
5. Submissions related to certain government purchasing programs
6. Submissions subject to statutory mandates or other legal requirements
7. Supplements for which expedited review is requested under 21 CFR 314.70(b)(4)

OGD has also been – and will continue to be – busy issuing new guidance documents explaining current policies and procedures in the post-GDUFA world of ANDA review and approval.  In a notice that will be published in the Federal Register later this week, OGD announced a public hearing on GDUFA implementation that will be held on September 17, 2014, from 9 AM to 5 PM.  In the notice, FDA is soliciting comment on five guidance documents, some of which have yet to see the light of day:

• ANDA Submissions – Content and Format of ANDAs
• ANDA Submissions – Refuse to Receive for Lack of Proper Justification of Impurity
  Limits
• ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA (see our previous post here) 
• ANDA Submissions – Prior Approval Supplements Under GDUFA (see our previous post here)
• Controlled Correspondence Related to Generic Drug Development 

The notice follows a January 2014 notice (see our previous post here) in which FDA announced the establishment of a public docket (Docket No. FDA-2014-N-0032) to receive input and suggestions on ways to improve the quality of ANDAs (original, amendments, and supplements) submitted to OGD and on how to best communicate those suggestions to the generic drug industry.  Thus far, FDA has received only a handful of comments in response to the solicitation.

In addition to canvassing for comments on OGD GDUFA guidances and future policy priorities, the September public hearing will tackle “GDUFA Implementation Related to Generic Drug Exclusivity” and “GDUFA Implementation and Potential First Generics.”  The second topic relates to the two MAPPs discussed above.  According to FDA:

Subsequent to GDUFA’s enactment, FDA has received numerous individual stakeholder comments on what should qualify as a first generic ANDA for the purposes of expedited review.  These comments reflect a range of options, for example, from a broad definition that would prioritize review of all ANDAs for each strength of a Reference Listed Drug submitted for which there is not already an approved ANDA at the time of submission, to a more narrow definition under which only ANDAs that contain a paragraph IV certification and qualify as a “first applicant” under section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act would be designated as a first generic eligible for expedited review.  In addition, several stakeholders have indicated that depending on the criteria FDA applies, first generic status could or should change over time based on other external factors, for example, withdrawal or rescission of approval of another applicant’s ANDA, or shifts in the patent or exclusivity landscape (for example, an unsuccessful patent challenge).

As such, FDA wants to hear from industry as to what specific criteria should FDA apply to identify an ANDA as a first generic eligible for expedited ANDA review, and whether there are there other topics related to first generics eligible for expedited review that require further consideration.

Moving on to “GDUFA Implementation Related to Generic Drug Exclusivity,” FDA is seeking to get a better handle on the topic that generates the most controversy under Hatch-Waxman and in the generic drug industry: 180-day exclusivity.  The current system FDA follows, under which 180-day exclusivity decisions are typically made at the last possible moment (and that sometimes result in a non-decision decision – e.g., 180-day exclusivity “punts” under the failure-to-obtain-timely-tentative-approval forfieture provision), is not optimal.  It is a drain on industry and FDA resources, and can lead to court fire drills.  So, FDA is considering building a better model, and wants to hear industry input on various questions:

1. Should FDA’s consideration of eligibility for 180-day exclusivity for a specific drug product be a public process, including consideration of whether a first applicant has forfeited its eligibility for exclusivity under section 505(j)(5)(D) of the FD&C Act? If a public process is advisable, would it be so in all instances, or is there a subset of circumstances in which the process should be public?  Also, what administrative mechanisms would best facilitate such a process?
2. Legal challenges to FDA’s decisions on 180-day exclusivity often must be resolved on an expedited basis which can be inconvenient for the parties and the court. What legal or regulatory mechanisms, if any, are available to better facilitate FDA’s determination of and orderly resolution of sponsors’ challenges to 180-day exclusivity determinations?
3. Are there other topics related to 180-day exclusivity on which you would like to comment?
4. Are there topics related to 180-day exclusivity that would benefit from FDA guidance?

Elsewhere, and in the more informal context of FDA’s “From a Clinical Perspective” pubication, the Agency is seeking comment on the five generic drug regulatory science priorities for Fiscal Year  2014: (1) post-market evaluation of generic drugs; (2) equivalence of complex products; (3) equivalence of locally acting products; (4) therapeutic equivalence evaluation and standards; and (5) computational and analytical tools.  Those topics were laid out last year consistent with the GDUFA goals document. 

By Kurt R. Karst –      

For several years now we’ve closely tracked the changes in user fees rates FDA sets each fiscal year under the Prescription Drug User Fee Act (“PDUFA”).  Last year, we added rates set pursuant to the Generic Drug User Fee Amendments of 2012 (“GDUFA”) and the Biosimilar User Fee Act of 2012 (“BsUFA”) (see our previous post here).  This year we’re a little late reporting on the Fiscal Year 2015 (“FY 2015”) rates established by FDA earlier this month . . . but with good cause.  While FDA was busy ascending on some user fee rates and descending on other user fee rates, this blogger was busy doing his own ascending and descending – up to and down from the summit of Mt. Kilimanjaro in Tanzania, Africa.  And while we were at the summit (Uhuru Peak, at 19,341 feet), we staked a claim for Hyman, Phelps & McNamara, P.C.  Here’s proof if you need it:

The FY 2015 PDUFA application user fee rate is set at $2,335,200 for an application requiring “clinical data” (defined here in an FDA guidance document), and one-half of a full application fee ($1,167,600) for an application not requiring “clinical data” and a supplement requiring “clinical data.”  FDA’s Federal Register notice announcing the new rates is available here.  These figures reflect FDA’s estimate of 115.042 fee-paying full application equivalents – an average of the number of full applications that paid fees over the lateset 3 years.  This figure is slightly lower than last year’s estimate of 116.333 fee-paying full application equivalents and explains somewhat the increase in the application fee rate.  Annual establishment and product fees have been set at $569,200 and $110,370, respectively, and are based on estimates of 472 establishments (an increase of 17 compared to FY 2014) and 2,434 products (an increase of 9 compared to FY 2014).    

The FY 2015 PDUFA user fee rates become effective on October 1, 2014 and generally represent a modest change vis-à-vis the FY 2014 user fee rates.  All BsUFA user fees – i.e., the initial and annual biosimilar Biological Product Development (“BPD”) fees, the reactivation fee, and the biosimilar biological product application, establishment, and product fees – are keyed to PDUFA user fees.  The FY 2015 rates have thus been set at $233,520 (initial and annual PBD), $467,040 (reactivation), $2,335,200 (application), $569,200 (establishment), and $110,370 (product).  FDA’s Federal Register notice announcing the new rates is available here. 

