By Kurt R. Karst –   

It’s been a while since we peeked in on the appeals Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) and Elliott Associates, L.P.,  Elliott International, L.P. and Knollwood Investments, L.P. (collectively “Elliott”) filed with the U.S. Court of Appeals for the District of Columbia Circuit after District Court Judge Ketanji Brown Jackson issued an Opinion and Order in January 2015 upholding FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares.  There’s been some recent court docket activity to report on . . . and there’s more activity on the way in October. 

As we previously posted (here, , and ), Takeda is the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, which FDA approved to prevent and treat gout flares, and that is listed in the Orange Book with several unexpired patents.  The MITIGARE 505(b)(2) NDA did not cite COLCRYS as a listed drug relied on for approval, but rather a different drug: COLBENEMID, a fixed-dose combination drug product containing probenecid (500 mg) and colchicine (0.5 mg) FDA approved under NDA 012383 on July 27, 1961, that is no longer marketed, and for which no patents are listed in the Orange Book.  Takeda sued FDA alleging that the Agency’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects:

First, FDA acted arbitrarily and capriciously in approving Hikma’s Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products.  Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label.  And third, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process.  [(Emphasis in original)]

Later, Elliott, which has investment interests in COLCRYS, filed a separate Complaint alleging that FDA’s approval of the MITIGARE NDA violated the FDC Act and the APA because Hikma was required to certify to patents listed in the Orange Book for COLCRYS.

Judge Jackson dismissed each of the allegations and ruled for FDA (and Intervenor-Defendants Hikma and West-Ward).  She nicely summarized her ruling on pages 31-32 of her 80-page Opinion:

[T]his Court concludes that Plaintiffs are wrong to characterize FDA’s actions with respect to Mitigare as unauthorized, unsafe, or unreasoned; to the contrary, it is clear on the record presented that FDA’s approval of Mitigare was consistent with the FDCA, the regulations the agency has promulgated pursuant to the FDCA, the Citizen Petition Responses FDA has issued, and the policies and practices under which the agency operates.  Furthermore, the record clearly reveals the reasonableness of FDA’s expert determination that Mitigare is safe and effective as labeled, and it supports the agency’s conclusion that Mitigare’s labeling best reflects current scientific information regarding the risks and benefits of Mitigare—a conclusion that, in any event, is entitled to a high degree of deference.  Consequently, Plaintiffs have failed to establish that summary judgment should be entered in their favor on their APA claims, and this Court finds that Defendants are entitled to summary judgment as a matter of law.

For more in-depth commentary and analysis of Judge Jackson’s decision and the issues presented in the case, see our previous post here.

In their Opening Briefs (here and here) filed in the D.C. Circuit, Takeda and Elliott pitch their appeals as presenting issues that, if not resolved with a reversal of Judge Jackson’s decision, would upset the balance Congress intended to create with the passage of the Hatch-Waxman Amendments: the balance between brand-name incentives, on the one hand, and for prompt approval of high quality and lower-cost generic drugs, on the other hand. 

Springboarding from Judge Jackson’s explanation that it’s not FDA’s reliance on the investigations underlying another drug product that triggers the 505(b)(2) patent certification requirement, but only a 505(b)(2) applicant’s reliance, Takeda frames FDA’s approval of the MITIGARE NDA as violating the APA in at least two ways:

First, FDA approved Hikma’s 505(b)(2) application without requiring Hikma to reference Colcrys and to make the Paragraph IV certifications required by statute.  Under Hatch-Waxman, a 505(b)(2) applicant must certify to patents for each previously approved drug “relied upon by the applicant for approval of the application.”  FDA emptied the statute of effect by permitting an applicant to certify only to those drugs expressly named in its application—even if FDA uses an unnamed drug’s data to approve the application.  That is inconsistent with the statutory text, with common sense, and with FDA’s longstanding interpretation that an applicant must certify to any drugs without which “the application cannot be approved.” . . .  And it is clear that Colcrys was necessary to Mitigare’s approval, despite Hikma’s gerrymandering of its application to avoid mentioning Colcrys. . . .

Second, FDA acted arbitrarily and capriciously in approving Hikma’s 505(b)(2) application without requiring the Mitigare label to include critical safety information it had previously deemed essential.  After Mutual’s groundbreaking studies, FDA determined that information about dose adjustments and a low-dose colchicine regimen was mandatory for all single-ingredient oral colchicine products’ labels.  The Mitigare label omits both types of information.  FDA gave no reasoned explanation for allowing those omissions.  [(Emphasis in original; citations omitted)]

Elliott’s arguments on appeal are more straightforward:

FDA’s approval of Mitigare without requiring certification to the Colcrys® use patents was arbitrary and capricious because it violated FDA’s own binding regulation.  21 C.F.R. § 314.50(i)(1)(iii)(B) requires a 505(b)(2) applicant to file “an applicable certification” if “the labeling of the drug product for which the applicant is seeking approval includes an indication that” according to the Orange Book “is claimed by a use patent.” Mitigare’s label contained an indication for “prophylaxis of gout flares.”  Takeda’s Colcrys® use patents are listed in the Orange Book as claiming that very indication.  FDA’s binding regulation accordingly required Hikma to certify whichever of the following was “applicable”: that Takeda had not submitted patent information to FDA, that the patents were expired, or that they were “invalid, unenforceable, or will not be infringed.”  Hikma filed no certification, and FDA’s acquiescence was an unlawful violation of its own regulation. . . .

FDA’s approval of Mitigare without requiring certification to the Colcrys® use patents also violated Section 505(b)(2) itself.  The plain language of the statute requires a 505(b)(2) applicant to certify to “each patent … which claims a use for such drug for which the applicant is seeking approval under this subsection.”  The Colcrys® use patents claim the use of colchicine for prophylaxis of gout flares, the precise use of colchicine for which Hikma sought approval.

The Pharmaceutical and Research Manufacturers of America (“PhRMA”), in an amicus brief filed late last month, falls in line with the “upending Hatch-Waxman” theme in the Takeda and Elliott briefs, but PhRMA also addresses Judge Jackson’s interpretation of FDC Act § 505(b)(2) in a more general and overarching sense:

The district court’s decision undermines Hatch-Waxman’s grand bargain by permitting section 505(b)(2) applicants to obtain the Act’s benefits without shouldering any of the corresponding burdens.  Specifically, the district court concluded that a section 505(b)(2) applicant may obtain approval of a follow-on drug—without providing the required patent certification—by omitting any mention of the pioneer drug in its application and relying on FDA to fill in the blanks.  That interpretation cannot be squared with the Act’s structure and purpose. . . . 

The decision below also conflicts with FDA’s regulations and guidance.  First, the district court assumed that a section 505(b)(2) applicant “relie[s] upon” one and only one pioneer drug, but FDA has made clear that section 505(b)(2) applications may rely on more than one drug.  Second, the district court incorrectly concluded that a section 505(b)(2) applicant faces no constraints in deciding which pioneer drug (or drugs) it will “rel[y] upon.”  While applicants have some freedom of choice, FDA has limited that flexibility by concluding that a section 505(b)(2) application may implicitly rely upon a similar pioneer drug.  Third, the district court failed to observe the rule that a section 505(b)(2) applicant may rely on the fact of a pioneer drug’s approval, but not the confidential data underlying that approval. 

FDA’s Opening Brief is due to the D.C. Circuit on October 16, 2015, as is the brief of Hikma/West-Ward.  Takeda and Elliott Reply Briefs are due on October 30, 2015.  We’ll be particularly interested in any discussion from FDA of the Agency’s February 6, 2015 proposed rule implementing certain provisions of the 2003 Medicare Modernization Act (see our previous post here), and specifically FDA’s proposal “to require a 505(b)(2) applicant to identify a pharmaceutically equivalent product, if already approved, as a listed drug relied upon, and comply with applicable regulatory requirements.” 

By Kurt R. Karst –

The Order handed down last week by the U.S. Court of Appeals for the Federal Circuit denying Amgen Inc.’s (“Amgen’s”) Emergency Motion For An Injunction Pending En Banc Consideration and Review and Sandoz Inc.’s (“Sandoz’s”) September 3, 2015 launch of the first biosimilar licensed pursuant to the provisions added to the law by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) – a biosimilar version of Amgen’s NEUPOGEN (filgrastim) called ZARXIO (filgrastim-sndz) that FDA licensed on March 6, 2015 under BLA 125553 – are not events marking the end to controversy over various provisions of the BPCIA, but are merely waysides along a highway that may very well end with a decision from the U.S. Supreme Court.  Putting aside Amgen’s recent Emergency Motion (Sandoz’s Opposition Brief is available here), the Federal Circuit’s July 21, 2015 split panel decision (see our previous post here) upholding Sandoz’s position that the complicated exchange of information provisions known as the “patent dance” is a voluntary process that biosimilar (also referred to as an “aBLA”, or abbreviated Biologics License Application) applicants may or may not partake in, but also upholding Amgen’s position that a biosimilar applicant’s notice to the holder of the reference product of an intention to begin commercial marketing in 180 days can occur only after the biosimilar is licensed, has already led to hundreds of pages of briefing.  And there’s likely to be a lot more ink spilled as interested parties continue to chime in at the Federal Circuit. 

