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

By Kurt R. Karst –      

We watched the World Cup final between Germany and Argentina this past weekend and were pleased with the outcome (well, at least this blogger was).  Things got pretty intense as the minutes in extra time ticked away, edging the match ever closer to a possible penalty shootout round to determine the winner.  Thankfully, Germany’s (Super) Mario Götze scored a goal in the 113th minute, giving Germany a fourth World Cup.  Zogenix, Inc. (“Zogenix”), the sponsor of ZOHYDRO ER (hydrocodone bitartrate) Extended-release Capsules, which FDA approved on October 25, 2013 under NDA No. 202880 for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, was not so lucky in its latest match against Massachusetts Governor Deval Patrick.  Last week, the U.S. District Court for the District of Massachusetts issued a decision allowing in part and denying in part the company’s Motion for a Preliminary Injunction, while denying the Commonwealth’s Motion to Dismiss (opposition briefs are available here and here).  Zogenix had hoped to score a total victory against the Commonwealth, but the court’s ruling means that we are likely far off from naming a winner in this match.

As we previously reported (here and here), Zogenix first sued Massachusetts Governor Deval Patrick and other Commonwealth officials after the Massachusetts Department of Public Health (“DPH”) and its Commissioner, Cheryl Bartlett, RN, took actions to combat opioid overdose, including granting DPH “emergency powers” to, among other things, ban the prescribing and dispensing of ZOHYDRO ER.  Zogenix filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction alleging that the Commonwealth’s ban on ZOHYDRO ER is unconstitutional because the ban violates the Supremacy Clause, the dormant Commerce Clause, and the federal Contracts Clause of the U.S. Constitution.  Shortly thereafter, the district court found that Governor Patrick’s March 27, 2014 Declaration of Emergency and the March 27th order of the Commissioner of the Department of Public Health banning the sale and distribution of ZOHYDRO ER obstructed FDA’s Congressionally-given charge.  The court allowed Zogenix’s motion for preliminary injunctive relief and enjoined, until April 22, 2014, the Commonwealth from taking any action to implement or enforce the declaration and order.

Though down, the Commonwealth was not out.  Commonwealth officials went right to work after the district court’s decision to come up with emergency regulations that might pass muster under a preemption analysis.  The result was the announcement of an April 22, 2014 emergency order from DPH Commissioner Bartlett and an emergency regulation promulgated by the Board of Registration in Medicine (“BORIM”) requiring an individually licensed prescriber to do the following before prescribing “a hydrocodone-only extended release medication that is not in an abuse deterrent form” (i.e., ZOHYDRO ER):

(a) Thoroughly assess the patient, including an evaluation of the patient’s risk factors, substance abuse history, presenting conditions(s), current medication(s), and a check of the online Prescription Monitoring Program;

(b) Discuss the risks and benefits of the medication with the patient;

(c) Enter into a Pain Management Treatment Agreement with the patient that shall appropriately address drug screening, pill counts, safe storage and disposal and other requirements based on the patient’s diagnoses, treatment plan, and risk assessment;

(d) Supply a Letter of Medical Necessity as required by the Board of Registration in Pharmacy that includes the patient’s diagnoses and treatment plan, verifies that other pain management treatments have failed, indicates that a risk assessment was performed and that the licensee and the patient have entered into a Pain Management Treatment Agreement; and

(e) Document 243 CMR 2.07(25)(a)-(d) in the patient’s medical record.

Other ZOHYDRO ER regulations followed in the coming weeks.  First, On May 6, 2014, the Board of Registration in Pharmacy (“BORIP”) promulgated two regulations (here and here) saying that “[a] certified pharmacy technician, pharmacy technician, pharmacy technician trainee, or pharmacy intern may not handle [ZOHYDRO ER],” and that before dispensing ZOHYDRO ER a pharmacist must satisfy a bevy of prerequisites,  including: (1) storing Zohydro in a locked cabinet; (2) dispensing Zohydro in a container with a child-proof safety cap; (3) reviewing the Letter of Medical Necessity; (4) including a warning about Zohydro’s dangers; (5) providing counseling on various issues; and (6) checking the patient’s history on the Prescription Monitoring Program.  Second, on May 8, 2014, the Board of Registration of Physicians Assistants (“BOROPA”) promulgated a set of regulations identical to the ones BORIM passed two days before.  These and the previous April 2014 regulations are referred to generally in court papers as the “Letter of Medical Necessity (‘LMN’) regulation” and the “pharmacist-only regulation.”