The table below shows the changes in PDUFA user fee rates for the latest iteration of the law – PDUFA V.  Hisorical tables for user fee rates changes since the enactment of PDUFA are avilable here. 

GDUFA establishes several types of user fees that together generated $299 million in funding for FDA in FY 2013 (including $50 million from the one-time ANDA backlog fee).  That $299 million base amount is adjusted annually, and in FY 2015 has been set at $312,224,000. (The FY 2014 adjusted base figure was $305,659,000.)  Several of the FY 2015 GDUFA user fee rates FDA announced earlier this month, and which go into effect this October, are peddled back vis-à-vis the FY 2014 user fee rates; however, the Active Pharmaceitical Ingredient (“API”) and Finished Dosage Form (“FDF”) facility fee rates did take a hike up vis-à-vis the FY 2014 user fee rates. 

The original ANDA and PAS fees, which make up 24% of the $312,224,000 (or $74,934,000 rounded to the nearest thousand dollars), are based on a total number of 1,276 fee-paying full application equivalents expected to be received in FY 2015.  Dividing $74,934,000 by the total number of fee-paying full application expedted to be received results in an original ANDA fee of $58,730 and a PAS fee of $29,370 for FY 2015.  The 1,276 fee-paying full application equivalents figure FDA identifies is significantly higher than the 1,148.8 figure used in FY 2014, and therefore, largely explains a drop in the original ANDA and PAS fees.  Interestingly, that figure is an estimate of ANDAs that excludes the massive bolus of applications submitted in June 2014, before FDA’s enhanced ANDA stability requirements went into effect.  That bolus – any any bolus of applications submitted when the GDUFA performance goals go into effect in October 2014 – will be reflected in future user fee figures, and could lead to user fee rate decreases over the following years.

The Drug Master File (“DMF”) fee, which makes up 6% of the $312,224,000 ($18,734,000 rounded to the nearest thousand dollars), is based on an estimate of 701  fee-paying DMFs in FY 2015 – a significant increase over the 583 fee-paying DMFs estimated for FY 2014.  The resulting fee is $26,720 for FY 2015, which is a drop from the $31,460 user fee rate set for FY 2014.

The API and FDF facility fees are based on data submitted by generic drug facilities through the self-identification process.  The FDF facility fee revenue makes up 56% of $312,224,000 ($174,845,000 rounded to the nearest thousand dollars), and the API facility fee makes up 14% of $312,224,000 ($43,711,000 rounded to the nearest thousand dollars).  According to FDA, the total number of FDF facilities identified through self-identification was 681 (271 domestic and 410 foreign), and the total number of API facilities identified through self-identification was 795 (103 domestic and 692 foreign).  These numbers translate into FY 2015 FDF facility fee rates of $247,717 for a domestic facility and $262,717 for a foreign facility, and API facility rates of $41,926 for a domestic facility and $56,926 for a foreign facility.  These are pretty hefty increases compared to the FY 2014 FDF and API facility user fee rates, and are likely explained by the significant decrease in self-identified facilities.  In FY 2014, the number of self-identified facilities used to calculated the facility fee rates was 748 (315 domestic and 433 foreign) FDF facilities, and 903 (128 domestic and 775 foreign) API facilities. 

The table below shows the changes in GDUFA user fee rates for the first iteration of the law.

By Kurt R. Karst –      

The Major Contribution to Patient Care (“MC-to-PC”) basis for demonstrating that an orphan drug is clinical superiority, and is therefore not the “same drug” as a previously approved orphan drug containing the same active moiety, is supposed to be a pretty rare event.  Though still rare, we’ve been seeing greater use of the clinical superiority argument and greater acceptance of MC-to-PC theories by FDA’s Office of Orphan Products Development.  Indeed, it was just last week that we posted on one such case concerning cysteamine bitartrate (PROCYSBI) (see our previous post here).  That precedent added to the three other instances of which we were aware that MC-to-PC theories were accepted by FDA (see our previous post here).  Now another case has come to light. 

MC-to-PC clinical superiority is one of the three bases the sponsor of an orphan drug can use to argue that the company’s drug is different from a previously approved orphan drug, thus making the company’s product eligible for orphan drug designation and orphan drug exclusivity (and, where applicable, the ability to “break” another sponsor’s unexpired orphan drug exclusivity).  Specifically, FDA’s orphan drug regulations provide that a drug is “different” from an approved orphan drug if it is “clinically superior” to the approved orphan drug.  A clinically superior drug is “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 MC-to-PC. 

There is only one instance where FDA found a drug to be clinically superiority based on greater effectiveness.  In 2002, FDA determined that Serono’s REBIF (interferon beta-1a) (BLA No. 103780) was clinically superior to Biogen’s AVONEX (interferon beta-1a) (BLA No. 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.  To support a claim of clinical superiority based on superior safety, the second product must, as discussed in the preamble to FDA’s 1992 final orphan drug regulations and in FDA’s orphan drug regulations, provide “[g]reater safety in a substantial portion of the target populations.”  Even “a small demonstrated improvement in efficacy or diminution in adverse reactions may be sufficient to allow a finding of clinical superiority.”  There are several (less than 10 that we know of) instances in which greater safety has been OOPD’s basis for designating and orphan drug and granting orphan drug exclusivity. 

To support a MC-to-PC claim of clinical superiority, FDA has acknowledged in the Agency’s regulations that it will do so only in “unusual circumstances.”  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.  However, this determination will have to be made on a case-by-case basis.

As to how much superiority might constitute a “major contribution to patient care,” FDA also remarked:

There is no way to quantify such superiority in a general way.  The amount and kind of superiority needed would vary depending on many factors, including the nature and severity of the disease or condition, the quality of the evidence presented, and diverse other factors. . . .  While comparative trials are, of course, preferred and will usually be required, it is possible that, in some circumstances, a demonstration of a major contribution to patient care can be made without such trials.

The latest MC-to-PC precedent concerns NYMALIZE (nimodipine) Oral Solution, 60 mg/20 mL, which FDA approved pursuant to the FDC Act’s 505(b)(2) NDA procedures on May 10, 2013 under NDA No. 203340 for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with Subarachnoid Hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).  Previously, FDA had approved – thougth not under the FDC Act’s orphan drug provisions – another nimodipine drug product for the same use as NYMALIZE: Bayer’s NIMOTOP (nimodipine) Capsules (NDA No. 018869; approved on December 28, 1988).

