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. 

By Jay W. Cormier & Alan M. Kirschenbaum –

In an advisory opinion posted on Monday, July 28, 2014, the Office of the Inspector General of the Department of Health and Human Services (“OIG”) determined that no enforcement action would be taken against a drug manufacturer’s direct-to-patient discounted sales program that operates outside of  Federal health care programs.  

Advisory Opinion 14-5 involves a program under which a brand name drug manufacturer offers to sell one of its products to patients at a heavily discounted fixed cash price.  The opinion explains that this product is either not included on most third party payor formularies due to the availability of generic equivalents, or, where it is covered, it is placed on non-preferred formulary tiers and subject to prior authorization, step therapy, or other coverage and reimbursement restrictions.  Under the discount program, Medicare Part D patients with a valid prescription are able to obtain the drug from an online pharmacy, which dispenses the product on behalf of the manufacturer at a fixed price established by the latter.  The manufacturer supplies the product to the pharmacy pursuant to a bailment arrangement, under which the manufacturer retains title to the product until the Pharmacy dispenses it to patients.  The manufacturer pays the pharmacy a fair market value fee for the dispensing services.  Neither the pharmacy nor the patient seeks reimbursement for the product from any third party payor, government or private, nor does either the manufacturer or the pharmacy discuss or otherwise market any other product or service to patients who have opted into the discount program. 

In analyzing this program under the Federal health care program antikickback statute (“AKS”, 42 USC 1320a-7b(b)), the OIG recognized that the program operates entirely outside of all Federal health care programs, meaning that patients obtain the product without using their Medicare Part D benefit or any other Federal health care program benefit.  Nevertheless, the OIG reasoned that the AKS could be implicated if (1) the discount induced patients to purchase other products marketed by the manufacturer that are reimbursed under Federal programs, or (2) the discount induced patients to switch to the product and then, if the manufacturer terminated the discount arrangement, use their Part D plan or other federal program to purchase the Product.  OIG concluded that that the risk of the first type of inducement was minimized because the manufacturer certified that it would not use the discount as a vehicle to market other Federally reimbursable products that it manufactures.  With regard to the second type of inducement, if the discount program were terminated, few Part D enrollees would be able to obtain coverage of the product through their Part D plans because of the prevalent coverage exclusions and limitations applicable to the drug, whereas  enrollees could easily obtain coverage of generic equivalents.

The OIG also found that the dispensing arrangement with the pharmacy did not constitute an unlawful swapping arrangement under the AKS – i.e., a vehicle for the manufacturer to provide fees to the pharmacy for dispensing the product to cash paying patients as an inducement for the pharmacy to recommend the manufacturer’s other drugs that are covered under Federal programs.  The OIG’s primary consideration in this regard was the manufacturer’s certification that the fees paid to the pharmacy are consistent with fair market value in an arm’s-length transaction, and do not take into account the value or volume of referrals or other business generated between the parties.

The OIG also determined that the arrangement does not have the potential to influence Medicare or Medicaid beneficiaries to use the online pharmacy for federally reimbursed products, so that there is minimal risk of a violation of the civil monetary penalty prohibiting beneficiary inducements (42 USC 1320a-7a(a)(5)).

By Kurt R. Karst –      

In a 2-1 decision handed down last week, a panel of judges from the U.S. Court of Appeals for the Second Circuit reversed both a March 2012 decision and a June 2012 decision from the U.S. District Court for the Southern District of New York (Magistrate Judges Theodore H. Katz and James C. Francis IV) granting Motions for Summary Judgment to the National Resources Defense Council (“NRDC”) and other nonprofit advocacy organizations relating to Notices of an Opportunity for Hearing (“NOOH”) FDA issued in 1977 on proposals to withdraw approval of all subtherapeutic uses of penicillin in animal feed and nearly all subtherapeutic uses of tetracyclines (oxytetracycline and chlortetracycline) in animal feed, as well as to two Citizen Petitions requesting that FDA withdraw approval of subtherapeutic uses of penicillin and tetracyclines in animal feed because of a threat to human health.  The reversal was immediately criticized as a blow to the public health.

Both district court decisions stem from a lawsuit the NRDC, et al. filed in 2011 (see our previous post here).  The groups allege in their Complaint that FDA, in violation of the Administrative Procedure Act (“APA”), failed to comply with the Agency’s statutory duty to withdraw approvals of subtherapeutic uses of penicillin and tetracyclines in animal feed as required by FDC Act § 512(e)(1) (21 U.S.C. § 360b(e)(1)) and as proposed in 1977.  That statutory provision, which addresses FDA’s authority power to withdraw approval for new animal drugs, states:

(1) [FDA] shall, after due notice and opportunity for hearing to the applicant, issue an order withdrawing approval of an application filed pursuant to subsection (b) of this section with respect to any new animal drug if the Secretary finds . . .

(B) that new evidence not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved . . . ;

The Plaintiffs further contend that FDA’s failure to timely respond with final decisions to Citizen Petitions submitted to the Agency in 1999 (Docket No. FDA-1999-P-1286) and 2005 (Docket No. FDA-2005-P-0007) on the same topic is an unreasonable delay in violation of the APA.  FDA denied both petitons in November 2011, saying that an alternative strategy to withdrawal of approval would be more efficient (i.e., less costly and lengthy), and then withdrew the 1977 NOOHs in December 2011.  The Plaintiffs then amended their Complaint alleging that FDA’s petition denials was arbitrary and capricious. 

In its March decision, the District Court ordered FDA to institute withdrawal proceedings as discussed in the 1977 NOOHs and then withdraw drug approvals.  In its June 2012 decision, the District Court agreed with Plaintiffs that FDA’s denial of the 1999 and 2005 petitions was arbitrary and capricious.  According to the District Court, FDA failed to offer a reasoned explanation, grounded in the statute, for its refusal to initiate withdrawal proceedings.  See our previous posts here and here for a more detailed discussion of the decisions.  

On appeal to the Second Circuit, the Court framed the “required hearing claims” – i.e., the circumstances under which the “shall . . . issue an order withdrawing approval” language at FDC Act § 512(e)(1) comes into play – as follows:

The principal question presented by this appeal is whether 21 U.S.C. § 360b(e)(1) requires the FDA to proceed with withdrawal hearings for certain previously approved subtherapeutic uses of antibiotics in animal feed because the FDA has made a finding that those uses are not shown to be safe for humans.  The text of § 360b(e)(1) clearly requires withdrawal of approval once such a finding has been made; it does not equally clearly specify when the agency makes such a finding, and in particular whether the type of finding that mandates withdrawal of approval is a conclusion based on internal agency deliberations that precedes (and then requires) the holding of a hearing, or a finding that represents the conclusion reached as the result of such a hearing.