Zogenix filed a Motion for Preliminary Injunction on May 23, 2014 arguing that the new slate of regulations have the cumulative effect of creating an implicit ban on ZOHYDRO ER (i.e., obstacle preemption) and therefore “suffer[] from the same preemption problem as the first ban the Court already enjoined.”  Zogenix also alleged that the regulations violate the Contract Clause and the Commerce Clause of the U.S. Constitution, as well as the Equal Protection Clause “by singling out Zohydro™ ER for draconian restrictions not applicable to any other extended-release opioid products.”  (Nearly a doppelgängerof the counts Zogenix lodged in the company’s initial court papers filed in April.)

The Commonwealth shot back with a Motion to Dismiss. 

The Boards’ emergency regulations are not preempted by the [FDC Act] because, as the FDA itself has repeatedly acknowledged, States retain their traditional authority to regulate the medical and pharmacy professions, including the prescribing and dispensing of medications.  Nor do these emergency regulations begin to constitute an “effective ban” on Zohydro.  As the FDA Commissioner has indicated, they are instead reasonable requirements consistent with both best medical practices and longstanding parallel federal and state responsibilities in the field of drug regulation.  And Zogenix’s class-of-one equal protection claim is equally unavailing, because (1) the claim is not available in the circumstances present here, (2) critical elements of the claim are not (and cannot be) alleged, and (3) clear rational basis exists for the Board’s emergency regulations.

The Commonwealth also argued that Zogenix lacked standing to bring the suit and that the case should be dismissed for lack of subject matter jurisdiction.

In her July 8th decision, Judge Rya W. Zobel zeroed in on the essence of the case: obstacle preemption.  (Judge Zobel gave short schrift – the German spelling – to Zogenix’s Equal Protection Clause argument, saying “[t]hat argument is misplaced.”  Similarly, Judge Zobel did not consider Zogenix’s Contract Clause and the Commerce Clause arguments, saying that they were “undeveloped.”)  But to make such a preemption analysis, Judge Zobel she must do what the U.S. Supreme Court instructed in Savage v. Jones, 225 U.S. 501 (1912): “assess whether the regulations prevent the accomplishment of the FDCA’s objective that safe and effective drugs be available to the public.”  Her assessment: the LMN regulation is ambiguous and unclear, and the pharmacist-only regulation is uncertain. 

By any reckoning, the text of the “LMN regulation” is ambiguous.  Exactly what “pain management treatments” must fail before a doctor may prescribe Zohydro?  Plaintiff believes other opioids must fail.  Defendants do not believe a physician must prescribe other opioids before she may prescribe Zohydro. . . .  [I]f the Commonwealth interprets its regulation to make Zohydro a last-resort opioid, it undeniably makes Zohydro less available.  That presents a constitutional problem.

The “LMN regulation” is unclear in another way.  How long ago must the “other pain management treatments” have failed? . . .  If the Commonwealth interpreted its regulation to require a fresh failure as a precondition to each 30-day Zohydro prescription, it would severely frustrate Zohydro’s availability and pose significant constitutional concerns.

As for the “pharmacist-only regulation,” the parties rely on competing affidavits.  In a sealed declaration, Zogenix co-founder and Chief Executive Officer Roger L. Hawley discloses that unspecified major retail pharmacy chains do not plan to stock Zohydro because the “pharmacist-only regulation” is “fundamentally incompatible with personnel infrastructure and established policies for dispensing ER/LA opioids.”  Defendants present the affidavit of Michael Reppucci, R. Ph., owner of and pharmacist at Inman Pharmacy in Cambridge, Massachusetts.  Reppucci states that because BORIP already regulates pharmacy technicians, “prohibiting any pharmacy technicians from transporting and handling Zohydro does not add any substantial administrative burden or present substantial logistical problems.”  Neither party directs the court to any pharmacy’s announcement that it will or will not carry Zohydro.