The original sponsor of NYMALIZE had requested orphan drug designation, but did not provide an adequate explanation for clincal superiority, according to OOPD’s review of the orphan drug designation request.  The sponsor implied that there were two advantages to an oral solution dosage form of nimodipine: an oral solution dosage form eliminates the need to extract the capsule contents with a syringe, which could reduce the incidence of accidental intravenous administration, and an oral solution would allow for more precise dosing and would provide another option for patients who may not require nasogastric administration but who have difficulty swallowing oral capsules.  OOPD treated these two arguments as greater safety and MC-to-PC clinical superiority arguments, respectively. 

Ultimately, OOPD consulted the FDA Review Division responsible for review of the NYMALIZE IND and NDA, and asked whether the oral solution dosage form was important, and whether it could be considered clinically superior based on safety or MC-to-PC grounds.  The FDA Review Division’s response paved the way for OOPD’s designation and orphan-exclusive approval.  According to the FDA Review Division:

The oral solution is a very big deal to us in the Neurology Division.  It represents a major safety initiative that we have undertaken to eliminate a rare, but persistent error that may be, and has been, fatal.  We feel it will provide greater safety in a substantial portion of the target population and will provide a major contribution to patient care over the currently available product.  We feel the proposed oral solution represents a major advantage over the current product and anticipate withdrawing the current product from the market following approval of an oral solution.  

Despite the FDA Review Division’s statement on greater safety, OOPD determined that MC-to-PC would be the basis for designation and for granting exclusivity:

In this application, while the sponsor has not provided evidence of greater effectiveness, nor has shown that the product will provide safety in a substantial portion of the target population, rationale has been provided that the oral solution formulation of nimodipine constituters a major contributiojn to patient care given the major safety initiative undertaken by FDA to eliminate this rare but persistent medication error that had resulted in patient death. 

The orphan-exclusive approval of NYMALIZE is a prime example of how a sponsor can make relatively small changes to a previously approved drug, and without much investment from a non-clinical and clinical perspective, to reap significant benefits.  Indeed, the NYMALIZE NDA largely relied on FDA’s previous approval of NIMOTOP for approval.  According to FDA’s review documents, the NYMALIZE 505(b)(2) NDA included no clinical data and was the sponsor was granted a biowaiver.  The application contained only chemistry and manufacturing controls data, as well data from short-term animal toxicity studies.

By Kurt R. Karst –

We thought Eisai Inc.’s (“Eisai”) beef with FDA over New Chemical Entity (“NCE”) exclusivity might resurface at some point . . . and now it has.  Last Friday, Eisai filed a Complaint in the U.S. District Court for the District of Columbia alleging that FDA erroneously triggered periods of 5-year NCE exclusivity for two drug products – BELVIQ (lorcaserin HCl) Tablets (NDA No. 022529; approved on June 27, 2012) and FYCOMPA (perampanel) Tablets (NDA No. 202834; approved on October 22, 2012) – by using the NDA approval dates instead of the dates the products could be legally marketed to calculate the five-year exclusivity terms. 

BELVIQ and FYCOMPA contain controlled substances that required scheduling decisions by the DEA under the Controlled Substances Act (“CSA”) before the drug products could be marketed.  Those decisions did not become effective until June 7, 2013 for BELVIQ and until January 2, 2014 for FYCOMPA.  Eisai unsuccessfully challenged the DEA in Court over the glacial pace of the scheduling decision for FYCOMPA (see our previous post here).  Congress is currently considering legislation to speed up DEA scheduling decisions (see our previous post here).

As we previously reported (here and here), Eisai submitted a Citizen Petition (Docket No. FDA-2013-P-0884) to FDA in 2013 requesting that the Agency conclude that the NCE exclusivity start dates for BELVIQ and FYCOMPA are triggered only when FDA-approved labeling incorporating the final DEA CSA scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  FDA denied Eisai’s petition requests (as well as those of another petitioner for a different drug) in April 2014.  According to FDA, “[t]he legal and regulatory framework on exclusivity and drug approvals contemplate only a single date of approval for determining when exclusivity begins for an NDA.  For each NDA at issue, that date is the date that FDA completes its review and issues an approval letter.” 

Eisai alleges in its August 8, 2014 Complaint that FDA violated the FDC Act and the Administrative Procedure Act (“APA”) by using the NDA approval dates as the triggering events to start the NCE exclusivity periods, thereby possibly accelerating by a year or more 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.

Eisai also takes issue with FDA’s alleged different treatment of BELVIQ and FYCOMPA compared to other NCEs and similarly situated products. “FDA is unfairly penalizing Eisai for developing and seeking to commercialize NCEs recommended for CSA scheduling,” says Eisai.  “While BELVIQ® and FYCOMPA® will be deprived of their full five-year market exclusivity periods, sponsors of NCEs that do not require CSA scheduling enjoy full five-year exclusivity periods.”  Moreover, argues Eisai,

FDA’s actions have also resulted in disparate treatment among sponsors of CSA scheduled products themselves.  For example, an examination of NCEs that FDA recommended for scheduling demonstrates that FDA submitted its recommendation to DEA anywhere from 367 days before issuing an approval letter (PROVIGIL®) to as many as 94 days after issuing an approval letter (LYRICA®).  FDA has offered no explanation and no sound policy rationale for this disparate treatment, even though FDA’s wildly varying timeframe for providing DEA with scheduling recommendations can substantially diminish an NCE’s five-year market exclusivity period.

Eisai also says that FDA’s refusal to recognize the dates BELVIQ and FYCOMPA could be legally marketed as the start dates for NCE exclusivity is inconsistent with at least one previous FDA decision concerning RAZADYNE ER (galantamine hydrobromide) Extended-release Capsules, which FDA approved on December 22, 2004 under NDA No. 021615.  According to Eisai:

On June 13, 2006, long after RAZADYNE® ER was commercially launched, FDA decided to reach back and move the date triggering the drug’s exclusivity period to April 1, 2005, because the agency concluded that was the earliest date that RAZADYNE® ER could have been marketed.  FDA then officially changed the trigger date for RAZADYNE® ER’s market exclusivity period from December 22, 2004 to April 1, 2005 in the Orange Book. . . . Despite this clear agency precedent, FDA has refused to take such appropriate actions with regards to BELVIQ® and FYCOMPA®.  And, in doing so, FDA has also failed to provide a reasonable basis for treating BELVIQ® and FYCOMPA® differently.