Not surprisingly, FDA and the NRDC interpret this provision differently.  On the one hand, FDA

reads the statute as requiring the sequence: hearing, finding, order. In effect, it reads the provision to say, “If, after notice and a hearing, the secretary finds that a drug is not shown to be safe for use,” she is required to withdraw approval of the drug.  In this interpretation, the withdrawal process begins with a notice from the FDA to a drug sponsor of its concerns about an drug, and offering the opportunity for a hearing regarding the safety of the animal drug.  If, at the conclusion of the hearing, upon consideration of the evidence presented, the secretary finds that the drug is indeed not shown to be safe for use, she must then issue an order withdrawing approval of the drug.  That order of events depends upon the conclusion that a finding that an animal drug is not shown to be safe can be made only after the drug’s sponsor’s due process rights – notice and an opportunity to be heard – have been respected.  Therefore, the mandatory “shall” applies only to the action – withdrawal of approval – that the Secretary must take if the hearing results in a finding adverse to the drug.  On the government’s reading, the mandatory “shall” does not apply to the holding of the hearing itself, which the government argues is a discretionary action that the agency may undertake, or not, in its discretion, based on its judgment about whether the scientific evidence and sound public policy warrant instituting proceedings to withdraw approval.

On the other hand, the NRDC read the statute as requiring the sequence: finding, hearing, finding, order.  In effect, wrote the Second Circuit, Plaintiffs

read the statute to say, “If the secretary finds a drug is not shown to be safe for use, she shall provide notice to the applicant, hold a hearing, issue a second finding, and then withdraw approval.”  In their interpretation, the initial finding that the drug is not shown to be safe is based on the agency’s internal investigations of the scientific evidence, and comes before any hearing is held.  On plaintiffs’ reading, once the agency reaches the conclusion that the drug is not shown to be safe, the mandatory language of the statute becomes applicable – the agency must issue an order of withdrawal, though it must hold a hearing first.  The mandatory “shall” thus in effect governs not only the remedy that must follow a formal conclusion after a hearing, but also the process itself; after reaching its initial conclusion that the drug is not shown to be safe, the agency is required to institute proceedings and effectuate them through a hearing, after which (if the evidence present at the hearing sustains the finding) she must issue an order of withdrawal.

Circuit Judge Lynch and District Judge Forrest (sitting by designation) ultimately agreed with FDA, stating:

Our survey of the text, the context, the regulations, and the background legal principles leave us firmly persuaded that Congress has not required the FDA to hold hearings whenever FDA officials have scientific concerns about the safety of animal drug usage, that the FDA retains the discretion to institute or terminate proceedings to withdraw approval of animal drugs by issuing or withdrawing NOOHs, and that the statutory mandate contained in § 360b(e)(1) applies to limit the FDA’s remedial discretion by requiring withdrawal of approval of animal drugs or particular uses of such drugs only when the FDA has made a final determination, after notice and hearing, that the drug could pose a threat to human health and safety.

. . .  Although the text is not unambiguously clear, we believe that the FDA put forth the more natural reading.  The statute requires the FDA to withdraw approval of an animal drug only “after due notice and opportunity for hearing” has been afforded, and then only “if the Secretary finds” that the drug is not shown to be safe.  21 U.S.C. § 360B(e)(1). That language most naturally refers to a finding that is issued as a result of the hearing. That interpretation, moreover, avoids injecting a second, unexpressed “finding” into the sequence of events mentioned in the statute.

Circuit Judge Lynch and District Judge Forrest also rejected Plaintiffs’ alternative argument that FDA’s Citizen petition denials and withdrawal of the 1977 NOOHs violated the APA as arbitrary and capricious.  According to the Court, “the decision whether to institute or terminate a hearing process that may lead to a finding requiring withdrawal of approval for an animal drug is a discretionary determination left to the prudent choice of the FDA.”

But FDA did not get off scot-free.  In a 48-page dissent (out of a 113-page decision), Chief Judge Katzmann vehemently opposed the majority opinion:

I cannot agree with the majority’s conclusions.  In light of the statutory structure and its purposes, I am convinced that 21 U.S.C. § 360b(e)(1) requires the FDA to continue the proposed withdrawal proceedings . . . .  I am likewise convinced that the agency’s decision to deny the citizen petitions was arbitrary and capricious . . . because it failed to address the statutory question of whether the animal drug uses at issue were shown to be safe.

Today’s decision allows the FDA to openly declare that a particular animal drug is unsafe, but then refuse to withdraw approval of that drug.  It also gives the agency discretion to effectively ignore a public petition asking it to withdraw approval from an unsafe drug.  I do not believe the statutory scheme can be read to permit those results. . . .

Given Chief Judge Katzmann’s strong dissent, Plaintiffs will probably appeal the panel decision and seek an en banc rehearing.  But as Second Circuit Courts Committee recently noted, the Second Circuit has proceeded to a full hearing en banc only in rare and exceptional circumstances.  Given the odds, the panel decision reversing the District Court’s decisions, remanding the case to the District Court with instructions to deny the Plaintiffs’ Motion for Summary Judgment, granting FDA’s Motion for Summary Judgment, and dismissing the action seem likely to stand.  

By Kurt R. Karst –      

In a rather lengthy (33-page) response to two citizen petitions submitted to FDA by AbbVie Inc. (Docket No. FDA-2011-P-0610) and Auxilium Pharmaceuticals, Inc. (Docket No. FDA-2013-P-0371) concerning their testosterone gel 1% drug products – AbbVie’s ANDROGEL (NDA No. 021015) and Auxilium’s TESTIM (NDA No. 021454) – FDA refused to conduct a rulemaking under the Administrative Procedure Act (“APA”) before deciding on whether or not to grant a Therapeutic Equivalence (“TE”) rating to “generic” versions of both drug products submitted and approved pursuant to Section 505(b)(2) of the FDC Act.  At the same time, FDA granted an “AB” rating to Perrigo Israel Pharmaceuticals Ltd.’s testosterone gel 1% drug product (NDA No. 203098), and a “BX” rating to Teva Pharmaceuticals USA’s testosterone gel 1% drug product (NDA No. 202763) – both of which are follow-on versions of ANDROGEL.  FDA has not yet decided on what TE rating to assign to Upsher-Smith Laboratories, Inc.’s follow-on version of Auxilium’s TESTIM approved in June 2014 (VOGELXO; NDA No. 204399).  All three 505(b)(2) NDAs were submitted to FDA because of a change in formulation (i.e., penetration enhancer) vis-à-vis the reference drug that FDA previously determined (here and here) could not be the subject of an ANDA because of the need for clinical safety studies.

As we previously reported, in August 2011, a Citizen Petition was submitted to FDA on behalf of AbbVie (then Abbott Laboratories) calling into question the Agency’s authority for granting TE ratings to drug products approved pursuant to FDC Act § 505(b)(2).  Specifically, AbbVie requested that FDA refrain from granting a TE rating to any 505(b)(2) application approved version of ANDROGEL until FDA has conducted a rulemaking under the APA “to modify the procedures that apply to such ratings.”  That rulemaking, said AbbVie, “should establish procedures for (1) FDA’s assignment of TE ratings to drugs that are the subject of [505(b)(2) drugs] and (2) FDA’s public listing of such ratings in [the Orange Book].”  At a minimum, FDA’s new regulations should “characterize FDA’s assignment and listing of TE ratings for § 505(b)(2) drugs as either orders or substantive rules for purposes of the APA, describe what legal process is available to interested parties for commenting on or challenging a proposed listing, and establish a coherent set of standards governing such a listing.” 