For starters, there are the August 20, 2015 Petitions For Rehearing En Banc filed by both Amgen and Sandoz (here and here).  Amgen and Sandoz take the positions one would anticipate them taking.  Amgen argues that the patent dance is a mandatory process, while Sandoz argues that providing 180-day notice of launch after biosimilar licensure (instead of beforehand) creates a new automatic injunction remedy that effectively grants a period of 180-day exclusivity for all biological products beyond what Congress expressly provided in the BPCIA.  On September 8, 2015, Amgen and Sandoz filed Responses (here and here) to one another’s Rehearing Petitions defending each company’s respective wins before the Federal Circuit panel.  According to Amgen, the BPCIA’s text is clear with respect to 180-day notice and the Federal Circuit Panel correctly held that PHS Act § 351(l)(8)(A) requires notice after FDA licensure of an aBLA.  Sandoz’s two arguments for why notice should not have to follow FDA licensure are flawed, argues Amgen:

First, Sandoz argues that notice at the time of FDA approval is superfluous, because FDA licensure is itself a public act.  But the required notice is notice of the timing of first commercial marketing, which cannot be presumed merely from the grant of a license.  It is also notice of the scope of that first commercial marketing: As the Panel noted, it is only upon FDA approval that “the product, its therapeutic uses, and its manufacturing processes are fixed.”

Second, Sandoz argues that the thirty-month stay of approval of a generic drug under the Hatch-Waxman Act confirms, by its absence in the BPCIA, that Congress did not intend litigation to delay approval or marketing of a biosimilar.  The absence of a thirty-month stay under the BPCIA confirms only that Congress did not pattern this part of the BPCIA after the Hatch-Waxman Act.  Instead of conditioning FDA licensure on the outcome or pendency of patent litigation, Congress linked the Applicant’s obligation to provide notice of commercial marketing to the event of FDA licensure.  This makes sense for a statute that uses a standard of biosimilarity, rather than identity, under which the ultimately approved product may differ from the reference product in its structure, manufacture, and uses. Whereas the Hatch-Waxman Act maintains the status quo through a thirty-month stay of FDA approval, the BPCIA vests in the district courts the authority to determine whether to preserve the status quo beyond the 180-day notice period through a preliminary injunction sought by the [Reference Product Sponsor].  Anticipating the increased burden and disruption this would create for the courts, Congress established a defined statutory window of no less than 180 days after FDA approval and before commercial marketing “during which the court and the parties can fairly assess the parties’ rights prior to the launch of the biosimilar product.”  [(Emphasis in original; internal citations omitted)]

According to Sandoz, Amgen’s arguments on the mandatory nature of the patent dance are flawed:

[The BPCIA’s amendments to the law] create artificial acts of infringement, enabling declaratory judgment actions before actual infringement is imminent.  Who can bring such an action, when, and for what relief depends on the actions or inactions of the applicant and the sponsor at each step of a multi-step patent-exchange process regarding the sponsor’s possible patent claims.  Congress carefully spelled out both the action the applicant or sponsor “shall” take as a condition precedent to continue the process, and if that party declines, what follows.  Each step has benefits and burdens for both parties.  Critically, the BPCIA provides no means to force either participant to take any of those steps.  Instead, each step is simply a procedural means to a substantive goal: resolving patent disputes so that biosimilars can be available to patients as soon as possible.

Lining up behind Sandoz are amici curiae Hospira, Inc., Celltrion Healthcare Co., Ltd. and Celltrion, Inc. (collectively “Celltrion”), Mylan Inc. (“Mylan”), and the Biosimilars Council (a division of the Generic Pharmaceutical Association consisting of companies and other stakeholders focused on issues relating to biosimilars). 

Celltrion, which is embroiled in litigation with Janssen Biotech, Inc. (“Janssen”) over a biosimilar version of Janssen’s REMICADE (infliximab) (see our previous post here) says in its brief that the Federal Circuit’s panel decision on 180-day notice “exceeds the judicial role contemplated by Congress in the BPCIA, and calls out for en banc review,” and warns that “[t]he decision has major implications for industry and consumers.” 

Amici file this brief to emphasize three points.  First, review is needed now.  Although the panel’s ruling addresses an issue of first impression, that issue is vital to the competitive structure of the biosimilar industry.  Litigation over the meaning of the ruling continues in the lower courts; further percolation will not advance the law; and settling the issue will spur competition.

Second, the ruling flouts the [BPCIA’s] text and Congress’s purpose in passing it.  In the panel’s view, a potential second phase of litigation—which involves patents that only the sponsor deems relevant—cannot even begin until after FDA approval.  But as even the Biotechnology Industry Organization (“BIO”) has noted, the Act is designed “to identify and resolve patent issues before a biosimilar is approved.” 

Third, the ruling conflicts with a host of cases. . . governing when courts may recognize a private right of action or extra-statutory remedy.  That precedent bars the automatic, bondless injunction entered here—one that not only was granted without any findings that satisfy the traditional requirements for equitable relief, but is unmoored from any patent rights.  [(Internal citation omitted)]

Mylan, which reportedly has “a robust pipeline of biologic products in development, both for the global marketplace and to be submitted for licensure in the United States as biosimilar products under the [BPCIA],” says in its brief that rehearing and reversal of the panel decision on 180-day notice are necessary: 

The majority’s interpretation distorts the statutory scheme, contradicts the plain language, and would produce “real world” outcomes contrary to Congress’ intent.  The consequences cannot be overstated: the majority interpretation would necessarily, in every case where notice is provided, extend the reference product’s monopoly six months past the 12-year market exclusivity Congress granted.  This exclusivity extension, implied from a simple notice provision, disrupts the statutory bargain and improperly delays competition. [(Internal citation omitted)]

Finally, the recently launched Biosimilars Council says in its brief that the Federal Circuit’s panel decision on 180-day notice should not stand:

The panel’s incorrect reading of (l)(8)(A) converts notice into the trigger for an automatic six-month injunction against the marketing of a licensed biosimilar, sub silentio extending to 12 ½ years Congress’s carefully crafted 12-year reference product exclusivity.  This automatic, extra-statutory delay, if left uncorrected, would broadly undercut Congress’s goal of greater competition in biologics markets and dramatically reduce savings to the U.S. healthcare system from biosimilars.  This Court en banc must correct a reading of the BPCIA that Congress could not have intended and that will delay millions of patients’ access to needed treatments. . . .

The clear meaning of 42 U.S.C. § 262(l)(8)(A) is that notice provided under that subsection must occur at least six months “before the date of the first commercial marketing” of the relevant biosimilar, without limiting when notice can first be given.  However, the majority effectively rewrote this straightforward notice requirement to dictate both the earliest and the latest possible time for notice.

The panel’s reading is incorrect because the word “licensed” is clearly intended to modify “the product” that is the subject of notice and not to circumscribe the timing of notice.  Congress used the past-tense “licensed” because the right to commercially market a product, regardless of when notice is given, only exists after FDA licensure.  In other words, the statute simply provides for notice that the applicant intends to market its product once it has been “licensed,” not to limit the earliest date notice can be provided.

There may be a lineup of amici curiae behind Amgen, perhaps including BIO and Janssen, in the days and weeks ahead as we travel further down the highway in this litigation to another wayside.   

By Kurt R. Karst –      

Finger through the “Discontinued Drug Product List” section of the Orange Book and youl’ll quickly realize that there are a lot of drug products no longer marketed.  The “Discontinued Drug Product List” spans 337 pages in the current annual edition of the Orange Book, and more drug products are added each month with the Cumulative Supplement.  You see the additions when the term “DISC” (defined as “Discontinued. The Rx or OTC listed product is not being marketed and will be moved to the discontinuedsection in the next edition.)” is added to a particular drug product listing.  The “Discontinued Drug Product List” encompasses several categories of drugs.  As explained in the Orange Book Preface, it is “a cumulative list of approved products that have never been marketed, are for exportation, are for military use, have been discontinued from marketing, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing.” 

There are various reasons why a company may discontinue marketing a drug product.  Perhaps a brand-name manufacturer has lost interest in a product because of generic competition and loss of market share.  Or perhaps a company obtains approval of an ANDA and is not ready to market the drug because of ongoing patent infringement litigation or because of a settlement agreement that sets a marketing date that is years away.  In either case, the application is put into a coma-like state; it is effectlvely mothballed. 