Finally, Eisai argues that FDA’s denial of the company’s Citizen Petition was arbitrary, capricious, and short of statutory right.  “In denying the Petition, FDA ignored its clear statutory mandate from Congress to ensure that products such as BELVIQ® and FYCOMPA® receive full five-year market exclusivity periods,” writes Eisai, which also lays out in the Complaint several reasons as to how FDA’s decision is improper. 

Eisai requests that the court declare FDA’s decision as to BELVIQ’s and FYCOMPA’s NCE exclusivity periods to be a violation of the APA.  Eisai also wants the court to compel FDA to commence the 5-year exclusivity periods for both drug products on the date each drug’s CSA scheduling was complete and labeling incorporating the scheduling information allowed the products to be launched into interstate commerce (i.e., June 7, 2013 for BELVIQ, and January 2, 2014 for FYCOMPA.)

By James E. Valentine* & James C. Shehan —

On August 5, 2014, FDA announced the availability of its most recent biosimilars guidance entitled, “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act” (“FDA Draft Guidance”). The Draft Guidance puts some sponsors of BLAs past, present, and future, on notice that FDA wants them to submit certain information for their biologics to be considered for “reference product exclusivity.”  But that’s a burden that sponsors will likely gladly bear, because FDA’s proposed broad interpretation of structural modification, a key term in determining whether a related product differs enough from a sponsor’s structurally related product to merit its own exclusivity, makes more products eligible for exclusivity than is required under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).

By Riëtte van Laack —

On July 29, 2014, the D.C. Circuit decided that USDA’s Country of Origin Labeling (COOL) regulation passed constitutional muster. Our previous posts regarding this case provide details on the background.  Congress required COOL on many foods, including some meat products, and passed a law defining “country of origin” for meat to be based on where the animal had been born, raised, and slaughtered (or “harvested”).  After a WTO panel found that the first USDA regulations violated the U.S. international obligations, USDA issued an amended regulation requiring more precise information on the location of each production step, and eliminating the option of labeling commingled animals.

Previously, the lower court and the Court of Appeals panel found that USDA’s regulation did not violate free speech protections.  However, the Court of Appeals noted (in a footnote) that the full court hear the case en banc (i.e., all active judges on the court decide the case instead of just three judges) to provide a clear ruling on the issue regarding the reach of Zauderer; i.e., is it limited to mandatory disclosure of purely factual and uncontroversial information appropriate to prevent deception (as AMI argued) or does it also apply to purely factual and uncontroversial disclosures serving other government interests?  

The en banc majority first determined that the issue was mandatory disclosure rather than a ban on certain speech.  Thus, Zauderer rather than Central Hudson provided the appropriate standard.  It next determined that Zauderer was not limited to mandatory disclosures that would prevent deception.  To the extent that other D.C. Circuit decisions might be read as limiting Zauderer to cases in which the governmental interest is preventing deception, these decisions are now overruled. 

Thus, the remaining question was whether the government had a substantial interest in promulgating its COOL regulation.  Referring to USDA statements in the rulemaking process, AMI had characterized the interest at stake as merely satisfying consumers’ “idle curiosity.”  However, the Court did not limit the search for the governmental interest to review of USDA’s statements.  The interests served by the rule were also those advanced by Congress when it adopted the statute, even if USDA failed to assert those interests.  According to the Court, it would be improper to allow “perfectly adequate legislative interests properly stated by congressional proponents” to be “doomed by agency fumbling (whether deliberate or accidental),” because that rule would “allow the executive to torpedo otherwise valid legislation simply by failing to cite . . . the interests on which Congress relied.”  Congress identified the purpose of the statute as “enabling customers to make informed choices based on characteristics of the products they wished to purchase, including United States supervision of the entire production process for health and hygiene.”  The Court also pointed to “the ‘time-tested consensus’ that consumers want to know the geographical origin of potential purchases has material weight in and of itself.”  It concluded that “[t]he context and long history of country-of-origin disclosures to enable consumers to choose American-made products; the demonstrated consumer interest in extending country-of-origin labeling to food products; and the individual health concerns and market impacts that can arise in the event of a food-borne illness outbreak” combined created a substantial interest.

The Court held that the disclosures were “purely factual and uncontroversial information” about the good or service being offered, COOL does not require corporations to carry messages biased against or expressly contrary to the corporation’s views, and the mandatory disclosures do not rule out ordinary advertising methods.  Thus, the government’s interests were sufficient to sustain COOL under the Zauderer standard.

The decision was not unanimous.  Judges Rogers and Kavenaugh wrote concurring opinions and Judges LeCraft Henderson and Brown dissented.  Judge Brown’s dissent (in which Judge LeCraft Henderson joined) is notable in its wording.  She asserted that the decision by the majority looks to “disembowel” court precedent and put “crony capitalism or ideological arm-twisting” ahead of first amendment rights.

Whether COOL requirements for meat will survive, however, ultimately will depend on the WTO decision.  The rumor is that the WTO has ruled on the fair trade challenge filed against COOL by Mexico and Canada and that it does not bode well for USDA.  Moreover, AMI has the option of seeking redress from the U.S. Supreme Court.

By Ricardo Carvajal —

FDA is set to start enforcing its gluten-free labeling rule (for our prior posting on the rule, see here).  To make sure you didn’t miss the onset of the compliance deadline of August 5, FDA issued reminders in the form of a Constituent Update and a blog posting by Deputy Commissioner for Foods and Veterinary Medicine Michael Taylor.  FDA also included a reminder in the most recent edition of CFSAN’s News for Educators, which asserts that “an estimated 5 percent of foods currently labeled ‘gluten-free’ contain 20 ppm or more of gluten.”  That assertion suggests that FDA will have little difficulty identifying potential candidates for its inaugural enforcement activities.

 FDA’s blog posting notes that the gluten-free labeling rule applies to packaged foods, but also states that “restaurants making a gluten-free claim on their menus should be consistent with FDA’s definition” (emphasis ours).  The blog links to a National Restaurant Association web page which suggests that restaurants “must” comply with the rule.  We leave it to others to elaborate on the distinction between “should” and “must.”  For practical purposes, we suspect that plaintiffs’ lawyers won’t perceive much of a difference – a phenomenon that at least some insurance brokers seem to be counting on.