According to AbbVie, a rulemanking is necessary because TE ratings are far more than advisory:

They have been expressly incorporated into state pharmacy practice statutes that control which drug products pharmacists may dispense and, therefore, which drug products patients receive when filling prescriptions at the pharmacy.  TE listings also directly affect federal, state, and private insurance reimbursement schemes, and are expressly relied upon in Medicare Part B, among other federal laws.  These listings materially impact the economic rights of competing drug sponsors.  Thus, TE listings have automatic and significant binding legal consequences under state and federal law.

In addition to FDA’s 1979 (proposed) and 1980 (final) rulemaking establishing the Orange Book and TE ratings, AbbVie relied on Tozzi v. U.S. Dep’t of Health & Human Servs., 271 F.3d 301 (D.C. Cir. 2001), for the proposition that there is precedent establishing that TE listings have a binding legal effect.  In that case, concerning a HHS decision to change in a report the carcinogenic status of dioxin, the Court explained that “[r]eviewability under the APA hinges upon whether the listing has ‘legal effect, which in turn is a function of the agency’s intention to bind either itself or regulated parties.’” 

In March 2013, Auxilium’s submitted its own Citizen Petition to FDA incorporating by reference many of the arguments raised by AbbVie.  Meanwhile, in March 2014, Perrigo launched a lawsuit against FDA alleging that the Agency shirked a statutory duty by failing to timely act to update the Orange Book to add a TE rating for the company’s follow-on version of ANDROGEL that FDA approved in late January 2013 (see our previous post here).  That litigation was put on hold with FDA’s promise to address the TE rating issue by the end of July 2014.  The case was voluntarily dismissed last week with the announcement of FDA’s petition decision. 

FDA, in the Agency’s July 23, 2014 petition decision, said that the statutory authority FDA relied on in the 1979-1980 rulemaking for making TE decisions – before the 505(b)(2) process was created in September 1984 by the Hatch-Waxman Amendments – “continues to be sound as it relates to products approved pursuant to 505(b)(2) NDAs.”  And as to whether TE ratings continue to be advisory in nature and AbbVie’s (and Auxilium’s) arguments to the contrary?  They are still advisory, concluded FDA:

The Agency’s reasoning in the 1979-1980 notice-and-comment rulemaking, that TE ratings are advisory and the listing is not binding, still stands.  As in 1979-1980, the listing today neither determines the legal rights of any drug manufacturer or distributor, nor imposes any requirement or restriction upon any person. . . .  [I]ncorporation of FDA’s advisory TE ratings into other laws and reimbursement schemes, which are not administered by FDA, does not make TE ratings binding for purposes of determining whether any additional process, such as notice-and-comment rulemaking, is required under the APA.  The case law you rely on for your argument that TE ratings create a binding legal effect [(i.e., Tozzi)] is not directly relevant to the question of whether the process available in a given context is sufficient.

Instead, FDA cites to another, more recent case, Nat’l Ass’n of Home Builders v. Norton, 415 F.3d 8 (D.C. Cir. 2005), where the D.C. Circuit held “that materials promulgated by a Federal agency did not create a binding effect, even though the materials were adopted by local governments as part of a permitting process.”

The bulk of FDA’s petition decision is dedicated to explaining why the Agency decided to grant an AB rating to Perrigo’s testosterone gel drug product and a BX rating to Teva’s drug product.  You can read the details of FDA’s decisons in the petition response, but the conclusions are right there on pages 29 and 32:

FDA has determined that the Perrigo topical testosterone gel product is therapeutically equivalent to AndroGel 1%.  The Perrigo topical testosterone gel product is: (1) approved as safe and effective; (2) pharmaceutically equivalent to AndroGel 1% in that the products (a) contain identical amounts of the same active ingredient in the same dosage form and route of administration, and (b) meet applicable standards of strength, quality, purity, and identity; (3) bioequivalent to AndroGel 1%; (4) adequately labeled; and (5) manufactured in compliance with CGMP regulations. . . .

[T]he Teva topical testosterone gel product has not been demonstrated to be bioequivalent to AndroGel 1% because the study results fall outside the range for demonstrating bioequivalence.  Thus, FDA has assigned a TE rating of “BX” to the Teva topical testosterone gel product because the data that have been reviewed by the Agency are insufficient to determine TE to AndroGel 1%.

Whether there will be a showdown in court over FDA’s legal determination that there is no need to conduct a rulemaking under the APA before deciding on whether or not to grant a TE rating to a drug product approved pursuant to FDC Act § 505(b)(2) remains to be seen.  We’re keeping a close eye on the court docket.  

By Ricardo Carvajal & JP Ellison –

The Vermont Public Interest Research Group ("VPIRG") and Center for Food Safety ("CFS") filed a motion to intervene in the lawsuit challenging Vermont’s new law requiring labeling for foods produced with genetic engineering (see our prior posting here).  VPIRG and CFS (collectively Applicants) contend that the lawsuit “threatens to upend” the new law, thereby “negating Applicants’ extensive efforts and severely injuring their core organizational missions as well as the personal interests of thousands of their members.” 

The memorandum in support of the motion details VPIRG’s grassroots campaign and other efforts mounted in support of the bill – including the provision of supporting materials and testimony regarding the law’s constitutionality.  It also references CFS’s “work with dozens of states on GE labeling legislation.”  Applicants thereby claim a “clear interest in the continuing constitutional viability” of the law.  Applicants also claim their members have “strong interests” that support intervention, including their “need to know whether foods they eat and feed their families are genetically engineered for health, environmental, economic, and other reasons.”

Applicants further argue that Vermont’s representation of their interests might not be adequate because of the state’s “serious financial concerns regarding the cost of [the] litigation” – reportedly estimated to cost between $1 million and $5 million.  As noted in the memorandum, the law created a fund to collect donations in part to pay for the law’s defense.  The balance of that fund has risen from $15,000 on June 9 (according to Applicants) to over $100,000 on July 11 (according to the fund’s Facebook page).

 By Jay W. Cormier & David B. Clissold —

Although an apple a day idiomatically keeps the doctor away, it appears true to one federal judge that one bad apple (or in this case three) really does spoil the bunch. 

As we previously reported here, in 2011, Lorillard, Inc., Lorillard Tobacco Company, and R.J. Reynolds Tobacco Company sued the FDA, DHHS, Kathleen Sebelius, Margaret Hamburg, and Lawrence Deyton seeking declaratory and injunctive relief to bring the membership of the Tobacco Products Scientific Advisory Committee (“TPSAC”) and the membership of the Constituents Subcommittee of the TPSAC into compliance with applicable laws, and to prevent the defendants from taking any action based on any report or advice provided by the TPSAC or the Constituents Subcommittee.  Among the reports issued by TPSAC, perhaps none has the potential for spurring more effect and controversy than the 2011 “Menthol Report,” which concluded in part that “removal of menthol cigarettes from the marketplace would benefit public health in the United States.”