But just as humans can awake from a coma after many years (here and here), so too can a drug.  Every once in a while you see the notation “CMFD” added to a monthly Orange Book Cumulative Supplement.  That notation is defined as “Change.  The product is moved from the Discontinued Section due to a change in marketing status.”  And just as there are various reasons why a company may discontinue a drug product, there are also several reasons why a drug product may be re-marketed.  For example, perhaps ownership in an NDA or ANDA has been transferred and the purchasing company intends to re-introduce the drug to the market.  In some cases, the approval for a product in the discontinued list has been withdrawn, and it will therefore never awaken from its coma.  (Though the drug can serve as a Reference Listed Drug for an ANDA applicant, provided FDA determines that the brand-name drug was not withdrawn for safety or effectiveness reasons – see our previous post here). 

For many years, the process of moving a drug from the “Discontinued Drug Product List” to the “Prescription Drug Product List” or to the “OTC Drug Product List” – i.e., from “DISC” to CMFD” – was relatively simple.  A company would notify FDA of the change and it would occur.  That changed, however, a couple of years ago after there was “an incident” (about which we don’t know the details) with a drug that was re-marketed after spending some time on the “Discontinued Drug Product List.”  Afterwards, FDA developed a more formal process for when a sponsor wants to have a drug product removed from the “Discontinued Drug Product List.”

When a sponsor notifies FDA that the company intends to remarket a dormant drug, the sponsor will probably receive correspondence from FDA asking a few questions.  That correspondence might look something like this:

Please submit a general correspondence to the application and a courtesy email copy to the Orange Book general inbox (DrugProducts@cder.fda.gov) with the following information:

1) What is the launch date of the product?
2) How long has it been off the market?  When was it last manufactured?
3) Has there been a transfer of ownership since the last manufacturing date?
4) Is the product using the same API supplier/facility, drug product manufacturer/facility and drug manufacturing process/equipment?
5) Will a supplement be needed before the product can be marketed?

We encourage you to submit your request two months before the launch date to allow the Orange Book to process your request in a timely manner.

A company’s responses to these questions ahead of a change to marketing status in the Orange Book gives FDA some cushion to evaluate the re-marketing situation for a particular drug (and presumably, to determine whether or not such a change is appropriate given the particulars of a case).

By Alan M. Kirschenbaum, Michelle L. Butler & David C. Gibbons –

On August 28, 2015, the Health Resources and Services Administration (HRSA) of the Department of Health and Human Services published an omnibus guidance document to implement the 340B Drug Discount Program (the Proposed Guidance).

Since the inception of the 340B Program in 1992, HHS has implemented the program by issuing a series of guidances on various topics, typically after notice and comment.  The new Proposed Guidance accomplishes the dual purpose of consolidating and updating the previous guidances and implementing a number of program integrity mandates added to the 340B statute by the Patient Protection and Affordable Care Act in 2010.  As reported in this blog, the Proposed Guidance was initially intended to be issued as a regulation, but, before publication, HRSA transformed it into a guidance following a federal district court ruling, in a case involving a related 340B regulation, that HRSA has statutory authority to issue regulations only in specific, narrowly defined areas. 

The Proposed Guidance provides HRSA’s interpretation of the 340B statute, along with implementing policies, in a number of key areas: 

A.        340B Program eligibility and registration

B.        Drugs eligible for purchase under the 340B program

C.        Individuals eligible to receive 340B drugs

D.        Covered Entity responsibilities

E.         Contract pharmacy arrangements

F.         Manufacturer responsibilities

G.        Rebate option for AIDS Drug Assistance Programs

H.        HHS audits of Covered Entities and manufacturers, and manufacturer audits of Covered Entities

You will find here our memorandum summarizing the Proposed Guidance in each of these areas.

By James C. Shehan & Andrew J. Hull –

The U.S. Court of Appeals for the Eighth Circuit recently issued an opinion in the case of Lytle v. U.S. Department of Health and Human Services, Nos. 14-3715, 15-1214 (8th Cir. Aug. 21, 2015), affirming that private membership associations (“PMAs”) cannot thwart FDA’s regulatory authority over the marketing of medical devices through distribution of devices only to PMA members.  The decision, arising from two related cases from the United States District Court for the District of South Dakota and a long regulatory history, affirmed the district court’s dismissal of pro se appellant Dr. Larry Lytle’s action for declaratory judgment challenging FDA’s authority to execute administrative warrants to inspect his laser-device businesses.

Specifically, Dr. Lytle argued that, because his companies’ laser devices were only distributed to members of his PMAs, FDA had no authority to regulate those devices.  Not surprisingly, FDA disagreed that membership in a private club excluded its jurisdiction, and the Eighth Circuit agreed with the government’s position.  Citing section 201(e) of the Federal Food, Drug, and Cosmetic Act, (defining persons subject to the Act to include associations) and another recent case finding that a cow-sharing PMA that gave raw milk to members was not immune from regulation by FDA, the court held that the activities of Dr. Lytle and his companies fell under FDA’s regulatory authority.

In addition to affirming the dismissal of the declaratory judgment in the first case, however, the court remanded the second case, in which the district court entered a preliminary injunction against Dr. Lytle to prevent him from manufacturing, processing, holding, or distributing laser devices for medical uses not approved by FDA, for further consideration of whether the injunction could have been more narrowly tailored.

Dr. Lytle, a dentist whose license was permanently revoked by South Dakota in 1998, has been marketing his lasers since 1997 and sparring with FDA over them since 2002.  Given this history and this decision inviting more inspections and a narrower injunction, this story is likely to have further chapters.  But it is not likely that other efforts to avoid FDA jurisdiction by forming PMAs will find success in the courts.

By Ricardo Carvajal –

FDA issued a warning letter to Hampton Creek alleging that its Just Mayo products are misbranded, in part because they purport to be a food governed by a standard of identity – namely, mayonnaise – that the products fail to meet.  This alleged violation was at the heart of a lawsuit filed against Hampton Creek last year by Unilever, which Unilever subsequently dropped so that Hampton Creek could “address its label directly with industry groups and appropriate regulatory authorities” (see Unilever’s press release here).  To the extent any such efforts were undertaken by Hampton Creek, they appear to have been unsuccessful in warding off FDA’s warning letter.  The focus now shifts to whether the company can devise a way to resolve FDA’s concerns without having to make changes so extensive as to adversely affect the brand’s early success. 

In addition to expressing concerns with the product names and logo, FDA found that the labels include unauthorized use of nutrient content and health claims.  These alleged violations, coupled with the alleged violation of the standard of identity, can be expected to serve as grist for the plaintiffs’ bar.  The take-away for start-ups is fairly straightforward: in a highly regulated sector such as food, success will quickly draw attention to regulatory non-compliance, and good intentions can’t be counted on to keep the hounds at bay.

By David C. Gibbons – 

An August 28, 2015 letter to Judge Paul Engelmayer, U.S. District Court for the Southern District of New York, from the attorneys representing Amarin, Inc. (“Amarin”) indicated that the parties on both sides of Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. filed May 7, 2015), may be engaged in settlement discussions.  See Joint Letter, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 28, 2015), ECF No. 75 (“Joint Letter”).  We previously discussed the court’s decision granting Amarin’s Motion for Preliminary Injunction (“PI Motion”) against FDA prosecution for Amarin’s off-label promotion of Vascepa here.  In an Order issued three days after the court’s decision, Judge Engelmayer directed the parties to confer no later than August 24 and submit a joint letter no later than August 28 regarding “the future course of and next steps in the case.”  Order, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 10, 2015).

The Joint Letter stated that “[t]he parties have agreed to explore the possibility of settlement” in the case and requested that further proceedings be stayed until October 30, 2015.  At that time, the parties would file another joint letter to the court, providing notice regarding the next steps they plan to take.

Certainly FDA, on the heels of losing the PI Motion, may believe it is likely to lose the case on the merits if the case proceeds to final judgment.  Settlement may allow FDA to cut its losses at this point and regroup on its strategy concerning the regulation of off-label promotion. 

Amarin too may have something to gain if it settles.  With the leverage of its victory on the PI Motion, Amarin may be able to obtain FDA approval for Amarin to continue to promote the use of Vascepa in patients with persistently high triglycerides, perhaps through at least the reporting of results from the REDUCE-IT trial in approximately 2018.  The court, in its decision on the PI motion, was not prepared to extend its injunction for any given period of time, given that the court’s Opinion was based on the “current record,” thus the court recognized that statements Amarin may make today that are fair and balanced “may become incomplete or otherwise misleading in the future as new studies are done and new data is acquired.”  Opinion and Order at 66, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 7, 2015).

One important question now is: what happens if Amarin is settled?  The most significant effect might be that the parties agree, as a term of settlement, to jointly request that the court vacate its August 7, 2015, Order granting Amarin’s PI Motion.  We certainly think vacating the court’s August 7 Order could be a term on the table during settlement negotiations, but it remains to be seen whether Amarin and the other plaintiffs would agree to such a term, if they agree to settle at all.