By Jennifer D. Newberger —

We previously posted about CDRH’s guidance on the appeals process contained in the Food and Drug Administration Safety and Innovation Act (FDASIA), and its issuance of a draft Q&A discussing section 517A.  Section 517A imposed timeframes for appeal decisions that were shorter than those originally proposed by CDRH, and required CDRH to provide a “substantive summary” of the rationale for any “significant decision” being appealed.

On July 30, 2014, CDRH issued the final Q&A, with only two modifications:

• Clinical hold decisions have been added to the list of significant decisions subject to the shorter review timeframes in 517A.  Since clinical holds do have a substantial impact on the ability of a company to proceed with its product development, adding this to the list of significant decisions is likely non-controversial and appropriate.
•   Examples of non-significant decisions have been provided, including 510(k) requests for additional information, PMA major deficiency letters, refuse to accept letters, 522 orders, CLIA waiver decisions, Warning Letters, and responses to requests under section 513(g). 

Otherwise, the draft and final guidance documents are the same.  This means that the final Q&A still fails to answer the most critical question:  when will the substantive summary be provided to the requester?  As we noted in our prior post, under section 517A, the appeal must be filed within 30 days of the significant decision.  If the substantive summary is provided beyond the 30 day timeframe, or even late in the timeframe, it will be of little to no use in preparation of the appeal, contrary to the apparent statutory intent. It is disappointing that the final guidance does not clearly state that the summary must be provided promptly so as to facilitate the timely preparation of an appeal that directly responds to FDA’s concerns.

By Allyson B. Mullen & Jeffrey N. Gibbs —

On July 31, 2014, in accordance with Section 1143 of the Food and Drug Administration Safety and Innovation Act (FDASIA), FDA notified Congress of its intent to issue two draft guidance documents regarding oversight of laboratory developed tests (LDTs).  FDA, Notification to Congress, July 31, 2014.  The two draft guidance documents are entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” (the Framework Guidance) and “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)” (the Notification Guidance) – the guidances are available via the same link as the notice to Congress.  On the same day, FDA rejected the Washington Legal Foundation’s citizen petition challenging FDA’s authority to regulate LDTs.  Brushing aside WLF’s arguments, FDA unequivocally stated it could regulate LDTs as devices and do so through guidance documents, not rulemaking.

At long last, we now know how FDA intends to regulate LDTs – and it’s not pretty.  Of course we will have a much more detailed analysis of the draft guidance documents once we have had time to fully digest these documents, but for now we wanted to share a high-level summary.

The Framework Guidance

The Framework Guidance defines an LDT as “an IVD that is intended for clinical use and designed, manufactured and used within a single lab.”  Framework Guidance at 4.  FDA also identifies a number of laboratory tests that have been considered by industry to be LDTs in the past, but FDA believes are in fact IVDs.  Thus, FDA simultaneously answers the question of what it considers to be an LDT and then rendered the answer moot by saying that it will handle all of these tests the same way. 

 According to the Framework Guidance, FDA plans to take a risk-based approach to regulating LDTs.  This means that there will be three groups of LDTs: LDTs subject to full enforcement discretion; LDTs subject to partial enforcement discretion; and LDTs subject to full FDA regulation.

 FDA plans to continue to exercise enforcement discretion with respect to LDTs that are used solely for forensic (law enforcement) purposes, and certain LDTs for transplantation when used in CLIA-certified, high-complexity histocompatibility laboratories.   

FDA plans to exercise enforcement discretion with respect to compliance with premarket submission and quality system requirements for the second group of LDTs, but these LDTs will be required to register and list with FDA (or provide Notification – discussed below) and report adverse events.  The LDTs falling into this second category are:

• Low-risk LDTs, class I devices;
• LDTs for rare diseases\“Traditional LDTs”; and
• LDTs for Unmet Needs.

  Low-risk LDTs are those that are classified as a class I medical device.

An LDT for a rare disease will follow the definition of a Humanitarian Use Device (HUD) in 21 C.F.R. § 814.3(n).  To qualify under this definition, the laboratory will have to perform less than 4,000 tests per year, which seems unrealistic.  A therapeutic device can qualify as a HUD if it is intended for a disease or condition that “affects or is manifested in fewer than 4,000 individuals in the United States per year”.  However, a diagnostic test qualifies only if fewer than 4,000 patients a year would be tested with the device.  Thus, the exemption is not truly for “rare diseases,” but for “rarely performed tests.”  For example, a recent study published in the New England Journal of Medicine just recommended testing for the “bubble boy” disease because if treated within 3.5 months of birth, it could save the child’s life.  This disease affects only 1 in 100,000 newborns (although recent reports suggest it may be slightly higher at 1 in 50,000 newborns), making it very rare.  But because testing is recommended at birth to identify the genetic mutation (rather than waiting until an individual is symptomatic) over 4,000 tests will be performed, this test would not be deemed to be “rare” for the Framework Guidance. 

Traditional LDTs are “IVD devices that reflect the types of LDT[s] available when FDA began its policy of generally exercising enforcement discretion over LDTs in 1976” – essentially the preamendment device equivalent.  The Framework Guidance identifies a number of factors that FDA will consider when determining if an LDT qualifies as a “Traditional LDT,” including, whether the LDT meets the definition of an LDT set out in the Framework Guidance, whether the LDT is manufactured and used at a single health care facility for a patient that is being treated in the same healthcare facility or healthcare system, whether the LDT is comprised of only legally marketed components (e.g., no RUO or IUO components), and whether the LDT is interpreted by a qualified healthcare professional, without use of software or automated instrumentation.  These factors will limit the vitality of this category for many novel tests.  It is not clear how or if FDA will make the determination as to what constitutes a “Traditional LDT,” or if FDA will rely on laboratories to self identify. 

Finally, “LDTs for Unmet Needs” are LDTs for which there is no FDA-approved or cleared equivalent device available.  Similarly to “Traditional LDTs,” the guidance lists several factors FDA will consider when determining whether an LDT qualifies as being for an unmet medical need.  One such factor is “whether there is [a] FDA cleared or approved IVD available for that specific intended use.”  Clarity regarding how FDA will define “specific intended use” will certainly be needed before this guidance becomes final.  For example, is a sequencing test for a specific mutation the same intended use as a test system that is cleared for genetic sequencing generally, or if the LDT can identify additional mutations?