Monday, in a scathing rebuke to FDA, the United States District Court for the District of Columbia issued its summary judgment ruling, stating that FDA violated the Administrative Procedure Act and the Federal Advisory Committee Act when it appointed three members because they were consultants to pharmaceutical companies developing nicotine replacement therapies and were involved in tobacco-related litigation. 

Congress enacted a specific conflict of interest provision applicable to members of the TPSAC. 21 U.S.C. § 387q(b)(1)(C).  The court initially noted that even the plaintiffs did not allege that the three members violated that conflict provision “because this provision only contemplates conflicts arising from one perspective: it bars voting members from receiving any remuneration from tobacco industry businesses.”

Nevertheless, the court felt compelled to examine whether other laws applicable to special government employees ("SGEs") precluded these three members from serving on the TPSAC due to financial conflicts of interest.  Under the circumstances presented in this case, the court agreed with plaintiffs that the three members’ participation in certain TPSAC activities had a “direct and predictable effect” on their financial interests.  FDA claimed that it had conducted extensive screenings of each TPSAC member and had determined that there was no conflict of interest presented by members’ consulting work.  Discussing FDA’s assertion that these members had no competing financial interest due to their consulting work, Judge Richard J. Leon’s reaction was simple:  “Please!”   He ruled that such a “conclusion defies common sense” and that FDA exhibited a “clear error in judgment.”  With respect to the three members’ participation in tobacco litigation, the Court concluded that when individuals have “repeatedly” testified in litigation against tobacco industry and had commitments to do so in the future, FDA acted arbitrarily and capriciously when it nonetheless appointed such individuals to the TPSAC.  The court noted that “numerous commentators and media outlets” had publicly questioned the impartiality of these appointments.  Expanding upon the conflicts provisions of the Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), which expressly disqualifies any member who received “any salary, grants, or other payment or support” from any tobacco company in the 18 months before serving on the TPSAC, Judge Leon wrote that “it stands to reason that past remuneration from direct competitors of those companies, such as manufacturers of smoking-cessation drugs, would also constitute a conflict of interest.”

As a result, the Court concluded that appointment of those members to the TPSAC “fatally” and “irrevocably tainted its composition and its work product.”  The court found that the TPSAC findings and recommendations, including the Menthol Report, “are, at a minimum, suspect, and, at worst, untrustworthy.”  Accordingly, the Court instructed FDA to appoint an entirely new TPSAC constituted of interest-free members and barred FDA from using the TPSAC’s Menthol Report.

FDA is not obligated to follow the recommendations of its advisory committees, including TPSAC.  Indeed, in April 2014 FDA announced that it is conducting its own review of all the information regarding menthol, including the Menthol Report.

Nevertheless, potentially the biggest winner here, at least in the short term, may be Reynolds, which earlier this month offered to purchase its fellow-plaintiff, Lorillard, for $25 billion in cash, a move that, if approved by anti-trust regulators, will dramatically increase Reynolds’ portfolio of menthol-containing tobacco products. 

FDA and the other defendants have 60 days to file a notice of appeal.  Given the significance and breadth of the ruling, we expect that a notice of appeal will be filed.

By Michelle L. Butler –

On July 21, 2014, the Department of Health and Human Services (“HHS”)/Health Resources and Services Administration (“HRSA”) announced the availability of an interpretive rule titled “Implementation of the Exclusion of Orphan Drugs for Certain Covered Entities Under the 340B Program,” which is scheduled to be published in the Federal Register on July 23, 2014. 

In its Notice announcing the availability of the interpretive rule, HHS stated that, as the court “decision did not invalidate HHS’s interpretation of the orphan drug exclusion,” “there still is a need for HHS to clarify its interpretation of how the orphan drug exclusion in the 340B Program should be implemented to be consistent with [the statute].”  Consequently, HHS issued an interpretive rule, which states that HHS

interprets section 340B(e) of the Public Health Service Act as excluding drugs with an orphan designation only when those drugs are transferred, prescribed, sold, or otherwise used for the rare condition or disease for which the drug was designated under section 526 of the Federal Food, Drug, and Cosmetic Act (FFDCA) Section 340B(e) does not exclude drugs that are transferred, prescribed, sold, or otherwise used for conditions or diseases other than for which the drug was designated under section 526 of the FFDCA.

Interpretive Rule, at 6.

In articulating the reasons for its interpretation, HHS discussed the purpose and effect of the Orphan Drug Act and the orphan drug exclusion in the Public Health Service Act.  HHS stated that “it is appropriate to construe the orphan drug exclusion consistent with FDA’s longstanding interpretation of the orphan drug provisions of the FFDCA – distinguishing the use of a drug for an orphan indication from its use for other (non-orphan) indications.”  Id. at 4.  Moreover, HHS stated that ‘[i]nterpreting the statutory language to exclude all uses of drugs with an orphan designation, including indications for other (non-orphan) diseases and conditions would nullify the benefits of the expansion of the 340B Program” for newly-eligible entities.  Id. at 5.  Accordingly, HHS “concluded that interpreting the statutory language to exclude all indications for a drug that has an orphan drug designation would be contrary to the Congressional intent of section 4340B(e) to balance the interests of orphan drug development and the expansion of the 340B Program to new entities.”  Id. 

According to the Notice, the effective date for the interpretive rule will be the date of publication in the Federal Register.  HRSA’s website contains information pertaining to implementation of the orphan drug exclusion, including orphan drug lists to be used to “assist all stakeholders in complying with HRSA’s policy.” 

HHS/HRSA’s decision to implement its interpretation of the statute as an interpretive rule appears to set the stage for another round of judicial review.  As previously described, in May, in a suit brought by the Pharmaceutical Researchers and Manufacturers of America (“PhRMA”), the United States District Court for the District of Columbia vacated HHS’s substantive rule on the orphan drug exclusion on the ground that HHS did not have the authority to promulgate its rule as a substantive rule.  Having reached its decision on this ground, the court did not come to a final decision on whether the rule could be upheld as interpretive, but seemed skeptical of the argument and invited further briefing on the subject.  PhRMA subsequently filed a motion requesting briefing on the matter of an interpretive rule, which HHS opposed as moot in light of its decision to issue “new, separate interpretive guidance.”  HHS argued in its opposition that any challenge to HHS’s interpretive guidance would be a challenge to “new agency action,” which would require a new suit or amendment of the complaint to include such a new claim.  Last week, PhRMA filed a reply brief to its request for briefing on whether the rule “(however packaged) can survive as an interpretive rule,” particularly in light of HRSA statements that PhRMA argues demonstrate the binding effect HRSA appears to intend for the interpretive rule to have.  We will continue to monitor the developments in this case as HHS/HRSA and PhRMA continue their battle over the orphan drug exclusion.