Given the uncertainty as to how the Commonwealth might interpret and enforce the regulations, and a lack of an enforcement record on which to assess whether there is a case for obstacle preemption, Judge Zobel allowed Zogenix’s motion to preliminarily enjoin the LMN regulation, but with the caveat that “[i]f defendants provide adequate and constitutional guidance to physicians regarding the prerequisites for prescribing Zohydro in compliance with the regulation, then they may thereafter move to lift the injunction.”  On the other hand, with respect to the pharmacist-only regulation, Judge Zobel concluded that “[b]ecause its sealed declaration does not provide sufficient detail that pharmacies will not carry Zohydro, plaintiff has not met its burden of proof on the “pharmacist-only regulation,” and that Zogenix’s Motion for a Preliminary Injunction “is denied without prejudice to renewal upon a more detailed submission.”

So it’s not quite “goodbye” to this controversy, but rather – and quite literally – “auf Wiedersehen” (until we meet again).

By Ricardo Carvajal –

FDA released data for its Total Diet Study (TDS) covering the period from 2006 to 2011.  Under the TDS, FDA collects data on levels of pesticide residues, industrial chemicals, toxins, and nutrients present in foods to monitor changes in the levels of those substances and help the agency evaluate potential risks to public health.  Because the TDS is intended to monitor levels of those substances in foods as consumed, FDA collects samples for the study by shopping at grocery stores and restaurants around the U.S.

FDA cautions that “[i]ndividuals who intend to use either the data summaries or individual analytical results are urged to review all the information” on the study design and data collection “to ensure a good understanding of the study and the data” – perhaps an effort to discourage armchair analysts from casually perusing the data and jumping to erroneous conclusions.  FDA’s bottom line advice: consumers should “eat a varied, well-balanced diet, consistent with the Dietary Guidelines for Americans.”  Nonetheless, the updated data could reveal trends of interest.  One such result is pointed out by FDA in its news release: “the agency found statistically significant declines in sodium contents of several processed foods.” 

It’s July, and that means the American Bar Association (“ABA”) has initiated the annual process for selecting the top legal blogs (or “blawgs”) in the blogosphere.  The 8th iteration of the list will be revelaed later this year when the ABA announces the “Blawg 100” in the print and electronic versions of the ABA Journal.  The ABA’s initiation of the selection process also means that we at the FDA Law Blog once again need to go to the well and ask our loyal readers to nominate us for the Blawg 100.  With your help, we’ve made the top 100 list three times before.  We would like nothing more than to make the 2014 list so that we can add another badge to the “Awards and Honors” collection posted on our blog webpage.  So here’s our best Arnold Horshack “Ohh, Ohh, Ohh . . . Choose me” plea for nominations. 

To nominate the FDA Law Blog for the 2014 Blawg 100, readers should use the Amici Form – available here – supplied by the ABA and submit a friend-of-the-blawg brief.  Although it’s called a brief, it’s not legal in nature.  In fact, you only have 500 characters to say why you’re a fan of the blog.  Remember, when you complete the nomination form, our URL is www.fdalawblog.net.  Friend-of-the-blawg briefs are due no later than than 5 PM ET on Friday, August 8, 2014.  (That’s the same day one of your Blogmeisters is scheduled to be at Uhuru Peak of Mt. Kilimanjaro; so while he’s literally on top of the world – or at least the roof of Africa – you can figuratively keep the Blogmeisters flying high and on top of the world by timely submitting your nomination.)  ABA editors make the final decisions about what blogs to include in the Blawg 100.  We hope they’ll be impressed with what our readers have to say about us.  Thank you!

By Kurt R. Karst –      

Earlier this week, and just a day after the second anniversary of the 2012 FDA Safety and Innovation Act that, among other things, includes the Generic Drug User Fee Amendments (“GDUFA” ), FDA announced the release of two draft guidance documents that explain how the Agency (and the Office of Generic Drugs in particular) intends to implement the rather complex ANDA amendment and Prior Approval Supplement (“PAS”) provisions and performance metric goals contained in the Program Performance Goals and Procedures (“Commitment Letter”) accompanying GDUFA.  The draft guidances, along with pre-recorded webinars (here and here) and slides (here and here), come less than three months before the October 1, 2014 date when GDUFA goes into full effect, and when the generic drug industry will be forever changed.

