By Alexander J. Varond –

In a recent FDA Voice blog post, titled “More Collaboration, Research Needed to Develop Cures,” FDA discusses the speed of drug discovery and development.  The blog post also references a white paper released the same day, titled “Targeted Drug Development:  Why Are Many Diseases Lagging Behind?”  The white paper briefly describes “the state of scientific knowledge and its effect on drug development in four key disease areas other than cancer and HIV/AIDS.”  These disease areas are:  (1) Alzheimer’s disease, (2) diabetes, (3) rare diseases, and (4) hepatitis C.  We provide snippets from the white paper on each of the disease areas below.  For the anxious reader, FDA’s topline answer to the question it presents in the title of its white paper is: there is “inadequate scientific understanding of specific diseases.”

Before getting to the particular disease areas, we note that, when taken in the context of the current legislation before Congress (e.g., 21st Century Cures Act), the blog post and white paper seem to indicate a degree of defensiveness on the part of FDA.  The blog post, in particular, begins by stating that FDA’s drug approval process “is the fastest in the world.”  It then relates that “[w]hen research does not offer answers to important scientific questions, cures cannot be developed.  And when viable cures are not in the pipeline, focusing on regulation will not improve the situation . . . .”

While it is true that basic science and research is necessary to advance the understanding of diseases and develop cures, the conclusion that “focusing on regulation will not improve the situation” is too dismissive.  Even a cursory review of the 21st Century Cures Act reveals myriad examples of new regulation that will help therapies already in the pipeline by, for example, helping to calibrate benefit-risk profiles from patient input.  There have also been countless examples in the past, including providing new incentives to drug sponsors and expressly allowing the approval of drugs on the basis of a single study with confirmatory evidence.

The blog post and white paper also confound unvalidated surrogate endpoints with validated surrogate endpoints and conflict with a recent analysis that shows that FDA has not, in fact, used the accelerated approval pathway and unvalidated surrogates widely or to its full potential.  While the white paper states that “between 50% and 60% of rare disease therapies were approved on the basis of surrogate endpoints,” this number likely includes approvals using validated surrogates (drugs approved on the basis of validated surrogates are granted “full” approval rather than accelerated approval) and therapies for cancer and HIV/AIDS.  In reality, fewer than 20 therapies for non-cancer, non-HIV/AIDS indications have been approved on the basis of unvalidated surrogates via the accelerated approval pathway.  In fact, both the 2012 President’s Council of Advisors on Science and Technology report, entitled “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation,” and FDASIA have exhorted FDA to increase its use of unvalidated surrogates to approve therapies via the accelerated approval pathway.

FDA’s effort to take stock of these four disease areas is admirable—after all, each of the disease areas represents a very clear opportunity to broadly improve public health.  However, the conclusion that everyone must “continue to work together to improve our understanding of disease and the tools to translate scientific discovery into cures” (which could be seen as supporting the 21st Century Cures’ proposal for increases in funding to NIH) should be expanded.  New legislation and regulatory tools for FDA would be an important step toward developing new cures.

Below, we provide an overview of FDA’s discussion on each of the four disease areas:

Alzheimer’s disease

“For all but rare genetic forms of the disease . . . scientists have not yet confirmed that any potential biomarkers can accurately identify individuals who have Alzheimer’s, predict its clinical progression in specific patients, identify successful drug targets, or identify subsets of patients who might respond differently to different treatments.  Thus far, promising biomarkers, when tested, have all failed to predict clinical improvement. . . .  FDA is helping to facilitate development of potential treatments for the disease by allowing surrogate endpoints to support product approvals, encouraging the use of enrichment designs in clinical trials, and collaborating with the healthcare community on the development of biomarkers.”

Diabetes

“Although the major factors associated with the development of diabetes are generally understood, the exact genetic, molecular, and environmental causes of both type 1 and type 2 diabetes remain to be discovered. . . .  Without this information, it is not yet possible to develop drugs targeted to prevent or treat diabetes in particular patients.  And it remains necessary to test new diabetes drugs in a broader patient population. . . .  Despite scientists’ incomplete understanding of diabetes and its causes, FDA has long allowed manufacturers to show that a diabetes drug works by using a simple surrogate endpoint: lowered blood sugar.”