By Alexander J. Varond —

FDA recently released its report entitled “Complex Issues in Developing Drugs and Biological Products for Rare Diseases and Accelerating the Development of Therapies for Pediatric Rare Diseases Including Strategic Plan: Accelerating the Development of Therapies for Pediatric Rare Diseases.”  The report fulfills the requirements set out in PDUFA V and in Section 510 of FDASIA, which require FDA to hold a public meeting to discuss ways to encourage and accelerate the development of new therapies for pediatric rare diseases (“PRDs”), and to issue a report that includes a strategic plan for encouraging and accelerating such therapies See our previous posts here and here).

FDA’s 86-page report summarizes the difficulties facing sponsors of drugs for PRDs, outlines legislation and approaches to expedite and accelerate rare disease medical product development, provides an overview of the three-day workshop held on January 6-8, and sets forth FDA’s strategic plan.  The first two days of the workshop focused on “complex issues in developing drug and biological products for rare diseases,” while the third day focused on “complex issues in developing medical devices for pediatric patients affected by rare diseases.”

FDA noted that its strategic plan is not a legislative wish list, but is instead an outline of what FDA can reasonably achieve under its existing authority to encourage and accelerate the development of new therapies for PRD.  The report includes a helpful summary of FDA’s strategic plan that we include here:

Objective 1:  Enhance foundational and translation science for PRD

• Drugs/biologics strategies
• Facilitate the conduct of natural history studies for PRD
• Publish draft guidance on common issues in rare disease drug development
• Device strategies
  • Identify unmet PRD needs in medical device development
  • Refine and expand the use of computational modeling
  • Explore the use of registry data for use in both premarket and postmarket evaluation of medical devices intended for pediatric populations

Objective 2:  Strengthen communication, collaboration and partnering for PRD within and outside FDA

• Drugs/biologics and devices strategies
• Continue to foster interagency (public-public) and public-private partnerships
• Continue to foster international collaborations
• Continue to foster Intra-Agency collaborations

Objective 3:  Advance the use of regulatory science to aid clinical trial design and performance for PRD

• Drugs/biologics strategies
• Develop additional FDA guidance relevant to PRD
• Increase engagement of the Study Endpoints and Labeling Development (SEALD) Staff early in instrument development to navigate COA process
• Facilitate increasing the knowledge of biomarkers and COAs useful for PRD, including engaging with investigators and organizations in biomarker and clinical outcome qualification programs to advise during their development
• Develop training programs for pediatric clinical investigators
• Explore modeling and simulation approaches  (e.g., physiologically-based pharmacokinetic [PBPK] models) to provide preliminary data for drugs used in PRD to inform the design and conduct of PK/PD studies and other clinical trials for investigational drugs in PRD population
• Device strategies
• Develop expedited approval pathway for certain devices intended to treat unmet medical needs
• Evaluate the results of an analysis of approved medical devices to explore the feasibility of shifting some premarket data requirements to the postmarket setting for future medical devices
• Support the development of Medical Device Development Tools to improve clinical trial performance
• Develop curriculum for undergraduate/graduate studies to increase understanding of regulatory approval process for device development
• General strategies
• Use FDA web-based resources to update and expand awareness of PRD product development issues
• Increase awareness in pediatric rare disease researchers, product developers, and patient community of funding opportunities through OPD grant program

Objective 4:  Enhance FDA’s review process for PRO products

• Drugs/biologics strategies
• Foster FDA’s efforts to obtain patients’ and caregivers’ perspectives for incorporation in drug development
• Further develop and implement a structured approach to benefit-risk assessment in the drug review process
• Issue Rare Pediatric Disease PRV draft guidance document
• Continue reviewer training for rare and PRD
• Explore potential for innovation in data analysis
• Device strategies
• Further develop methods to implement the incorporation of patient preferences into assessments of premarket approval and de novo classifications of devices
• Establish a patient engagement panel as part of CDRH’s Medical Advisory Committee
• Analyze the HDE process for medical devices that diagnosis and treat PRD
• Set standards for whole genome sequencing that can he used as a comparator
• General strategies
• Continue to enhance FDA’s expertise to review innovative products

By Kurt R. Karst —       

Beginning in 1999, around the time FDA issued a (still) draft guidance document on 505(b)(2) applications, and lasting until about 2009, this blogger taught an introduction to drug law course at FDA to FDAers.  The focus of my talk was – surprise, surprise – Hatch-Waxman.  Each time I arrived at the section of the talk on 505(b)(2) applications I would take a poll of participants: “How many of you have heard of the 505(b)(2) NDA?”  In 1999, 15 years after the enactment of the Hatch-Waxman Amendments, which created the 505(b)(2) NDA, and 8 years after two of my colleagues wrote what might be the first analysis of the statutory provision (see Sasinowski FJ, Scarlett T. Reliance on Phantom ANDAs to Access NDA data. Reg Affairs. 1991;3: 467-482), only a few hands in an audience of about 50 participants would be raised.  By 2009, almost every participant raised a hand.  That significant change in the familiarity with the 505(b)(2) NDA tracks industry’s use of the approval route – and which increase continues today.  Ahh, but with greater use comes greater controversy. . .  (just as as Uncle Ben would say to Peter Parker) with great power comes great responsibility.  And that’s where we begin our story today.    

In a recent response to a March 2014 citizen petition (Docket No. FDA-2014-P-0318) submitted by Antares Pharma, Inc. (“Antares”), and the subtext of which might be “make sure you get your publicly available facts straight when petitioning FDA,” FDA denied Antares’s request that the Agency refrain from approving (and withdraw) any 505(b)(2) application submitted by Medac Pharma, Inc. (“Medac”) directed to a methotrexate drug product for subcutaneous injection if such application does not reference Antares’ single-dose auto-injector OTREXUP (methotrexate) Injection, 10 mg/0.4 mL, 15 mg/0.4 mL, 20 mg/ 0.4 mL and 25 mg/0.4 mL, and that FDA order Medac to submit a new application citing OTREXUP as a listed drug (that would, of course, include certifications to any patents listed in the Orange Book for OTREXUP). 

FDA approved OTREXUP on October 11, 2013 under NDA No. 204824 for severe rheumatoid arthritis including polyarticular juvenile idiopathic arthritis, and for symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy.  That 505(b)(2) NDA, which was submitted to FDA on December 14, 2012, is identified in the Orange Book as the Reference Listed Drug (“RLD”) for an injectable methotrexate solution with a subcutaneous route of administration. 

Meanwhile, Medac was developing its own methotrexate injection drug product – a prefilled pen available in 10 strengths called RASUVO (methotrexate) Injection – for the same uses as OTREXUP.  Medac submitted its 505(b)(2) NDA No. 205776 for RASUVO to FDA just a few weeks before FDA approved OTREXUP – on September 10, 2013.  And notwithstanding Antares’ petition to stop the approval of RASUVO, FDA approved NDA No. 205776 on July 10, 2014.  Enter FDA’s intervening NDA approval policy. . . .

FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.”  21 C.F.R. § 314.101(d)(9).  FDA explained how the Agency interprets this regulation in a June 2004 response to a citizen petition (Docket No. FDA-2003-P-0338).  In that case, which concerned a then-pending 505(b)(2) application for Loratadine Tablets, 10 mg, FDA determined that an intervening NDA approval for the same drug product does not bar the Agency from approving a pending 505(b)(2) application.  Specifically, FDA ruled that 21 C.F.R. § 314.101(d)(9) “bars 505(b)(2) applications for products eligible for approval under section 505(j) of the Act only if the product described in a 505(b)(2) application may be approved via section 505(j) at the time of the application’s submission” (emphasis added).  A 505(b)(2) application submitted to FDA before the approval of another NDA – an intervening NDA – that would otherwise render the 505(b)(2) application drug product a duplicate of an approved drug is, according to FDA, unaffected by the intervening NDA approval.

More recently, FDA discussed the Agency’s intervening NDA approval policy as part of a May 17, 2012 decision granting a citizen petition to designate VELTIN (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025% (NDA No. 050803) as a second RLD in the Orange Book.  A comment submitted to FDA contended, among other things, that VELTIN could have been submitted via an ANDA given the intervening approval of NDA No. 050802 for ZIANA (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025%.  According to FDA, however:

Because there were no pharmaceutically equivalent products approved at the time that Veltin was submitted, it would not have been appropriate for the Veltin application to be submitted as a 505(j) application.  Although we approved the Ziana NDA while the Veltin application was under review, our policy is that we do not require applicants to withdraw and resubmit applications if another pharmaceutically equivalent drug product is subsequently approved.  Therefore, the 505(b)(2) NDA was an appropriate pathway for Veltin’s application.

Under othercircumstances, FDA has decided (Docket No. FDA-2008-P-0329) that the intervening approval of an NDA after the submission of an ANDA made pursuant to an approved suitability petition, and where the NDA approval renders the pending ANDA a duplicate of an approved drug, requires the generic applicant to submit a new ANDA citing the newly approved NDA drug product as the RLD.

Given the longstanding FDA policy on intervening NDA approvals as a result of the Agency’s interpretation of 21 C.F.R. § 314.101(d)(9), why would Antares petition FDA?  Antares’ petition requests may have been triggered by a January 27, 2014 Medac press release announcing FDA’s acceptance of the RASUVO 505(b)(2) NDA.  That press release did not mention FDA’s PDUFA goal date for acting on the NDA.  Ok, so without a PDUFA date, one might speculate that FDA slipped up and accepted the RASUVO 505(b)(2) NDA after the October 11, 2013 approval of OTREXUP.  But not long after Antares submitted its petition to FDA, Medac made known in a  the PDUFA date for the application: “the PDUFA date for Rasuvo is July 10, 2014.”  Based on a standard 10-month review, that meant the RASUVO 505(b)(2) NDA was submitted to FDA on September 10, 2013.  But the petition was not withdrawn.

Although Antares raised in its petition, among other things, choice of listed drug and pharmaceutical equivalence issues, all FDA needed to deny the petition was to answer one very simple question: “Is September 10, 2013 before October 11, 2013.”  According to FDA:

Antares’ claims are based on a number of erroneous assumptions, the first and foremost of which is the date of submission of Medac’s NDA.  Contrary to what Antares asserts, Medac submitted its application not after Otrexup was approved on October 11, 2013, but before Otrexup’s approval, that is, on September 10, 2013.  FDA’s policy is that when reviewing 505(b)(2) applications, FDA will not require sponsors to withdraw and resubmit applications if pharmaceutically equivalent product is approved after the application is submitted but before it is approved. That is precisely the factual situation here. . . .

Therefore, regardless of whether Otrexup is pharmaceutically equivalent to Medac’s product, Medac was under no obligation to resubmit its application and reference Otrexup.  Since it did not rely for approval on Otrexup in its application, Medac also had no obligation to certify any patents listed for Otrexup.  The date of submission of a complete 505(b)(2) NDA is the only controlling factor in this instance.  Thus, for the purposes of responding to this Petition, the Agency does not need to reach the issue of whether Otrexup is pharmaceutically equivalent to Medac’s product. [(Emphasis in original)]

By James E. Valentine* —

On July 15, 2014, FDA announced the availability of a draft guidance, titled “Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors” (“FDA Draft Information Sheet”).  When final, it will replace the Agency’s informed consent  1998 Information Sheet, “A Guide to Informed Consent,” and the related informed consent sections of “Frequently Asked Questions”. 

The proposed FDA Draft Information Sheet, builds upon its previous guidance, assisting parties involved in clinical investigations of FDA-regulated products in carrying out their responsibilities related to informed consent under 21 CFR part 50.  FDA’s recommendations cover the informed consent process, the elements of informed consent, and the documentation of informed consent.  

The basics remain unchanged, but FDA explained that it is issuing these proposed recommendations as a draft guidance because of revisions to the previous Information Sheets that respond to changes in regulation and regulatory policy, as well as to questions from external stakeholders. 

The FDA Draft Information Sheet emphasizes unique considerations for informed consent of certain vulnerable populations, including:

• Careful consideration of ethical ramifications of enrolling or excluding potential subjects when there is a language barrier between investigator and potential subjects, and ensuring the information presented is understandable to subjects who do not understand English;
• Modifications to the consent form and process when enrolling subjects with impaired consent capacity, and additional considerations to address challenges and provide safeguards for subjects who lack consent capacity;
• Safeguards for inclusion of children as subjects, explaining the framework that is based upon receiving parental permission and child assent; and
• Approaches to modification of informed consent for subjects with low literacy or numeracy.

The FDA Draft Information Sheet also provides new recommendations in other areas, including:

• Addressing the new element of informed consent for “applicable clinical trials,” the requirement to include a statement that clinical trial information and results have been or will be submitted for inclusion on www.ClinincalTrials.gov (see our previous posts on this requirement here and here);
• Determining whether review of patient records is considered part of the clinical investigations and requires informed consent;
• Discouraging subject participation in more than one clinical trial; and
• Notifying and providing study information to subjects in the events of study suspension or termination.

The FDA Draft Information Sheet comes at a time when HHS and the Office of Human Subjects Research are reviewing various ways to enhance regulations overseeing research on human subjects (see our previous post on the Advanced Notice for Proposed Rulemaking for revision to the Common Rule here).  FDA assured stakeholders that it is actively working with HHS to harmonize the Agencies’ regulatory requirements, and that the FDA Draft Information Sheet was developed as part of these efforts.

Comments on the FDA Draft Information Sheet can be submitted to FDA until September 15, 2014 here. 

* Not admitted in the District of Columbia

By Kurt R. Karst –      

Our FDA Citizen Petition Tracker is littered with petitions and petitions for reconsideration submitted to FDA over the past 18 months requesting that the Agency recognize a period of 5-year New Chemical Entity (“NCE”) exclusivity for certain Fixed-Dose Combination Drugs (“FDCs”) the Agency approved before announcing in February 2014 in a draft guidance document (and in a consolidated citizen petition decision) that FDA planned to change (but only prospectively for FDCs approved after the guidance is finalized) its interpretation of the FDC Act’s NCE exclusivity provisions to award 5-year exclusivity for a newly approved FDC containing an NCE and a previously approved drug (see our previous posts here, here, and here).  The period to comment on the draft guidance expired months ago, and there has been no indication as to when it might be finalized.  This, of course, raises the possibility that more companies will petition FDA as NDAs for FDCs are approved in the interim period.