Even if the August 7 Order is vacated, it may, like other significant rulings, live on.  Readers may recall the Washington Legal Foundation (“WLF”) line of cases that challenged FDA’s regulations concerning off-label promotion.  In particular, WLF filed a lawsuit claiming that certain FDA Guidance documents violated First Amendment protection of commercial speech.  Washington Legal Foundation v. Henney, 202 F.3d 331, 332-334 (D.C. Cir. 2000).  In that case, the district court granted WLF’s summary judgment motion, holding that FDA’s applicable Guidances violated the First Amendment, and enjoined FDA from prohibiting manufacturers’ dissemination of “enduring materials” as well as suggesting content to Continuing Medical Education program providers.  Id. at 334.  On appeal, during oral arguments before the Court of Appeals for the D.C. Circuit, FDA conceded that neither the Federal Food, Drug, and Cosmetic Act (“FDCA”) nor FDA Guidance documents gave FDA authority to restrict manufacturer speech in these areas.  Id. at 335.  With that admission on the record, there was no longer a “constitutional controversy between the parties that remain[ed] to be resolved,” and the court dismissed FDA’s appeal and vacated the district court’s decisions and injunctions declaring parts of the FDCA and FDA guidance documents unconstitutional.  Id. at 335, 336.  However, the district court’s reasoning and holding as it applied to FDA regulation of the dissemination of off-label information continued to carry weight and perhaps provided the impetus for later challenges to such regulation.

Similarly, a case involving a district court interpreting the Hatch-Waxman 180-day exclusivity provisions that was vacated as moot on appeal continued to carry some weight.  Inwood Laboratories, Inc. v. Young, 723 F. Supp. 1523 (D.D.C. 1989), vacated as moot, 43 F.3d 712 (D.C. Cir. 1989).  Despite being vacated, the Inwood decision has been cited in numerous recent cases on the subject of 180-day exclusivity.  See, e.g., Ranbaxy Labs., Ltd. v. Leavitt, 459 F. Supp. 2d 1, 3-4 (D.D.C. 2006).

Ultimately, we cannot Predict whether the Amarin case will be settled or, if so, whether the principles articulated by the court expounding and expanding on United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), will carry future weight.  But, we continue to watch the Amarin case and its further developments.

By Alexander J. Varond –

Hardly a week goes by without news of FDA’s priority review voucher (“PRV”) programs.  The last several weeks are no exception.  In this blog post, we focus on five key updates related to FDA’s tropical disease and rare pediatric disease (“Pediatric”) PRV programs: 

1. United Therapeutics Corporation (“United Therapeutics”) sold its Pediatric PRV for $350 million;
2. FDA added Chagas disease and neurocysticercosis to its list of eligible tropical diseases;
3. Sanofi-Adventis (“Sanofi”) successfully redeemed a Pediatric PRV to beat Amgen to market and became the first PCSK9 cholesterol therapy approved in the U.S.;
4. The Senate released its own version of the Advancing Hope Act; and
5. Three Duchenne muscular dystrophy sponsors received rare pediatric disease designation.

PRV Prices Continue to Climb

On August 19, United Therapeutics announced the sale of its rare Pediatric PRV for an incredible $350 million to AbbVie Inc.  We discussed FDA’s issuance of this Pediatric Voucher to United Therapeutics for Unituxin here.  As the graph below shows, the value of PRVs continues to climb dramatically.

FDA Adds Chagas Diseases and Neurocysticercosis to the List of Qualifying Tropical Diseases

On August 20, 2015, FDA published a final order to add two new diseases, Chagas disease and neurocysticercosis, to the list of qualifying tropical diseases.  Recall that, in order for a drug product to be eligible for a PRV, four requirements must be met: 

1. The application must be for a listed tropical disease;
2. The application must be submitted either as a 505(b)(1) NDA or a 505(b)(2) application;
3. The drug that is the subject of the application must not contain a previously-approved active moiety; and
4. The application must qualify for a 6-month priority review under FDA’s policies.

Thus, a sponsor for a drug that treats Chagas disease or neurocysticercosis that meets the requirements above would be eligible for a tropical disease PRV.

Section 524(a)(3)(R) of FD&C Act permits FDA to include “[a]ny other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations.” (Emphasis added.)  In its final order, the Agency also affirmed its commitment to using “a flexible approach” to tropical disease designations based on “scientifically informed, qualitative assessment of disease candidates.”  FDA also announced the establishment of a public docket that will remain open to receive future suggestions for tropical disease designations.  That docket is here.

The final order explains FDA’s interpretation of the key elements of section 524(a)(3)(R) of FD&C Act:

“Developed nations” - According to the order, “FDA will use a country’s presence on the World Bank’s list of ‘low income economies’ . . . as evidence that the country should not be considered a ‘developed nation’ for purposes of ‘tropical disease’ determination.”

“No significant market” - FDA notes the difficulty in providing a rigid definition of “no significant market” and instead proposes the following factors be considered in determining whether a “significant market” exists in developed countries:  (1) occurrence of the disease in developed nations; and (2) the existence of a sizeable indirect market for the tropical disease drug (e.g., government, including the military) that would constitute a financial incentive for drug development.

Disproportionately affects poor and marginalized populations - As with the term “no significant market,” FDA rejected a single definition in favor of four factors that must be weighed.  These factors are: (1) the proportion of global disability-adjusted life years for the disease that is attributable to developing countries; (2) the relative burden of the disease in the most impoverished populations within the countries in which it is found; (3) the relative burden of the disease in infants, children, and other marginalized segments of the population; and (4) whether WHO has designated it as a neglected tropical disease. 

Applying these standards, FDA exercised the authority granted to it by the Adding Ebola to the FDA Priority Review Voucher Program Act in December 2014 and added Chagas disease and neurocysticercosis to its list of diseases that qualify for the tropical disease voucher program. 

Bonus:  On August 24, 2015, Mid-Atlantic BioTherapeutics, Inc. submitted a citizen petition requesting that FDA add the rabies virus to the list of qualifying tropical diseases.  Notably, rabies is on WHO’s list of neglected tropical diseases, as is cysticercosis/taeniasis. 

Sanofi Successfully Uses its PRV

On August 19, 2015, FDA announced that Sanofi-Adventis had redeemed a Pediatric PRV for its Praluent (alirocumab) NDA.  With its approval on July 24, 2015, Praluent became the first approved PCSK9 cholesterol therapy in the United States.  The PCSK9 therapeutic class is expected to a blockbuster, with sales projected to be in the billions of dollars per year. 

The interesting part of this story is that Amgen’s Repatha beat Sanofi’s Praluent to market in Europe; but, ostensibly, through its redemption of a rare pediatric disease priority review voucher, Sanofi was able to reach the U.S. market before Amgen.  The Praluent approval came a month ahead of Repatha’s August 27, 2015 PDUFA date and approval. 

Drugs that are first-to-market often enjoy considerable benefits over second-comers.  U.S. payers, for example, are quick to cover new drugs, and products that are first-to-market often have significant marketing advantages and sales momentum.  Sanofi’s $67.5 million move to accelerate its entry into the U.S. market for its PCSK9 therapy will be closely watched.  After all, it will be a bellwether of whether industry can justify the high prices paid for priority review vouchers.  If things go well for Sanofi, the demand for and price of subsequent PRVs should be high.

An Update to the Advancing Hope Act

In March 2014, Representative G.K. Butterfield (D-NC) introduced the Advancing Hope Act (H.R. 1537) in the House of Representatives.  In our post on the bill, we noted the effort to make the Pediatric Voucher program permanent.  We also noted the bill’s proposal to change the tropical disease voucher program.  At the time, we noted that such changes not only seemed out of place, but they could be counterproductive. 

On July 28, 2015, the Advancing Hope Act (S. 1878) was introduced in the Senate.  The Senate version of the bill scrapped the amendments to the tropical disease priority review voucher program.  Instead, the Senate version proposes to make the Pediatric Voucher program permanent and to designate pediatric cancers and sickle cell anemia as rare pediatric diseases. 

Rare Pediatric Disease Designations Granted for DMD

On August 19, FDA awarded rare pediatric disease designation to BioMarin’s, Sarepta’s, and Santhera’s investigational products for Duchenne Muscular Dystrophy.  With the rare pediatric disease designation, each company will likely be eligible for a Pediatric Voucher upon approval of its drug product.

By James C. Shehan –

On August 27, 2015, FDA published its much–anticipated views on the non-proprietary naming of biological products.   Set forth in a proposed rule, a draft guidance, and a blog post, FDA proposes that a four letter suffix “devoid of meaning” be part of the name of all biological products, including reference products and biosimilar biologics.  The proposal solicits public feedback on whether in the alternative the suffix should not be meaningless but instead be derived from the name of the license holder.  The proposal also states that the four letter suffix will be different for each product except perhaps interchangeable products.  For interchangeable products, FDA declines to make a naming decision but instead solicits feedback on two alternatives: whether interchangeable products should also have distinct suffixes or share the same one.   By largely taking the position advocated by the makers of reference products, the proposal has already elicited negative comments in some quarters.