Rare diseases

“Scientific understanding about the causes of rare diseases—those affecting fewer than 200,000 patients–varies by disease.  For many . . . rare diseases . . . basic research is lacking, which limits scientists’ understanding of their causes or how to intervene in their progression.  As a result, we lack drug targets and biomarkers that can be used to help make clinical trials more efficient and successful.  Nevertheless, FDA is actively engaged in helping companies speed development of potential treatments for rare diseases by designing trials that address the challenges of small patient populations and novel endpoints.”

Hepatitis C

“For decades, hepatitis C infection was poorly understood . . . however, the knowledge and technology developed in the massive research effort on the HIV/AIDS virus helped unravel the genetic and molecular bases for other viral infections.  Since 2011, FDA has been approving targeted treatments for hepatitis C, and in December 2013, FDA approved the most dramatic improvement in therapy to date.  The targeted drug Sovaldi provides a greater than 90% virologic cure rate in the hepatitis C genotypes for which it is approved, has manageable side effects, and does not require co-administration of interferon for most patients.”

Each of the four disease states discussed in FDA’s white paper points out that FDA has, in fact, been able to make at least incremental progress despite imperfect understanding of the diseases.  Thus, legislation that gives FDA additional ways to do what it has already done (i.e., approve important drugs for these critical disease areas despite limited understandings of the underlying disease processes) should be encouraged.

By James C. Shehan & Kurt R. Karst –

On July 21, 2015, a fractured Federal Circuit issued its decision in the dispute between Amgen and Sandoz concerning various statutory issues under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  In a result that few would have predicted, the Court upheld Sandoz’s position that the complicated exchange of information provisions known as the “patent dance” is a voluntary process that biosimilar (also referred to as an “aBLA”, or abbreviated Biologics License Application) applicants may or may not partake in, but also upheld Amgen’s position that a biosimilar applicant’s notice to the holder of the reference product of an intention to begin commercial marketing in 180 days can occur only after the biosimilar is licensed.  The implications of this decision are manifold, including potentially freeing Zarxio, Sandoz’s biosimilar version of Amgen’s Neupogen (filgrastim), for a September launch; however, the implications will only be fully fleshed out in future court decisions and approvals.  And among those court decisions may be an en banc decision of the Federal Circuit on an appeal of this decision, and perhaps even a Supreme Court decision. 

We’ve extensively covered the Amgen-Sandoz melee in previous posts (see here and here).  In essence, it’s a patent infringement lawsuit that cannot be litigated until certain regulatory law matters are settled first.  Two main issues were in front of the Federal Circuit, on an appeal of a March 19, 2015 decision by U.S. District Court for the Northern District of California.  One was the district court’s determination that the patent dance is a voluntary process that a biosimilar applicant may or may not choose to follow.  The other was the district court’s determination that a biosimilar applicant may give notice of commercial marketing under 42 U.S.C. § 262(l)(8)(A) before FDA approval.

The decision of the Court was written by Judge Lourie.  Judge Lourie’s respect for the complexity of the BPCIA may my gleaned from his first footnote.  In it, he calls Winston Churchill’s characterization of Russia as “a riddle wrapped in a mystery inside an enigma” as an apt description of the BPCIA and then notes his desire to “unravel the riddle, solve the mystery, and comprehend the enigma.”  Alas, that effort seems to have failed.  On the patent dance issue, he conceded that the relevant language read in isolation indicates that the patent dance is mandatory.  But he found that the provision must be viewed in the context of the entire statute, and in that matter he found two other provisions dispositive – 42 U.S.C. § 262(l)(9)(C) and 35 U.S.C. § 271(e).  