The latest entrant to the “NCE for FDC Club” is Pfizer Inc. (“Pfizer”).  In a May 30, 2014 petition (Docket No. FDA-2014-P-0737) that was only recently made public on the federal government’s docketing system website (www.regulations.gov), Pfizer says FDA erred in not granting NCE exclusivity with respect to Pfizer subsidiary Wyeth Pharmaceuticals, Inc.’s DUAVEE (conjugated estrogens/bazedoxifene) Tablets on the basis that FDA never before approved a drug product under FDC Act § 505 containing bazedoxifene as an active moiety.  FDA approved DUAVEE on October 3, 2013 under NDA No. 022247 for use in women with a uterus for treatment of moderate to severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis, for the treatment of moderate to severe vulvar and vaginal atrophy associated with menopause, for the treatment of moderate to severe vasomotor symptoms associated with menopause, and for prevention of postmenopausal osteoporosis.  Six months later, in the March 2014 Orange Book Cumulative Supplement (published in mid-April), FDA finally made public the Agency’s decision to – not unexpectedly – award a period of 3-year new clinical investigation exclusivity.  But that doesn’t mean the decision is correct, says Pfizer. 

Similar to other “NCE for FDC Club” petitioners who have challenged FDA’s basis for denying NCE exclusivity, Pfizer argues that none of the reasons FDA articulated in the February 2014 Consolitated Petition Decision apply in this case.  Briefly, FDA said that the Agency would not immediately or retroactively apply its new interpretation of the statute’s NCE exclusivity provisions for several reasons:

First, although the relevant statutory and regulatory provisions are ambiguous, our existing interpretation of these provisions is longstanding and has been consistently applied in many prior cases presenting similar facts.  Second, the new interpretation we are proposing represents a departure from our past interpretation, and we wish to avoid any unnecessary disruption to regulated industry.  Third, if the new interpretation were to be applied to products for which ANDAs already have been filed, it could impose a burden on the ANDA sponsors, who relied on our existing interpretation in filing their applications.

In addition, we do not believe that applying our new interpretation to the Petitioners’ products would advance the goals of the Hatch-Waxman Amendments. . . . Recognizing additional exclusivity in this case is not necessary to encourage the development of novel drugs.  We believe that changing our interpretation going forward will foster Congress’s goal of encouraging the development and approval of novel drugs.  (Emphasis in original.)  

According to Pfizer:

None of the concerns articulated by FDA support denial of 5-year exclusivity for bazedoxifene.  The general presumption is that an agency will apply a new statutory interpretation adopted in the course of an administrative adjudication in that proceeding, and all subsequent adjudications.  There is no reason to depart from that general practice here.  Furthermore, none of the concerns about “retroactive” regulatory changes that might call for a different effective date are apposite here.  Certainly, FDA’s concerns about disrupting industry and burdening ANDA sponsors do not apply in the case of bazedoxifene.  Indeed, those concerns do not apply to any FDC drug products containing at least one new active moiety for which no ANDA was filed prior to the date of issuance of the Consolidated Response.  And, even as to ANDAs filed before the Consolidated Response, there is no impermissible retroactive effect on the ANDA applicants of FDA immediately applying its new policy to all cases adjudicated from that date forward, such as bazedoxifene.

There is no indication that an ANDA has been submitted to FDA for a generic version of DUAVEE.  In fact, FDA has not approved an ANDA for conjugated estrogens.  Way back in May 1997, FDA ruled in the context of PREMARIN (conjugated estrogens) Tablets, that because PREMARIN “is not adequately characterized at this time, the active ingredients of Premarin cannot now be definitively identified,” and that “[u]ntil the active ingredients are sufficiently defined, a synthetic generic version of Premarin cannot be approved.”  Instead, companies have generally pursued approval of 505(b)(2) NDAs – e.g., CENESTIN (synthetic conjugated estrogens, A) Tablets. 

Whether today, 17 years after FDA’s PREMARIN decision, FDA is willing to entertain approval of an ANDA for conjugated estrogens remains to be seen.  FDA has accepted ANDAs for conjugated estrogen drugs, as the Agency’s ANDA Paragraph IV List indicates that an ANDA was submitted for generic PREMARIN prior to March 2, 2004, and that ANDAs for generic CENESTIN were submitted in November 2008 and March 2009.  But years after these ANDA acceptances, there’s still not an approval. 

That raises the question of why NCE exclusivity for DUAVEE – and specifically for the bazedoxifene moiety – is so important to Pfizer.  An ANDA for a generic version of a drug product containing conjugated estrogens will likely be very difficult to push through FDA’s Office of Generic Drugs.  A 505(b)(2) NDA for the combination is perhaps more likely, though there is no mention of that approval route in the DUAVEE petition.  So that leaves us with bazedoxifene.  That moiety is currently under investigation for other uses according to ClinicalTrials.gov and other reports.  A grant of 5-year NCE exclusivity with respect to bazedoxifene would help extend the lifecycle of that drug if there are follow-on NDA approvals in the coming years. 

By James E. Valentine* & Sara A. Khan** –

On July 11, 2014, the House Energy and Commerce’s Subcommittee on Health held its fourth hearing, as part of its 21st Century Cures Initiative, to seek input regarding the incorporation of patient perspectives in drug development and review.  (See our coverage of two previous 21st Century Cures hearings here and here.)  The Subcommittee leadership set the tone early that the most important aspect of the 21st Century Cures Initiative is what medical innovation and faster cures mean for patients.  They also emphasized that there is a need to understand the patient perspective in order to focus on results for patients who lack adequate medical treatment options. 

The witnesses (representatives from patient groups, healthcare professional organizations, industry, and FDA) described the current state of patient input in drug development and review and highlighted models and frameworks to further integrate the patient perspective.  Recommendations for elevating the patient voice emerged as two distinct categories of “input:” (a) increasing the use of patient-reported outcomes (“PROs”) in clinical research and (b) incorporating the patient perspective, either directly or indirectly, in the drug development enterprise and throughout FDA review.

Patients as Participants in Clinical Research.  Historically, the role of patients in drug development has been limited to their role as research subjects, and measures of patient symptoms, overall mental state, or the effects of a disease on how a patient functions were captured by clinician observations or tests.  Recently, however, the medical community has begun to recognize that there is value in measuring the status of a patient’s health directly from the patient, rather than through the lens of a clinician. As such, various parties in the drug development process have begun to show an interest in incorporating PROs into clinical trials. 

As the FDA panelist at the hearing, Janet Woodcock, Director of FDA’s Center for Drug Evaluation and Research (“CDER”), discussed how CDER is working to advance development and improve the use of PROs under the Prescription Drug User Fee Act V (“PDUFA V”).  Previously, FDA did not have a rigorous process for qualifying PROs, but, now relying on the science of measurement, consortia can come to FDA to propose a PRO endpoint, if qualified (see here).  Qualified PROs, which are published on FDA’s website, are considered by FDA to be valid outcome measures that could be used to support drug labeling claims.  (We previously reported on FDA’s 2009 Guidance on review and evaluation of PROs here).  Dr. Woodcock noted that FDA is currently engaged in 79 PRO qualification projects.