How a biosimilar should be named has been one of the hottest issues in biosimilars (see our previous posts here, here, here, and here), despite it being an issue upon which the BPCIA is silent.  Advocates for unique non-proprietary names insist that they are necessary to ensure safety, accurate adverse event reporting and the preservation of physician and patient choice.  On the other hand, advocates for use of the same name argue that the safety and pharmacovigilance concerns are minimal and that different names will be a major barrier to marketplace acceptance of biosimilars.  The European Union long ago decided that distinct names were necessary, and the issue has been squarely in front of FDA since the BPCIA’s passage.   In addition, FDA has on two occasions approved biologics with unique non-proprietary names: (1) tbo-filgrastim for a Teva product approved before the BPCIA was passed; and (2) filgrastim-sndz, approved in March for Sandoz’s Zarxio but with a specific FDA notation that the non-proprietary name was a placeholder subject to change.

The draft guidance leads off with a simple summary of the Agency’s position: “FDA’s current thinking is that shared nonproprietary names are not appropriate for all biological products. There is a need to clearly identify biological products to improve pharmacovigilance and, for the purposes of safe use, to clearly differentiate among biological products that have not been determined to be interchangeable.”  FDA further explains that it hopes to avoid “inadvertent substitution” of products, facilitate pharmacovigilance “when other means to track a specific dispensed product are not readily accessible,” encourage routine use of suffixes in ordering, prescribing, dispensing, and recordkeeping,  and “avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway.”

Under the new system, FDA’s naming convention for biological products will be to assign a proper name that will include a “core name” and a designated suffix.  For originator biological products, FDA will make the core name the name adopted by the USAN Council  for the drug substance.  For other biological products (e.g., “related,”  biosimilar, and interchangeable products), the core name will be the name of the drug substance contained in the relevant previously licensed product.

FDA believes that use of a shared core name will indicate a relationship among products.  FDA chose to use a suffix instead of a prefix so that products with the same core name will be grouped together in electronic databases and thereby to help health care providers identify products.

FDA intends to apply this naming convention to both newly licensed and previously licensed biological products. 

A few products will be exempt: biological products for which a proper name is provided in the regulations (e.g., 21 C.F.R. part 640), and “certain categories of biological products for which there are well-established, robust identification and tracking systems to ensure safe dispensing practices and optimal pharmacovigilance (ISBT 128 for cord blood products).”  For previously licensed products, in most cases FDA will simply attach a hyphen and the four letter suffix to the product’s original proper name, one exception being the tbo-filgrastim product mentioned earlier, which will lose its prefix and gain a suffix.

As for the selection of those suffixes “devoid of meaning,” for new products FDA wants the sponsors of full BLAs to propose a suffix during the IND phase.  For existing products, FDA is considering the most effective regulatory approach and intends to provide will provide additional information.  In the near term, however, FDA is using the proposed rule to assign distinguishing suffixes to six products, including the Amgen, Teva and Sandoz filgrastims, Neulasta, Epogen, Procrit and Remicade.  These products were selected because either they are referenced by approved or publicly announced pending biosimilar applications, or are related products to those reference products.  FDA advises applicants for new biosimilar products to also propose a four letter suffix. 

FDA mandates that the proposed suffix should be four lowercase letters, be unique and be “devoid of meaning.”  The proposed suffix should not be promotional, “such as by making misrepresentations with respect to safety or efficacy,” not include abbreviations commonly used in clinical practice and therefore subject to misinterpretation,  not contain or suggest any drug substance name or core name, not look similar to the name of a currently marketed product or to any other product’s suffix.  FDA encourages applicants to conduct due diligence on their proposed suffixes.

FDA’s non-decision on interchangeables is set forth very simply:

FDA intends to apply the naming convention described in this guidance to interchangeable products licensed under section 351(k) of the PHS Act in an original application or a supplement and is considering two alternative approaches:

1. Distinct from the reference product: An applicant for a proposed interchangeable product submitted in an original application under section 351(k) of the PHS Act would propose a unique suffix composed of four lowercase letters for use as the distinguishing identifier included in the proper name designated by FDA at the time of licensure (see section V of this guidance). An applicant seeking a determination of interchangeability in a supplement to its 351(k) application would keep the existing suffix.

2. Shared with the reference product: An applicant for a proposed interchangeable product submitted in an original application or a supplement under 351(k) of the PHS Act would be assigned the same proper name and suffix as its reference product.

FDA's proposal elicited at least one immediate negative reaction.  In a statement, Dr. Bertrand C. Liang, Chairman of the Biosimilars Council (a division of GPhA), stated: “The FDA’s proposals today on naming conventions for biosimilars warrant serious scrutiny for their potential to erect barriers to patient access to new, more affordable medicines, and jeopardize their safety.  Because the Biosimilars Council shares the agency’s deep commitment to patient safety, we believe that biologics and biosimilars should be required to have the same International Nonproprietary Name (INN) with no added 'FDA-designated suffix.'”

The comment period on the draft guidance is open for 60 days, and the comment period on the proposed rule is open for 75 days.

By David C. Gibbons –

As we reported in a previous post, the House Committee on Energy and Commerce requested that FDA answer a number of questions regarding how FDA Centers issue and publicly disclose Untitled Letters (“ULs”).  As readers may recall, the letter to FDA questioned whether FDA’s practices concerning the issuance and disclosure of ULs has been “consistently fair, effective, or efficient” and solicited responses to numerous questions to provide color to the same.  In its brief response, FDA reiterated its general policies regarding the issuance and dissemination of ULs, clarified, to some extent, its approach on disclosure, and addressed the Committee’s assertion that FDA had ulterior motive in the timing of public disclosure of certain ULs.

FDA answered the Committee’s questions concerning the issuance of ULs by stating that ULs are means to “communicate and provide formal notice” to companies that FDA has determined a violation of FDA regulations has occurred that does not rise to the threshold of a WL.  FDA further stated that ULs provide “the factual basis regarding the violation,” communicate FDA’s concerns, but do not commit FDA to take enforcement action for such violation.  In answering these questions, FDA generally related information from its Regulatory Procedures Manual (“RPM”).  For example, FDA pointed to the RPM sections that describe certain types of Warning Letters (“WLs”) and ULs reviewed as a matter of course by FDA’s Office of Chief Counsel – additional detail can be found in RPM Exhibit 4-1 (here). 

More noteworthy was FDA’s response regarding public disclosure – that is, posting to FDA’s website – of ULs.  FDA clarified that Center-specific policies concerning the posting of ULs apply, but only when such policies do not conflict with the Agency’s approach to posting ULs proactively in consideration of its obligations under the Freedom of Information Act (“FOIA”).  FDA said that FOIA requires FDA to post “any Agency record subject to the FOIA,” including ULs, if:

• FDA has received three or more FOIA requests for a copy of such record; or
• The “content relates to a matter of significant public interest” and FDA expects to receive multiple FOIA requests for the record.

In defending its approach, FDA stated: “[t]his approach is consistent with Federal law, Department of Justice Guidelines, President Obama’s January 21, 2009, FOIA Memorandum, and Attorney General Holder’s March 19, 2009, Memorandum.”  Further, FDA said that Centers may utilize approaches that “provide a greater measure of transparency” by proactively posting ULs.  FDA also said that it has been “encouraged” to go beyond the legal requirements for public disclosure when deemed appropriate by FDA Centers.  Finally, FDA noted that its Centers regulate a broad array of products that vary widely in terms of risk as well as the availability of resources, both of which are taken into account when developing Center-specific approaches to the public disclosure of ULs.

FDA took issue with Congress’ suggestion that FDA had motives other than achieving regulatory compliance in issuing and posting some ULs.  In its letter to FDA, Congress questioned whether the timing of issuing ULs was meant to advance new FDA policy or interpretation outside the routine administrative process or impact investment decisions.  In its response to this issue, FDA expressly rejected the notion that it uses ULs to “announce new regulatory approaches or policy.”  With respect to timing, FDA responded by stating that it does not “investigate or evaluate” whether companies receiving WLs or ULs are publicly traded on a U.S. or foreign exchange or “seek to time [the] release [of WLs or ULs] based on market considerations.”  In a final point on this issue, FDA stated it “does not believe the Agency has a special expertise or a mission to change its own processes to attempt to time impacts on the stock market and determine whether impacts are desirable.” 

It will be interesting to see where this goes from here.  Was the Committee’s intent to take FDA to task over what FDA Centers should do, having FDA describe its existing policies regarding the issuance and posting of ULs?  If so, then we may not hear more from either Congress or FDA on the subject.  Or was it a more searching inquiry into what FDA Centers actually do?  If it was the latter, then FDA’s response likely does not provide Congress with what it was looking for and we may see more activity from the Committee, such as a request for a public hearing on the matter.

By Alexander J. Varond & James E. Valentine* –

FDA recently released a draft guidance, titled “Rare Diseases: Common Issues in Drug Development.”  The fourteen-page document amounts to more of a primer than a focused discussion of technical issues.  It serves as a useful reminder of the broader themes that confront orphan drug sponsors, and it is particularly helpful for those that are new to the rare disease space.  In a number of ways, the Draft Guidance is similar to another draft guidance published in May 2015, entitled “Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators,” which, as the title suggests, provides a high-level overview on how to prepare and submit an IND.