The last group of LDTs includes those high and moderate-risk tests for which FDA intends to fully regulate.  The highest risk LDTs are defined in the draft guidance as: (1) LDTs with the same intended use as a cleared or approved companion diagnostic; (2) LDTs with the same intended use as an FDA-approved class III device; and (3) certain LDTs for determining safety and effectiveness of blood or blood products.  Other high-risk LDTs will include those test classified as class III devices.  Moderate-risk LDTs are those that are classified as class II devices.  These LDTs will be required to submit and gain clearance or approval, as applicable.

The timing of these new regulatory requirements will be phased in, according to the Framework Guidance.  All LDTs in the second and third groups, will be required to register and list with (or notify) FDA within 6 months of the guidance being finalized.  Also, 6 months after the guidance is finalized, laboratories will need to begin reporting adverse events for these same LDTs.  Thus, labs will need to develop SOPs for evaluating potential Medical Device Reports.  With regard to premarket review, the high-risk LDTs will be required to start submitting premarket submissions 12 months after the guidance is finalized and will be phased-in over the following four years.  Then, beginning in year 5, moderate-risk LDTs will be required to submit premarket submissions.  Laboratories will be required to comply with the applicable sections of the Quality System Regulation at the time their PMA is submitted or 510(k) cleared.   Interestingly, the Framework Guidance indicates that “[high-risk] devices would remain on the market during review and FDA’s consideration of applications,” but there is no corresponding statement with respect to moderate-risk devices – we fully expect that this omission is an oversight, and will need to be clarified before issuance of the final guidance.  Id. at 12.  While the Framework Guidance focuses on the initial premarket approval or clearance that a test will require, the concept of changes to cleared or approved LDTs gets very little attention. 

It is also worth noting that the Framework Guidance does not just discuss evaluating the safety and effectiveness of LDTs as part of the new regulatory framework, but also clinical validity.  Clarification regarding how clinical validity will be demonstrated as part of the PMA and 510(k) process will be needed before this guidance is finalized.  Further, the Framework Guidance indicates that when the clinical validity of an LDT has been established in published literature, such literature may be used in the premarket submission for the test.  However, FDA’s current standards for IVDs do not often allow for the use of literature alone to demonstrate safety and effectiveness or substantial equivalence.  Thus, although the Framework Guidance states that literature may be used in a premarket submission, it is not clear whether literature alone will be sufficient to obtain clearance or approval. 

FDA intends to issue guidance to describe what the Agency considers to be class I, II and III devices with respect to LDTs within twenty-four months following finalization of the guidance.  In addition, during a briefing with industry regarding the draft guidances, Dr. Jeffrey Shuren, Director of CDRH, stated that CDRH will provide additional clarification regarding Quality System compliance for laboratories and the intersection between FDA regulatory requirements and CLIA. 

 In order to accomplish these lofty goals for regulation of LDTs, CDRH intends to employ the third-party review program to aid in reviewing new LDT 510(k) submissions.  We question the practicality of this plan given the low adoption rate for the current third-party review program.  More generally, it is not clear where the resources will come from for an enormous bolus of additional work.  Based on Dr. Shuren’s comments during a media briefing on the guidances, we understand that the third-party review program may expand to include CLIA accrediting entities. 

 Notification Guidance

The intent of the Notification Guidance is to explain to laboratories how they go about notifying FDA that they “manufacture, prepare, propagate, compound, or process” LDTs and how to comply with the MDR reporting requirements.

FDA plans to exercise enforcement discretion with regard to establishment registration and listing for all LDTs, provided that laboratories notify FDA of their LDTs within six months after FDA finalizes the Framework Guidance.  According to the Notification Guidance, such a notification must include: laboratory name, laboratory contact email address, test name, monthly test volume, intended use, clinical use of test, what is measured or detected (i.e., analyte, measurand, etc.), disease/condition for which the diagnostic device is indicated, patient population, whether the patient population includes pediatrics, sample type, test method, whether the test is a modification of an FDA cleared/approved test, and if so, what modifications were made.  There will be no user fee associated with notification.  Laboratories will not be required to register their establishment and list their LDT with FDA, until the laboratory submits a premarket submission to FDA for the LDT.  In sum, it appears to us that the notification to FDA is the first step in FDA’s process to determine what LDTs exist and what level of risk each may pose.  It is unclear what FDA will do with the information provided through the notification process, and whether FDA will communicate back to the laboratory what type of LDT it is running (e.g., a Traditional LDT, an LDT for an Unmet Need, etc.), or if FDA will rely on laboratories to self identify their tests.

After a laboratory notifies FDA of its LDT, as described above, FDA will issue the laboratory a notification confirmation number, which the laboratory will use in lieu of an establishment registration number when filing MDRs.  In short, the Notification Guidance restates the MDR reporting requirements for medical device manufacturers (or user facilities, as applicable) as being applicable to laboratories with LDTs.  Laboratories will also need to develop SOPs to decide what reports are reportable.  Based on the experience of IVD manufacturers, making these determinations will often not be easy.  

Finally, the Notification Guide indicates that laboratories will be required to comply with the requirements for reporting corrections and removals pursuant to 21 C.F.R. Part 806 just like any other medical device manufacturer.

In conclusion, we believe that these guidances present unsettling questions for the approximately 2,000 laboratories estimated to be affected by these guidance documents, not only with respect to their current LDTs, but to future innovation as well.  In addition, the documents do not address the costs that will be incurred.  And while FDA talks about the perceived risks associated with LDTs, it essentially ignores the benefits.  Thus, the new documents present questions not just for laboratories, but for the entire health care system.  These issues, as well as the legality of FDA’s proposed actions, are sure to be the subject of intense debate in the upcoming months.

By Kurt R. Karst – 

“Driveway moments” – most of us have had them.  It’s that moment when we feel compelled to stay in the car and finish listening to something on the radio.  This blogger recently had such a moment commuting home from work on the subway and then into the parking garage to hop in the car, albeit in the context of reading an orphan drug designation file instead of listening to a segment on the radio.  So what kind of regulatory page-turner of a story could be so compelling and captivating that it was impossible to start up the car to head home?  It’s the years-long, winding road story of FDA’s designation of PROCYSBI (cysteamine bitartrate) Delayed-release Capsules as an orphan drug for the treatment of nephropathic cystinosis in adults and children age 6 years and older.  FDA approved the drug, from Raptor Therapeutics, Inc. (“Raptor”), on April 30, 2013 under NDA No. 203389, and then later awarded 7-year orphan drug exclusivity that expires on April 30, 2020.  (The Orange Book does not yet reflect that award of exclusivity, though we understand that it will soon.)  But it seems to have been quite a slog to get the exclusivity.