Noting that in cancer drug development, certain self-reported symptoms that are measured qualitatively, such as nausea and pain, are often reported differently by physicians than by their patients, Dr. Leonard Lichtenfeld, the Deputy Chief Medical Officer of the American Cancer Society, advocated the use of PROs in all clinical trials.

Many panelists cited the lack of established and consistent methods to assess PROs as a barrier to their widespread acceptance and use.  Richard Pops, the Chairman and CEO of Alkermes, a pharmaceutical company that specializes in therapies for chronic central nervous system diseases, called for standardized methods for industry to follow when using patient-reported data.  Both Dr. Woodcock and Dr. Robert Beall, President and CEO of the Cystic Fibrosis Foundation, recommended that Congress provide federal agencies with increased resources for regulatory science, which could support efforts in this area.

The Patient Perspective in Drug Development & Review.  Of much greater interest to Subcommittee members and witnesses alike were models for incorporating the patient perspective in both industry and FDA decision-making throughout the drug development lifecycle.  As patients ultimately experience the risks and benefits of approved medical treatments, witnesses offered suggestions for increasing the patient voice in various aspects of drug development and review. 

Prior to the enactment of the Food and Drug Safety and Innovation Act (“FDASIA”), patient input in drug approval decisions was generally limited to patient representatives serving on FDA Advisory Committee meetings, which are mainly focused on approval decisions upon submission of a marketing application.  The FDA Office of Health and Constituent Affairs, in concert with the Agency’s medical product centers, recruits and trains patients to serve as Special Government Employees.  Recognizing the need to include patient input earlier in the FDA review process, Section 1137, which calls for FDA to develop and implement strategies to include the patient representatives earlier in drug review, at appropriate FDA-sponsor meetings, was included in FDASIA.  Dr. Lichtenfeld, from ACS, advocated that the FDA Patient Representative Program be expanded to include patient representatives in the review process, so that patients can provide input on risk tolerance and contribute to discussions of clinical trial design.  As Dr. Lichtenfeld pointed out, FDA Patient Representative Program would need additional resources in order to realize this goal.  The time burden for FDA to conduct conflict-of-interest screening of patient representatives is a barrier to their inclusion in FDA-sponsor meetings (i.e., pre-IND, end of Phase 2), which are scheduled under tight PDUFA-directed timeframes.  Although this barrier was not discussed at the hearing, it is important for the Subcommittee to recognize it when considering approaches to implement Dr. Lichtenfeld’s recommendation.

Dr. Woodcock described a more recent program for incorporating the patient perspective in FDA’s regulatory decision-making.  FDA committed under PDUFA V to hold at least twenty patient meetings over five years, each focused on a particular disease area, in an effort to obtain and utilize patient input in clinical trial design. This Patient-Focused Drug Development (“PFDD”) program provides an opportunity to more systematically obtain patient perspectives on how their disease impacts their daily lives, gauge the types of treatment benefits that matter most to patients, and assess the adequacy of available therapies for the disease with respect to the treatment benefits that patients desire.  Dr. Woodcock highlighted that the first meeting, which was held for patients with chronic fatigue syndrome (“CFS”) and myalgic encephalomyelitis (“ME”), resulted in a draft guidance for industry on CFS/ME drug development. 

Pat Furlong, Founder and CEO of Parent Project Muscular Dystrophy (“PPMD”), described her recent experience conducting a survey of on risk and benefit preferences in the Duchenne Muscular Dystrophy (“DMD”) community and suggested that other patient groups consider conducting similar surveys.  With FDA’s encouragement, PPMD developed and conducted the survey with the help of researchers at Johns Hopkins University.  PPMD shared the results of this study with FDA, showing that this population (parents of children with Duchenne Muscular Dystrophy, a condition that is 100% fatal at a young age) had a particularly high risk tolerance for treatment options. 

Dr. Marshall Summar, Director and Chair of the Scientific Advisory Committee for the National Organization for Rare Diseases (NORD), suggested that FDA develop guidance for patient groups to hold independent drug development meetings and present their findings to the Agency.  In the absence of such guidance, Ms. Furlong discussed PPMD’s six month effort, in collaboration with medical experts, industry, and their patient community to draft a guidance document to FDA on DMD clinical trial design and other drug development issues.  She described that their model was successful because of the structure the put in place with a multi-stakeholder Steering Committee, seven Working Groups to focus on various sections of the guidance, and an overarching Community Advisory Board, made up of DMD patient groups and patient advocates.  There was consensus among the witnesses that PPMD’s guidance development could serve as a model for other patient groups to effectively engage with FDA and industry and ultimately influence key issues in drug development. 

A final, and probably most dramatic, model for incorporating the patient perspective in drug development is for patients to provide resources that situate them as partners in drug development programs.  Dr. Robert Beall, President and CEO of the Cystic Fybrosis Foundation (“CFF”), discussed a series of investments his group made that led to the first approval of a drug for CF, as well as a second promising therapy in Phase 3 that targets a larger segment of the CF patient population.  First, in 1965, CFF created the first patient registry in the U.S., which enabled the group to collect the data that was needed to understand the natural history of the disease.  CFF also accredits health care centers, which treat 90% of all CF patients. The CFF accreditation program improves access to potential clinical research participants.  To further this goal, CFF created a CF clinical trial network, the first clinical trial network developed by a patient group, in 1998.  Finally, CFF raised funds and provided the initial investment in the biotech company developing the two drugs mentioned previously.  All of CFF’s efforts allowed for advancement in the research and development of product candidates for CF and ultimately de-risked the transition into clinical research.  CFF continues to engage with FDA on substantive regulatory and scientific issues, seen as an active partner in ongoing drug development programs.    

Piecing Together a Patient Engagement Framework.  Overall, there was consensus that patient engagement is not new, but the wide range of emerging models that further incorporate the patient perspective are advantageous to the drug development and review process.  There was also agreement that, to better incorporate patient perspectives, it is necessary to do so in a data-driven, systematic, and efficient manner.  Mr. Pops added, from the industry perspective, that the framework for patient input should not add new steps to the already complex drug development program.  Additionally, Dr. Woodcock stated that CDER believes it has the statutory authority it needs to meet the needs of expanded patient input into regulatory decision-making (although there are concerns regarding conflict-of-interest rules that are barriers to including FDA Patient Representatives in appropriate FDA-sponsor meetings).

For more information on FDA’s framework for patient engagement, Hyman, Phelps & McNamara, P.C.’s James E. Valentine presented an overview of FDA’s framework for patient engagement at the 2014 Drug Information Association Annual Meeting.  Best practices for effective engagement by industry and academia with patient groups around clinical trials will be emerging from the Clinical Trials Transformation Initiative, an FDA public-private partnership (see here).

* Not admitted in the District of Columbia
** Summer Associate