The first provision (42 U.S.C. § 262(l)(9)(C)) provides that if a biosimilar applicant fails to provide the reference product sponsor with its application and the other patent dance information, then the reference product sponsor (but not the biosimilar applicant), may bring a declaratory judgment action for patent infringement.  The second provision (35 U.S.C. § 271(e)) states that it is an act of infringement for a biosimilar applicant to fail to provide the biosimilar application and other information required by the patent dance provisions to the reference product sponsor.  Taken together, these provisions were found by Judge Lourie to indicate that biosimilar applicants have two options under the law: exchange information with the reference product sponsor, or forego the patent dance and take the chance that the sponsor will sue under any applicable patent.  Specifically, Judge Lourie wrote that:

read in isolation, the “shall” provision in paragraph (l)(2)(A) appears to mean that a subsection (k) applicant is required to disclose its aBLA and manufacturing information to the RPS by the deadline specified in the statute.  Indeed, the BPCIA refers to such information as “required” in other provisions.  See 42 U.S.C. § 262(l)(1)(B)(i), (l)(9)(A), (l)(9)(C); 35 U.S.C. § 271(e)(2)(C)(ii).  Particularly, paragraph (l)(1)(B)(i) provides that “[w]hen” a subsection (k) applicant submits an aBLA to the FDA, “such applicant shall provide . . . confidential access to the information required to be produced pursuant to paragraph (2) and any other information that the subsection (k) applicant determines, in its sole discretion, to be appropriate” (emphases added).  Thus, under the plain language of paragraph (l)(1)(B)(i), when an applicant chooses the abbreviated pathway for regulatory approval of its biosimilar product, it is required to disclose its aBLA and manufacturing information to the RPS no later than 20 days after the FDA’s notification of acceptance, but not when the “when” criterion is not met. . . .

We therefore conclude that, even though under paragraph (l)(2)(A), when read in isolation, a subsection (k) applicant would be required to disclose its aBLA and the manufacturing information to the RPS by the statutory deadline, we ultimately conclude that when a subsection (k) applicant fails the disclosure requirement, 42 U.S.C. § 262(l)(9)(C) and 35 U.S.C. § 271(e) expressly provide the only remedies as those being based on a claim of patent infringement. Because Sandoz took a path expressly contemplated by the BPCIA, it did not violate the BPCIA by not disclosing its aBLA and the manufacturing information by the statutory deadline.

Judge Lourie’s decision on 180-day notice follows similar logic.  He found licensure is required before an “operative notice” of commercial marketing can be given.  Addressing whether such notice is mandatory or optional, he stated that because the statute provides no option for what happens if notice is not given (unlike, in his opinion, the patent dance provisions), the 180-day notice is mandatory.  Specifically, according to Judge Lourie: 

We believe that Congress intended the notice to follow licensure, at which time the product, its therapeutic uses, and its manufacturing processes are fixed. When a subsection (k) applicant files its aBLA, it likely does not know for certain when, or if, it will obtain FDA licensure.  The FDA could request changes to the product during the review process, or it could approve some but not all sought-for uses.  Giving notice after FDA licensure, once the scope of the approved license is known and the marketing of the proposed biosimilar product is imminent, allows the RPS to effectively determine whether, and on which patents, to seek a preliminary injunction from the court. . . .

We therefore conclude that, under paragraph (l)(8)(A), a subsection (k) applicant may only give effective notice of commercial marketing after the FDA has licensed its product. The district court thus erred in holding that a notice of commercial marketing under paragraph (l)(8)(A) may effectively be given before the biological product is licensed, and we therefore reverse its conclusion relating to its interpretation of § 262(l)(8)(A) and the date when Sandoz may market its product.

Judge Newman concurred in part and dissented in part.  She agreed essentially without comment with Judge Lourie on the 180-day notice issue.  But she disagreed with Judge Lourie on the patent dance issue, stating that the process is mandatory.  In support of her position, she found that the balance in the BPCIA “requires the statutorily identified disclosures at the threshold, in order both to avert and to expedite litigation.”  Her rejoinder to Judge Lourie’s argument regarding subsection (l)(9)(c) is that that clause exists to distinguish product and use patent infringement claims from method of manufacturing claims, not to provide a wholly separate option to the patent dance. 

Judge Chen dissented from Judge Lourie’s ruling on 180-day notice, believing that that it is “part and parcel” of the patent dance and, like the rest of the patent dance, is optional.

The holdings of the three Circuit Court Judges on each of the two significant issues on appeal are summarized in the following table:

Where do we go from here?  In harmony with its opinion, the Federal Circuit has continued the injunction against a Zarxio launch through September 2, 2015.  Absent further court orders, Sandoz could launch Zarxio in the United States after that injunction expires. 