The amendment and PAS provisions of the Commitment Letter – and the amendment provisions in particular – are not for the faint of heart.  You’re left scratching your head after the first readthrough of the Commitment Letter wondering how this system is going to work, but by the tenth readthrough things begin to start sinking in.  And the two new draft guidances – ANDA Submissions – Prior Approval Supplements Under GDUFA and ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA – go a long way to elucidate how the submission system will work under GDUFA, and provide several very helpful real-world examples.

Let’s start with a few basics from GDUFA and the Commitment Letter, and some concepts shared among both draft guidances before moving on to some specifics from each draft guidance:

• ANDAs are now categorized according to cohort year (i.e., FY 2015, FY 2016, FY 2017).  PASs are also identified by the fiscal year of submission, but the term “cohort year” is not specifically used to refer to a particular submission year.
• Once an original ANDA is in a particular cohort year based on the original submission date made through FDA’s electronic gateway (see our previous post here), dates of submission of an amendment to that original ANDA do not change the cohort year.   In other words, if you submit your original ANDA in FY 2015, that application will forever be a cohort year 3 ANDA.  The same holds true for a PAS fiscal year submission. 
• FDA agreed to review and act on 60% of original ANDA submissions within 15 months from the date of submission for the year 3 cohort (FY 2015); 75% of original ANDA submissions within 15 months from the date of submission for the year 4 cohort (FY 2016); and 90% of original ANDA submissions within 10 months from the date of submission for the year 5 cohort (FY 2017). 
• FDA agreed to review and act on 60% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2015; 75% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2016; and 90% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2017. 
• Acting on an original ANDA and PAS includes issuance of a Complete Response (“CR”) letter, an approval letter, a tentative approval letter, or a refuse-to-receive action.
• The date of submission of an original ANDA or PAS is calculated in months beginning on the receipt date of arrival of the submission in the electronic submission gateway.  For example, if a complete PAS (not requiring an inspection) is submitted on November 3, 2014, the 6-month GDUFA goal date for FDA review and action is May 2, 2015.  Note that this calculation differs from the goal date calculation under the Prescription Drug User Fee Act.
• The 15-month and 10-month base period action dates for cohort year 3-5 ANDAs can change (i.e., are incremental and can be recalculated to a longer period/date) based on the type and number of amendments submitted to FDA and how they are tiered (i.e., Tier 1, Tier 2, and Tier 3).  Similarly, the 6-month and 10-month base period action dates for PASs can be recalculated.  GDUFA established certain review goals for the various types and tiers of amendments that are fully explained (with examples) in the draft guidances.

ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA:  The draft guidance delves into the details of the various categories of amendments to an original ANDA or PAS.  The number, classification, and tier group of amendments can affect FDA’s goal date for acting on an original ANDA or PAS, as well as the need for an inspection.  Amendments to an original ANDA or PAS are classified as solicited, unsolicited, or administrative.  Solicited amendments are identified as major, minor, or as an Easily Correctable Deficiency (“ECD”).  Unsolicited amendments are identified as delaying and non-delaying.  In addition, amendments are grouped as Tier 1, Tier 2, or Tier 3.  Together, they result in the matrix below from the draft guidance.

A solicited amendment is a submission made by an applicant in response to a CR letter.  The classification of such an amendment as major or minor (or as an ECD) is largely a matter of FDA discretion.  Nevertheless, FDA applies the following general principles, which are further explained with examples in appendices to the draft guidance:

• “Major amendments contain a substantial amount of new data or new information not previously submitted to or reviewed by FDA, requiring, in FDA’s judgment, a substantial expenditure of FDA resources.  In general, the type, quantity, or complexity of data contained in a major amendment requires a lengthy review by FDA, and consults from other divisions or offices may be required to complete the review.”
• “FDA review of a minor amendment requires, in FDA’s judgment, fewer FDA resources than are necessary to review a major amendment, but more than are necessary to review the information submitted in response to an ECD.”
• “FDA review of information submitted in response to an ECD requires, in FDA’s judgment, a modest expenditure of FDA resources.  An applicant should be able to respond to an ECD quickly as the applicant should already possess or be able to quickly retrieve the information needed for an adequate response to an ECD.”