By publishing the Draft Guidance, FDA may be seeking to increase the consistency and flexibility exercised in the review of orphan drugs in CBER and CDER as well as across the Centers’ various review divisions.  To be certain, the Draft Guidance highlights a number of ways FDA can exercise flexibility in its review of orphan drugs.  For example, the Draft Guidance discusses FDA’s views on the acceptance of historical controls, and reliance on a single trial with confirmatory evidence.  FDA also notes that “[t]here is no specific minimum number of patients that should be studied to establish effectiveness and safety of a treatment for any rare disease.”

Overview

The Draft Guidance addresses the following aspects of developing a drug for a rare disease:

• Adequate description and understanding of the disease’s natural history;
• Adequate understanding of the pathophysiology of the disease and the drug’s proposed mechanism of action;
• Nonclinical pharmacotoxicology considerations to support the proposed clinical investigation or investigations;
• Reliable endpoints and outcome assessment;
• Standard of evidence to establish safety and effectiveness; and
• Drug manufacturing considerations during drug development.

Natural History Studies

Perhaps the most interesting aspect of the Draft Guidance document comes in its discussion of natural history studies.  FDA’s Draft Guidance urges sponsors of drugs for rare diseases to develop an understanding of the natural history of the disease early in the development program so as to better inform the design and analysis of clinical trials. 

Natural history has been defined as “the natural course of a disease from the time immediately prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended and the patient is either cured, chronically disabled or dead without external intervention.” Stephen C. Groft and Manuel Posada de la Paz, “Rare diseases-avoiding misperceptions and establishing realities: the need for reliable epidemiological data,” Rare Diseases Epidemiology (2010).  In May 2012, FDA hosted a helpful workshop on natural history entitled, “Workshop on Natural History Studies of Rare Diseases:  Meeting the Needs of Drug Development and Research.”

The Draft Guidance accepts that the natural history of rare diseases is often poorly understood.  Although natural history studies are not required, FDA counsels that, for an orphan drug, “a well-designed natural history study may help in designing an efficient drug development program.”  Such studies, FDA notes, can help by:

• Defining the disease population, including a description of the full range of disease manifestations and identification of important disease subtypes;

• Understanding and implementing critical elements in clinical study design, such as study duration and choice of subpopulations;

• Developing and selecting outcome measures that are more specific or sensitive to changes in the manifestations of the disease or more quickly demonstrate safety or efficacy than existing measures; and

• Developing new or optimized biomarkers that may provide proof-of-concept information, guide dose selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy.

The Draft Guidance also notes that, because rare diseases are “highly diverse . . . with wide variations in the rates and patterns of manifestations and progression,” natural history studies should be broad and based on features of the disease, including those morbidities most important to patients.  The Draft Guidance then sets forth a number of helpful considerations in developing a natural history study, including:

• Selecting data elements that are broad and based on features of the disease, including morbidities that are most important to patients, among others.

• Because of the substantial phenotypic variability in many rare disorders, natural history studies should include patients across as wide a spectrum of disease severity and phenotypes as possible, rather than focusing too early on a particular subset;

• Natural history data should be collected for a sufficient duration to capture clinically meaningful outcomes and determine variability in the course of the disease; and

• The data for natural history studies can be collected prospectively or retrospectively, but prospective longitudinal natural history studies are likely to generate the most useful information about a disease.

It is important to note, however, that prospective longitudinal natural history studies can span years and even decades and waiting for the results of a such trials, prior to designing pivotal studies, may substantially delay drug development programs.  As such, patients with serious and life-threatening conditions may be denied access to promising therapies.  In addition, companies may find that conducting such prospective longitudinal natural history studies is not commercially viable.  This is particularly true for small companies, which make up a large percentage of the orphan drug space.

While the Draft Guidance emphasizes the utility of natural history studies as “critical background information” to inform sponsors’ decision-making regarding clinical trial design and provides guidance on developing natural history registries to support that activity, when it comes to the use of natural history data as a historical comparator, the Draft Guidance minimizes the credibility of using historical controls.  While the challenges associated with the use of historical controls are well recognized, FDA fails to recognize that natural history studies have been used in this way to support important approvals in the rare disease space; for example:

• Myozyme (alglucosidase alfa), the first treatment for patients with Pompe disease, was approved on the basis of two studies with historical controls where a natural history database was used to create a subgroup-matched historical control based on certain prognostic factors;

• Cresemba (isavuconazonium sulfate) was approved in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis, rare but serious infections, with one of the two studies’ effectiveness comparisons using a combination of both matched and unmatched historical controls; and,

• Cholbam (cholic acid) was approved in 2015 for both bile acid synthesis disorders due to single enzyme defects and as an adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders, which in the absence of sufficient natural history information was based largely on uncontrolled studies.

The use of natural history data as a historical control remains an area where a greater understanding of FDA’s flexibility in previous approval decisions would benefit the rare disease community.

Comments on the Draft Guidance are due by October 16, 2015 here.

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

By James E. Valentine* –

On August 17, 2015, FDA announced the availability of an update to its 11 year old guidance on botanical drug development.  Botanicals are plant materials, algae, macroscopic fungi, and combinations of those things that can be regulated as a food (including a dietary supplement), drug/biologic, medical device, or cosmetic under the Federal Food, Drug, and Cosmetic Act.  The updated guidance covers the development of those botanicals that are that are regulated as drugs (i.e., under an investigational new drug application to support a future new drug application submission, as part of over-the-drug monograph system).  While the general approach to botanical drug development has remained unchanged in the updated guidance, FDA has primarily modified and expanded the 2004 draft guidance to address late-phase development and NDA submission.  The updated guidance still covers these topics in drug development:

1. Description of the product and documentation of prior human experience;
2. Chemistry, manufacturing, and controls (CMCs);
3. Nonclinical safety assessment, including pharmacology and toxicology;
4. Clinical pharmacology and bioavailability; and,
5. Clinical considerations.

Therapeutic Consistency

While there are a number of smaller changes to what FDA requests of sponsors when embarking on clinical trials for botanical drugs, the Agency significantly expanded the quality control measures.  Given the heterogeneous nature of botanical drug products, and that it can be technically challenging to determine a botanical drug’s identity and ensure its consistency, the draft guidance maintains a “totality-of-the-evidence approach” to demonstrate that the commercial batches will be therapeutically consistent with those batches observed during premarket clinical development.  Such quality controls still consist of a combination of (a) botanical raw material controls (e.g., agricultural practice and collection), (b) quality controls by chemical tests, and (c) manufacturing controls.  However, it seems that FDA would like to see additional evidence that supports therapeutic consistency.  As such, the updated guidance includes two new quality control aspects: biological assays and clinical data.

Biological Assays.  While raw material controls and other CMC measures can help establish the identity and ensure the quality of botanical drug products, the draft guidance states that in certain cases information on correlations between such quality parameters and the pharmacological activity or clinical effect may be warranted to ensure that variations in raw materials and drug substance will not affect the product’s therapeutic consistency.  For a biological assay, FDA prefers one that reflects the drug’s known or intended mechanism of action.  At a minimum, FDA would like to see an appropriately validated biological assay that demonstrates accuracy, precision, specificity, linearity, and range.

Clinical Data.  The updated guidance requests clinical data beyond the primary efficacy analyses to show that clinical response to a botanical drug will not be affected by variations of different batches in two ways.  The first approach is to conduct multiple batch analyses, looking at batch effects on clinical endpoints.  This allows quantification of potential heterogeneity in clinical outcomes for subjects who receive different batches in the study.  This is in principle similar to other types of subgroup analysis.  The second approach is to show that clinical response is not sensitive to dose, while also demonstrating that the studied doses are more effective than placebo or control, or not inferior to active treatment.

Applicability of Combination Drug Regulations

Another major expansion to the updated guidance is the addition of a discussion on the applicability of FDA's combination drug regulations.  For a fixed-dose combination drug product, current regulations require sponsors to demonstrate each component’s contribution toward overall efficacy and/or safety.  However, the draft guidance clarifies that these regulations generally do not apply to naturally derived mixtures, such as those found within a single botanical raw material.  Therefore, botanical drug products derived from a single botanical raw material are generally not considered fixed-dose combination drugs because FDA considers the entire botanical mixture to be the active ingredient. 

On the other hand, botanical drug products derived from multiple botanical raw materials are currently considered by FDA to be fixed-combination drugs.  Since demonstrating each botanical raw material’s contribution to efficacy and safety in such a botanical product is not always feasible, FDA is reviewing the requirements for fixed-combination drugs and how they should be applied to botanical drugs.  For now, FDA is requesting nonclinical data from animal disease models or pharmacological in vitro assays to help show the contribution of individual components to the claimed effects.