The story begins in September 2006 when the University of California, San Diego submitted to FDA a request that FDA designate enteric-coated cysteamine for the treatment of cystinosis, a rare lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine that eventually leads to intracellular crystal formation throughout the body.  FDA previously designated and approved as an orphan drug, in 1991 and 1994, respectively, another sponsor’s cysteamine drug for the treatment of cystinosis – specifically, Mylan Pharmaceuticals, Inc.’s CYSTAGON (cysteamine bitartrate) Capsules (NDA No. 020392).  As such, in order for a subsequent sponsor’s cysteamine drug for the treatment of cystinosis to be designated as an orphan drug, the sponsor was required to provide a plausible hypothesis of “clinical superiority.”  (To be awarded orphan drug exclusivity in such a context, FDA requires that the sponsor demonstrate clinical superiority, though that requirement is currently being challenged in court – see our previous post here.)

By way of background, once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is “different” from the approved orphan drug, or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications.  (FDA may, however, approve a second application for the same drug for a different use.)  A drug is “different” from an approved orphan drug if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug.  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 (the so-called “MC-to-PC” basis for clinical superiority).  Clinical superiority was a topic of significant discussion in FDA’s recent clarification of the Agency’s orphan drug regulations (see our previous post here).

In October 2006, FDA awarded orphan drug designation based on a plausible hypothesis that enteric-coated cysteamine “may be safer (i.e., causes less side effects) than the approved formulation of cysteamine.”  Those side effects, according to a review from FDA’s Office of Orphan Products Development (“OOPD”), included less nausea and vomiting vis-à-vis CYSTAGON.  And as is typical when OOPD designates a drug based on a plausible hypothesis of clinical superiority, the Office noted in the letter granting designation that “[i]n order to obtain market exclusivity for your product . . . clinical studies submitted with the NDA must demonstrate that enteric-coated cysteamine is comparable in efficacy and safer than the approved formulation of cysteamine.”

A few years went by and a new owner of the drug and orphan drug designation, Raptor, approached OOPD about a second basis for designating enteric-coated cysteamine for the treatment of cystinosis: MC-to-PC.  Specifically, Raptor argued that enteric-coated cysteamine allows patients to be dosed with the drug every 12 hours instead of every 6 hours with CYSTAGON, and that as a result patients have an improved quality of life associated with improved patient compliance.  Why pursue MC-to-PC if designation has already been granted based on a plausible hypothesis of greater safety?  We’re not entirely certain, but we suspect it had something to do with the need to demonstrate superior safety vis-à-vis CYSTAGON to be granted orphan drug exclusivity.  A drug designated as an orphan drug on a MC-to-PC clinical superiority basis still has to demonstrate clinical superiority to be awarded exclusivity, but the demonstration is inherent in the characteristics of the drug that earned designation in the first place.  If those characteristics don’t change, then demonstrating clinical superiority seems to be in the bag.  In any case, OOPD concluded that a change from 6-hour dosing to 12-hour dosing does not meet the MC-to-PC regulatory threshold. 

Raptor, however, was not deterred.  The company came up with a new MC-to-PC theory: the company’s enteric-coated cysteamine causes less halitosis and body odor than CYSTAGON.  Both are effects of cysteamine treatment that clinicians have long recognized as interfering with patient compliance.  Still, OOPD was not convinced that Raptor provided adequate information to support a MC-to-PC clinical superiority decision, and the Office once again rejected the claim in December 2013 while Raptor’s NDA for enteric-coated cysteamine, known as PROCYSBI, was under review at FDA.

Raptor continued to press OOPD for a MC-to-PC designation that would guarantee them orphan drug exclusivity, even after FDA approved the company’s NDA for PROCYSBI, through the submission of additional correspondence and information.  Finally, OOPD’s threshold was met.  According to OOPD’s final review:

The determination of Clinical Superiority by a MC to PC is on a case-by-case basis considering the unique nature of the drug and the disease, among other factors.  Since 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.  The sponsor provides evidence . . . to show that the q12h delayed-release cysteamine product can maintain [white blood cell] cystine under 1.0 nmol/1/2 cystine/mg protein over 12 months in their long-term extension study RP103-04.

Not the type of “driveway moment” you might be familiar with . . . or were hoping for?  We understand; though to those of us who follow orphan drug issues closely, it is not only a story that gives us greater insight into FDA’s thinking on clinical superiority issues – and another precedent (see our previous post here) – but it has a good ending.

By Allyson B. Mullen —

On July 28, 2014, FDA issued the final guidance document “The 510(k) Program:  Evaluating Substantial Equivalence in Premarket Notifications [510(k)].”  The draft of this guidance was issued on December 27, 2011 (see our earlier blog post here).  Very little has changed since the draft guidance.  

As you may recall, many felt that the draft guidance represented a significant change in policy with respect to the 510(k) program.  See Minnesota Medical Device Manufacturer Alliance Citizen Petition (Jan. 22, 2013), which was supported, via the issuance of comments, by the Washington Legal Foundation, on October 31, 2013. Most notably, the draft guidance:   prohibited use of split predicates, use of one predicate for intended use and another predicate for technological characteristics (which had been previously disfavored by FDA, but not prohibited); introduced the concept of a reference device; and allowed FDA to consider information outside of the proposed device labeling and 510(k) when making a determination of substantial equivalence – all of these concepts still remain in the final guidance. 

Unsurprisingly, FDA received 26 sets of comments, totaling over 400 individual comments in response to the draft guidance.  70 Fed. Reg. 43753, 43754 (July 28, 2014).  What is perhaps surprising is that after all of those comments and two and a half years, the final guidance looks nearly identical to the draft, with a few notable exceptions, discussed below.  This guidance and FDA’s unapologetic dismissal of the Minnesota Medical Device Alliance’s Citizen Petition late last week suggest that FDA is holding firm to heightened standards for the 510(k) program, and industry should not expect FDA to ease up in the foreseeable future.

The final guidance does have two changes from the draft guidance that are blog-worthy.  First, the final guidance only includes Traditional 510(k)s.  The discussion of Special and Abbreviated 510(k)s in the draft guidance has been removed and apparently will be finalized separately.  70 Fed. Reg. at 43754.  The Special and Abbreviated 510(k) sections from the final guidance were removed because, according to FDA, they were the sections that received the most comments.  Id.  Thus, until a new guidance is issued, FDA advises industry to continue following FDA Guidance Document, The New 510(k) Paradigm – Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications (Mar. 20, 1998).