Unsolicited amendments, which are either delaying (Tier 1) or non-delaying (Tier 2), are submitted on an applicant’s own initiative and not in response to a CR letter.  As FDA explains, “[d]elaying amendments address actions by a third party that would cause delay or impede application review or approval timing and that were not a factor at the time of submission. ”  Thus, for example, “if a [citizen petition] requests certain [bioequivalence] data be submitted to support an ANDA for a particular drug product and FDA grants that petition, an ANDA applicant may submit the [bioequivalence] data reflected in the [citizen petition] response prior to FDA’s request of the data from the ANDA applicant.”  In contrast, non-delaying amendments “are unsolicited amendments that contain information that is not requested by FDA and is not the result of changes to the RLD or USP monograph, changes to the RLD labeling, a REMS and REMS modification, or generic approval requirements reflected in citizen petition responses issued by FDA.”  Finally, administrative amendments “are routine in nature and do not require scientific review.”  They do not fall within the tier matrix, and therefore do not affect GDUFA action dates.

The draft guidance also provides instructions for applicants that want to challenge FDA’s classification of an amendment by requesting reconsideration:

• “If an applicant is requesting reconsideration of a CR amendment, the applicant will submit a written request for a post-CR-letter meeting within 10 business days from issuance of the CR letter. . . .  The division will issue a decision about the request for reconsideration and notify the applicant of the decision within 10 business days from the date of the meeting.”
• “If an applicant wishes to request reconsideration of a change in classification that occurred after submission of the applicant’s CR amendment, the applicant should submit a request for reconsideration within 10 business days from issuance of the goal letter. . . .  The division will notify the applicant of the decision within 10 business days from the date the request for reconsideration was received.”

ANDA Submissions – Prior Approval Supplements Under GDUFA:  This draft guidance, which should be read in conjunction with the first draft guidance, addresses various topics in relation to PASs to approved ANDAs, including how the GDUFA performance metric goals apply to a PAS subject to the refuse-to-receive standards, a PAS that requires (or does not require) an inspection, and PAS amendments.  (It bears noting that the statutory and regulatory criteria for submitting information to an ANDA as a PAS – or as a changes being effected supplement, or as an annual reportable change – based on a major, moderate, or minor change were not altered by GDUFA.  These reporting criteria should not be confused with FDA’s categorization of amendments as major or minor.) 

Most ANDA sponsors have experienced at some point in time a delay in the approval of a submissions to FDA because of an “expired” inspection.  But FDA explains in the draft guidance that in some cases the Agency will cut sponsors some slack:

FDA intends to continue the practice of using a risk-based assessment in determining the need for an inspection, guided by a 2-year cycle for finished dosage product sites and a 3-year cycle for API sites and consideration of the type of finished product or API in the application.  Practically, this means that in making decisions about pending supplemental applications for which FDA does not have current inspection information within the time period indicated, FDA may use previous FDA inspection information and/or use inspection information from another regulatory authority as appropriate.  If FDA determines that an actual inspection is not required, the goal date would be revised from 10 months to 6 months.

The draft guidance also explains FDA’s approach to so-called “grouped supplements” – i.e., “multiple supplements (typically five or more) submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application.”  FDA says that each supplement in the group is considered an indivdual submission assessed a separate PAS user fee (with generally the same GDUFA goal date).  Alternatively, an ANDA sponsor may want to consider submitting a PAS with a comparability protocol outlining the change and the support for it.  “Once the PAS is approved, the agreed-upon reporting category could be used.  Thus, at the time the PAS containing the comparability protocol is approved, FDA can designate, where appropriate, a reduced reporting category for future reporting of changes covered by the approved comparability protocol (e.g., from a PAS to a CBE-30 supplement).”  This means that while the GDUFA performance metric goals and applicable user fees would apply to the initial PAS, they would not apply to future supplements submitted under the reduced reporting category.  What a deal (or not), depending on what’s more important to you – time or money.  (Though time is money, no?)