Other Modifications

In addition, the guidance document’s discussion of Phase 1 and Phase 2 clinical studies for botanical drugs is no longer split into separate recommendations and requirements for (a) marketed products without safety concerns and (b) non-marketed products or products with known safety concerns.  The new document has blended these requirements.  For example, the nonclinical pharmacology and toxicology information needed to support Phase 1 and Phase 2 clinical studies of botanical products still depends on the extent of previous human use, and if currently lawfully marketed in the United States as a dietary supplement, initial clinical studies may still be allowed to proceed without further nonclinical testing.  In the updated guidance, FDA has now further explained that regardless of whether the drug is currently lawfully marketed in the United States, if the anticipated exposure in the proposed clinical trials exceeds that in prior human use (e.g., higher doses or a longer duration), an additional nonclinical pharmacological/toxicological assessment is warranted to adequately address the difference between the prior human use and the proposed clinical trial.

Comments on the draft guidance can be submitted to the public docket through October 16, 2015 here.

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

By Riëtte van Laack - 

As we previously reported, FDA and FTC are reviewing their regulation of homeopathic drugs.  In March 2015, FDA issued a notice requesting comments on the current use of homeopathic drugs, and that agency’s approach to regulation of the category.  In June 2015, FTC announced a workshop in September to discuss advertising of over-the-counter (OTC) homeopathic products. 

Last week, FTC staff announced that it has submitted a comment to FDA.  The comment was approved by the Commission by a vote of 5-0.  Not surprisingly, FTC staff takes the position that claims for homeopathic drugs must be supported by competent and reliable scientific evidence.  The comment suggests that FTC believes that its position is compromised by FDA’s current conflicting policy that allows marketing of homeopathic drug products without proof of efficacy. FTC staff suggests that it has been “reluctant” to pursue action against homeopathic products because of this conflict.

FTC staff puts forward three possible approaches for FDA to resolve the conflict between FDA’s policy and FTC’s substantiation doctrine:

1. FDA discontinues its current policy and requires that homeopathic products meet the same standard as other conventional OTC drug products;
2. FDA removes the requirement for an indication for homeopathic drug products so that the inclusion of the indication becomes voluntary and, therefore, is no longer “sanctioned” by FDA but remains subject to FTC’s standard of competent and reliable scientific evidence;
3. FDA amends the current policy to require that the indication be supported by “competent and reliable scientific evidence.”

The FTC staff’s comment includes data from two studies – a focus group and copy test – to support its contention that consumers are confused about the nature of homeopathic products.  These studies and their interpretation will undoubtedly be a topic of discussion at FTC’s September workshop. 

The comment confirms that FTC is intent on holding homeopathic drug products to the same standard as conventional drug products.  The question now is whether FDA will accept the comment’s recommendations in furtherance of that objective or if FDA will continue to recognize the uniqueness of homeopathic drug products. 

By James C. Shehan –

We’ve all been told that consistency is a virtue and some recent developments have AbbVie’s consistency on display while that company questions FDA’s biosimilar labeling morality, or at least decision-making.  In a citizen petition supplement recently submitted to FDA, AbbVie renewed its efforts to change FDA’s policies on biosimilar labeling by assailing the logic behind FDA’s reliance on the Purple Book in response to a Congressional inquiry, by citing FDA’s own recent statements in the Amarin off-label matter and by continuing to assert the needs of prescribing physicians to be fully informed about biosimilars.

AbbVie’s specific requests are that the labeling of all biosimilars contain “clear statement[s] that the product is a biosimilar, that the biosimilar is licensed for fewer than all the reference product's conditions of use (if applicable), … that the biosimilar's licensed conditions of use were based on extrapolation (if applicable), [and] that FDA has not determined that the biosimilar product is interchangeable with the reference product (if applicable).”  AbbVie also asks for “[a] concise description of the pertinent data developed to support licensure of the biosimilar, along with information adequate to enable prescribers to distinguish data derived from studies of the biosimilar from data derived from studies of the reference product.”

The original AbbVie citizen petition was submitted by AbbVie in June in reaction to the Agency’s  removal from a final guidance document on “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product” of requirements that the labeling of a biosimilar biological product indicate that it is biosimilar to a reference product, and also to call out whether or not it is interchangeable with a reference product, two requirements that did appear in the 2012 draft version of the document (see our previous posts here and here).

AbbVie’s supplement references FDA’s response to an April 30th letter from Lamar Alexander and eight other Republican senators that questioned FDA’s decision to make the labeling of the first approved biosimilar,  Sandoz Inc.'s Zarxio (filgrastim-sndz) almost identical to that of its reference product, Amgen Inc.'s Neupogen (filgrastim).  The letter noted that Zarxio’s labeling “does not even include the word "biosimilar," which could further increase consumer confusion about how this product relates to the reference biologic.”

AbbVie zeroes in on FDA’s June 22 response to that letter, in which FDA stated that information about biosimilarity and interchangeability did not need to be included in biosimilar labeling because it was in the Purple Book: “The Purple Book enables a user to see whether a biological product has been determined by FDA to be biosimilar to, or interchangeable with, a reference product.”  The Purple Book is the biologics analog to the Orange Book drug listing guide (see our post here).  The Purple Book lists licensed biological products and contains information about reference product exclusivity, biosimilarity and interchangeability.

AbbVie notes that FDA also states in the June 22nd letter that "health care professionals should have product labeling that includes the essential scientific information necessary to make informed prescribing decisions for their patients," while the 2012 draft guidance said that information "regarding biosimilarity or interchangeability" is needed for informed prescribing decisions.  This leads AbbVie to conclude that “The proposition that the Purple Book could cure a material omission in the labeling for a biosimilar is indefensible, FDA regulations explicitly state that prescription drug labeling found "on or within the package" (in other words, the package insert) must contain all of the information that prescribers require to administer the drug to their patients safely and effectively. For decades, FDA, industry, and the medical profession have all understood that package inserts must provide ‘full disclosure.’ If information is necessary for prescribing decisions, it must appear in the package insert. That is a foundational principle of FDA law—and one that FDA fought long and hard to vindicate.”

AbbVie also notes two other pieces of information that are not in the Purple Book but are needed to make informed prescribing decisions- information about the indications and routes of administration for which a biosimilar has been found to be biosimilar to its reference product.  AbbVie asserts that this information will become increasingly important as more biosimilars are approved and the market evolves into “a highly complicated landscape of products with varying scopes of biosimilarity and interchangeability," and concludes that “The only way to convey that nuanced information to prescribers is through product-specific disclosures in the labeling of each biosimilar.”

In a separate section of the citizen petition, AbbVie cites FDA’s own statements in support of AbbVie’s position that biosimilar labeling should make clear which supporting clinical studies were conducted by the reference sponsor and which by the biosimilar sponsor.  In the Amarin case, which involves a challenge to FDA’s regulation of off-label statements by drug companies, (see our post here), Amarin included a letter to it from Janet Woodcock, the Director of FDA’s Center for Drug Evaluation and Research, concerning what Amarin could and could not say, in FDA’s opinion, about its Vascepa (isocapent ethyl) product.  Dr. Woodcock states: “[A] communication should not state or imply that studies conducted using products other than Vascepa were studies of Vascepa itself …. Rather, to ensure that your communications are not false or misleading, we recommend that they expressly disclose when studies were conducted using products other than Vascepa (in particular when those other products contain active ingredients that are different from the isocapent ethyl—an ester of EPA—that is contained in Vascepa) and that the results of the studies may not be applicable to Vascepa. 

AbbVie also quotes the government brief in the Amarin case as saying that it would be "misleading for Amarin to suggest or imply … that studies using products other than Vascepa were studies of Vascepa itself."

AbbVie points out that these FDA statements stand in contrast to FDA's current approach to biosimilar labeling, at least in the case of Zarxio. “As explained in the Petition, a biosimilar and its reference product are – like Vascepa and related products — similar, but not the same active ingredients or products. But, the labeling that FDA approved for Zarxio relies entirely on studies involving a different product without acknowledging that the studies were not conducted with Zarxio. As both FDA and DOJ have now represented to a federal court, a failure to "expressly disclose when studies were conducted using [other] products" is misleading.”

A third section of the AbbVie supplement concerns growing “stakeholder support for more transparent biosimilar labeling.”  AbbVie' cites three recent letters to FDA’s Acting Commissioner, an important conference on Capitol Hill, additional survey evidence, and a recent statement from the biosimilar industry.

Our two earlier posts on this topic analogized the issue of whether biosimilar labeling should or should not indicate that a product is a biosimilar to the affixing of a scarlet letter to Hester Prynne in Hawthorne’s classic novel.  Having completed a blog trilogy and seeing no end in sight for the issue of biosimilar labeling issues, we may need to move on to new references – perhaps Fast and Furious 8 will suffice.