Second, the final guidance features a new appendix with a sample 510(k) summary.  For those who have not written a 510(k) summary for a while, the new appendix may come as a bit of a shock.  In the olden days of the 510(k) program (circa early 2000’s and earlier), 510(k) summaries provided very little information.  The requirements of 21 C.F.R. § 807.92 were very narrowly (and literally) construed such that conclusory and generalized statements were often contained in the 510(k) summaries.  This approach resulted in 510(k) summaries that when read by someone who knew nothing about the subject device, were basically useless – one could typically find out more information about the device from the manufacturer’s marketing materials on its website.  If a company really wanted to find out what was in a predicate device’s 510(k), a Freedom of Information Act (FOIA) request was necessary.  Even then, what the company received back usually more closely resembled a zebra (covered with black lines) than a 510(k) submission because so much of the document was redacted. 

More recently, we have seen FDA requesting additional detail in 510(k) summaries.  For example, we have seen 510(k)s rejected under the Refuse to Accept policy for failure to include a comparison table showing the similarities and differences between the proposed and predicate devices (see our earlier blog post here).  Thus, the detailed, five plus page (single spaced) model 510(k) summary in Appendix C of the final guidance did not come as much of a surprise. 

Since approximately 2004, the Office of In Vitro Diagnostics and Radiological Health has been issuing decision summaries when a new IVD 510(k) is cleared (similarly to the summaries that are issued when a De Novo petition is cleared).  From what we understand, industry has found these summaries to be quite helpful in predicate device research. 

While the Office of Device Evaluation has not followed suit (see our earlier blog post on this topic), we have hope that the additional detail required in new 510(k) summaries may start to close the gap and provide more useful information for predicate device research.  It will depend, in part, upon whether FDA applies this guidance fairly and uniformly. 

From a competitive standpoint, we think additional detail in the 510(k) summaries will be helpful for companies struggling to understand the data requirements that a potential predicate device was required to meet in order to apply that knowledge to their own submission.  On the other hand, companies will want to be vigilant about not disclosing proprietary or confidential information in their 510(k) summaries.  We also wonder if this increased level of public information will result in FDA receiving more push back when it asks a company to do new or additional testing that was not required for a currently marketed predicate device.

In addition to these two main changes, the guidance includes a number of clarifying revisions that do not materially affect the overall messaging of the guidance.  These minor changes include small clarifications of the language in the Substantial Equivalence Decision Making Flowchart in Appendix A.  

The guidance document does provide a number of additional examples and scenarios to try to clarify and explain the “new” requirements.  Some might say that these helpful examples are too little too late, and they would have been more useful a few years ago before FDA implemented these “new” rules.

Since the final guidance is essentially the same as the draft, we do not expect to see significant changes in the 510(k) program as a result of finalizing this guidance – except for perhaps more 510(k)s refused under the RTA Policy for failure to contain a sufficiently detailed 510(k) summary.

By Douglas B. Farquhar –

While Wikipedia tells us that this year’s Beaujolais Nouveau will best be consumed during a flexible time period beginning November 21, drug manufacturers and drug wholesalers should be warned that there is less flexibility in an important deadline for the “pedigree nouveau” that must be distributed with each package of prescription drugs.  You must start sending out three separate transaction forms with each shipment of drugs on or before January 1, 2015.

This deadline is set by one of the little publicized provisions in the Drug Quality and Security Act, which was enacted in late November 2013 (see our previous posts here, here and here).  One section of the Act, entitled the Drug Supply Chain Security Act (the DSCSA), requires manufacturers of prescription drugs (including contract manufacturers) and wholesalers to provide a “transaction history,” “transaction information,” and a “transaction statement” each time they sell prescription drugs.  Because many manufacturers and wholesalers have not historically provided the “drug pedigrees” that were required under some circumstances under prior federal law and regulation, they may not be aware of the new requirements.

In the old days, wholesalers could qualify as “Authorized Distributors of Record,” and were not required to provide prior transaction history.  That is no longer the case, effective January 1, 2015.  Each time they engage in a transaction relating to prescription drugs, they will be required to provide a “transaction history” to their customers.  The transaction history must provide evidence about each transaction back to the manufacturer.  But the transaction history is not the only document that must be provided.  Manufacturers and wholesalers must provide, with each transaction, “transaction information” (defined as information about the drug, including lot number and quantities in “package;” the dates of transactions and the parties to the prior transactions) and a “transaction statement” (basically confirming compliance with applicable laws).

The DSCSA also defines manufacturers as including what it calls “co-licensed partners.”  If the distributor/marketer of a drug can meet the requirements of a “co-licensed partner” with the holder of the drug application (Abbreviated New Drug Application or New Drug Application), or with a person or entity who manufactures a drug that is not the subject of an ANDA or NDA, that entity does not have to list any transactions before the distributor/marketer’s  sale.  The term “co-licensed partner” is not defined by federal law or regulations.  Yet.

Also, third-party logistics companies, defined in the DSCSA as “an entity that provides or coordinates warehousing, or other logistics services of a product . . . on behalf of a manufacturer . . . but does not take ownership of the product, nor have responsibility to direct the sale or disposition of the product,” generally do not have to provide any transaction history, statement, or “transaction information.”

So, instead of – or in addition to – tasting a fresh French wine in late November or early December, wholesalers and manufacturers need to uncork their pedigrees nouveaux before January 1.

The American Conference Institute’s popular FDA Boot Camp, now in its 23rd iteration, is slated to take place at the Omni Parker House Boston in Boston, MA from Thursday, September 18 to Friday, September 19, 2014.  The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

The 23rd edition of the FDA Boot Camp will be co-chaired by Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, and Arnold & Porter LLP’s Daniel A. Kracov.  Attendees will be regaled by a stellar cast of presenters who will share their knowledge and provide critical insights on a host of topics, including:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs, biologics, and devices, including: INDs, NDAs, BLAs, OTC Approval, 510(k) submissions, and the PMA process
• Clinical trials for drugs and biologics and the clearance process for devices
• The classification of devices and the concept of “risk-based” classification
• The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
• Labeling in the drug and biologics approval process
• cGMPs and other manufacturing concerns relative to products liability
• Proactive adverse events monitoring and signal detection
• Recalls, product withdrawals, and FDA oversight authority

FDA Law Blog is a conference media partner.  As such, we can offer our readers a special $200 discount.  The discount code is: FLB200.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.