By Jenifer R. Stach* & Ricardo Carvajal –

On July 24, 2015, FDA issued a proposed rule amending the Agency’s previously issue proposed rule on Accreditation of Third-Party Auditors/Certification Bodies (see our prior posts here and here) and establishing user fees for the Agency’s proposed accreditation program (hereinafter “User Fee Proposed Rule”).  On the same day and in a related publication, FDA issued a draft guidance for Model Accreditation Standards (hereinafter “Draft Guidance”).  

On their face, the User Fee Proposed Rule and the Draft Guidance might seem to be of interest only to those who might participate in the Voluntary Qualified Importer Program (see our prior post here).  However, FDA’s accreditation standards can be expected to influence the content of similar standards currently used by third-party auditors and their certifiers.  In addition, because the accreditation program set up by FDA might not be revenue neutral, administration of the program could divert resources from other program areas – one of the several issues on which the Agency has requested comment.  Comments on both the User Fee Proposed Rule and the Draft Guidance are due October 7, 2015.  Below we provide summaries of both documents.  

User Fee Proposed Rule.  Section 808(c)(8) of the FDC Act (which was added by FSMA) requires FDA to establish a user fee program to set up and administer the Agency’s proposed accreditation program.  FDA explains the costs associated with establishing and maintaining the accreditation program in the User Fee Proposed Rule in a Q&A format. The Questions are presented as follows: (1) Who would be subject to a user fee; (2) What user fees would be established; (3) How will FDA notify the public about the fee schedule; (4) When must the user fees be submitted; (5) What are the consequences for not paying a user fee on time; and (6) What are the possible exemptions?

(1) Who would be subject to a user fee?

Accreditation Bodies (ABs) and third-party auditors/certification bodies (CBs) would be subject to user fees.  As presented in the proposed § 1.700, FDA identifies four main groups subject to a user fee:

• ABs submitting applications or renewal applications for recognition in the third-party accreditation program;
• Recognized ABs participating in the third-party accreditation program subject to FDA monitoring activities;
• CBs submitting applications or renewal applications for direct accreditation; and
• Accredited CBs (whether accredited by recognized ABs or by FDA through direct accreditation) participating in the third-party accreditation program subject to FDA monitoring activities.

(2) What user fees would be established?

The proposed language in § 1.705 establishes application fees and annual fees for ABs and CBs in the four categories listed in the above section “Who would be subject to a user fee?”  FDA bases the costs for this proposed User fee program on other established User fee programs such as the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee Act (MDUFA).  These exiting User fee models show that every seven full-time federal employees (FTEs) who perform direct FDA work require three indirect and supporting FTEs.  FDA calculates the base unit for the hourly fee rate of an FTE as $202.  The base unit for the hourly fee rate of an FTE requiring foreign inspection travel is calculated at $305, and the hourly fee rate of an FTE requiring domestic inspection travel is $217.

In the User Fee Proposed Rule, FDA estimates the amount of time it will take to perform the functions necessary to establish and maintain the accreditation program.  For example for FDA to accredit an AB applying for recognition, FDA estimates that it will take approximately 60 person-hours to review a submitted application, 48 person-hours to perform an onsite performance evaluation, and 45 person-hours to prepare a written report.  Therefore, the total estimated average cost for FDA to review an application submitted by an AB is $35,850.      

Using similar hourly estimate calculations, FDA provides user fee costs for the following functions:  

• AB Applying for Recognition, $ 35,850 (as discussed in the example)
• AB Renewal Application,  $18,853
• CB Applying for Direct Accreditation from FDA, $35,850
• CB Renewal Application, $26,930
• Annual Fees for Recognized ABs, $7,928 over 5 years  
• Annual Fees for CBs Directly Accredited by FDA, $21,104
• Annual Fees for CBs Accredited by a Recognized AB, $7,928 over 4 years  

FDA states that the proposed fee structure for ABs and CBs is consistent with the current industry model.  FDA is requesting comment on whether these fees should be paid as a flat fee or billed on an hourly basis.  FDA proposes that the alternative approach of an hourly bill may incentivize ABs and CBs to submit higher quality applications, in other words, applications that are faster to review because of the substantive quality of the application.  FDA also requests comment on a proposed flat fee, hourly fee, or whether a hybrid approach of flat fee and hourly would be appropriate.   

(3) How will FDA notify the public about the fee schedule?

Under the proposed § 1.710, FDA intends to notify the public annually in the Federal Register prior to the beginning of the fiscal year for which the fee will apply.  As an example, MDUFA fee rates were published on July 30, 2014 for fees beginning in 2015.   

(4) When must the user fees be submitted?

Application and renewal fees will be submitted concurrently with an application or renewal.  FDA will not review an application or renewal until the fee has been submitted.  FDA also notes that user fees are not refundable.  FDA tentatively concludes that this is the simplest approach to encourage high quality applications for ABs and CBs who have made a thoughtful decision to stay in the program for subsequent years.    

(5) What are the consequences for not paying a user fee on time?

Annual fees will be paid within 30 days of the due date.  After 30 days, the entity (AB or CB) will face suspension.  After 90 days, the status of the entity will be revoked.  

(6) What are the possible exemptions?

In the proposed rule, FDA does not provide an exemption or reduced fee for small businesses or entities.  FDA is requesting comment on whether the final rule should account for small businesses by offering an exemption or fee reduction.  FDA also proposes to charge user fees to foreign governments that are participating in the program as either an AB or CB.  FDA requests comment on whether for trade reasons, or other reasons, they should consider a different approach.  

Draft Guidance.  Section 808(b)(2) of the FDC Act requires FDA to develop Model Accreditation Standards for recognized accreditation bodies (ABs).  Pursuant to the statute, ABs shall use these model standards to qualify third-party auditors/certification bodies for accreditation.  FDA noted that the Draft Guidance, “if finalized, will constitute the model accreditation standards referred to in section 808(b)(2) of the FD&C Act.  In instances where this draft guidance provides different or more specific recommendations than are contained in the ISO/IEC 17021:2011, or conflicts with ISO/IEC 17021:2011, the recommendations of this guidance apply.”  As is the case with any guidance, alternative approaches may be used to the extent that they meet the requirements of the statute, and in this case, the proposed rule.    

• Authority and responsibility:  A third-party auditor/certification body must demonstrate the authority, as a governmental entity or through legally enforceable contractual rights, to exert any authority necessary to perform credible audits and certifications of the program.  Specifically, a third-party auditor/certification body must have authority to (1) Review relevant records; (2) Conduct onsite audits; and (3) Suspend or withdraw certification for failure to comply with requirements of the program.  
• Capacity and competence:  A third-party auditor/certification body must demonstrate that it has the adequate number of competent personnel to implement the program, as well as sufficient finances to operate in compliance with the program.  Competent personnel must have relevant knowledge, skills, and experience to audit and assess compliance with FDA requirements under the program.  Competency is based on education, industry experience, ongoing training, and professional development in the area of food safety.  A third-party auditor/certification body should have a documented process to ensure that audit agents and managers meet the requirements for competency.      
• Conflicts of interest:  A written program must be in place to prevent conflicts of interest between a third-party auditor/certification body and entities seeking certification.  The written program should include measures for promoting independence, objectivity, and impartiality and procedures for effectively identifying, investigating, and resolving potential conflicts. 
• Quality assurance:  A third-party auditor/certification body must implement a written program to conduct periodic self-assessment, implement corrective actions, and prepare a report written in English documenting the results of the self-assessment.  FDA recommends that the third-party auditor/certification body establish procedures to conduct annual reviews for their self-assessment.   The annual review would include areas of improvement for deficiencies, corrective action taken to address deficiencies, assessment of the effectiveness of the corrective action, an evaluation of personnel compliance with conflict of interest measures, and an identification of resource needs.  
• Records:  A third-party auditor/certification body must maintain written procedures to establish, control, and retain records.  The written procedures must include requirements that records must be written in English and retained electronically for four years.  A third-party auditor/certification body should also have legal authority to grant FDA access to relevant records. 
• Regulatory audit reports:  Within 45 days of completing a regulatory audit, an accredited auditor/certification body must prepare and submit a report written in English to FDA and to its accreditation body.  In the case of direct accreditation, an accredited auditor/certification body would only submit the report to FDA.  The audit report should include the name and address of the facility; the FDA food facility registration number, if applicable; the date and scope of the audit; the processes and foods observed during the audit; the identity of the person responsible for compliance at the facility; deficiencies observed, and the reasonable probability that the deficiency poses a serious adverse consequence to public health; corrective action for any deficiency; whether sampling or analysis was used at the facility; whether a food-safety recall has been issued in the last 2 years, and the reason for the recall; whether significant changes have been made to the facility, processes, or products in the last 2 years; and a list of any food or facility certifications issued to the entity in the last 2 years.         
• Miscellaneous:  A third-party auditor/certification body must maintain an updated list of eligible entities on its website.  For each eligible entity listed, the website should identify the duration and scope of the certification and the date the entity paid, or was reimbursed for, a fee associated with their certification.  Also, a third-party auditor/certification body must issue food or facility certifications electronically in English.    

*Admitted only in Maryland.  Practicing under the supervision of the Firm.