The implications of this case – and the Federal Circuit’s decision (if it stands) – are fascinating.  At a glance, it seems to point to an easier path to market for biosimilars by making a lengthy and uncertain patent dance merely an option.  And that might be true for the initial batch of biosimilar applications for which there is not a particularly robust patent portfolio remaining.  However, for newer biological products with a robust patent portfolio, biosimilar applicants may, in fact, choose to engage in the patent dance in an effort to winnow down the number of patents to litigate.  In this respect, the Federal Circuit’s decision enures to the benefit of reference product sponsors, because the lasting effect of the Court’s decision on the patent dance may be far less than that of the commercial notice part of the decision, which seems to result in a de facto 12.5-year period of exclusivity for reference product sponsors (or, in the case where there is no longer a 12-year period in effect, a new 6-month exclusivity period).  (Judge Lourie apparently does not think that this is the case.  He notes that some but not all biologics will have a 12.5-year period of exclusivity and makes reference to applications filed “during the 12 year exclusivity period.”  From this, one can speculate that he believes that FDA can approve an application during the 12 years, or perhaps that notice of commercial marketing could be given after a tentative approval a la Hatch-Waxman.)  During the 180-day notice period there presumably would be ample time for a reference product sponsor to seek and obtain an injunction against launch of a biosimilar, with the added weight of being able to argue that such an injunction would not disturb the status quo.  

Further court orders are certainly possible, if not likely.  A decision as fractured as this one greatly increases the likelihood of a successful appeal by one or both parties asking the Federal Circuit to re-decide this case en banc.  Whether an en banc appeal request is granted or not, a certiorari request to the U.S. Supreme Court is also likely, and this case may well be interesting enough to draw the closer scrutiny of the Justices.   

By Riëtte van Laack –

On July 14, the House Agriculture Committee approved The Safe and Accurate Food Labeling Act (H.R. 1599), advancing the legislation another step in the long legislative process.   The Act is an amended version of legislation introduced in March by Representative Mike Pompeo (R-KS).   (a copy of the report accompanying the bill is available here.) 

The proposed Act is intended to address labeling of genetically engineered (here referred to as “GMO”) foods.  Importantly, the Act would preempt state GMO labeling efforts and block states or local jurisdictions from imposing bans on GMO crops.  It aims at creating a “uniform national policy” for GMO labeling.  The preemption clause addresses the possible threat to interstate commerce resulting from a patchwork of state GMO labeling laws.  As explained in a report accompanying H.R. 1599:

Section 303 of this Act amends Section 403(A) of the FFDCA, as amended by section 103 of this Act, by requiring that no State or political subdivision of a State may directly or indirectly establish under any authority or continue in effect as any food in interstate commerce any requirement for the labeling of food of the type required by section 403(z) that is not identical to the requirement by such section.

The proposed Act would order the Agricultural Marketing Service of the USDA (AMS) to develop a voluntary National Genetically Engineered Food Program for non-GMO claims similar to the Organic Certification Program administered by AMS.  It specifies that labeling or advertising material on, or in conjunction with, non-GMO products may not suggest that they are safer or of higher quality than their GMO counterpart (unless FDA has determined that there is a material difference and the GMO product must be labeled).  

The bill would also make FDA’s current voluntary consultation process for producers of GMO foods mandatory.  It specifically provides FDA with the authority to require GMO labeling of a food if the Agency determines that  “(A) there is a material difference in the functional, nutritional, or compositional characteristics, allergenicity, or other attributes between the [GMO] food . . . and its comparable food; and “(B) the disclosure of such material difference is necessary to protect public health and safety or to prevent the label or labeling of the food so produced from being false or misleading in any particular.”

The bill addresses details such as how to deal with processing aids and enzymes and specifies that milk and meat products would only be certified as non-GMO if the animals have been fed non-GMO feed.

The Act also would require FDA to issue regulations regarding natural claims and specifies that natural claims encompass the terms “natural” “100% natural,” “naturally grown,” “all natural,” and “made with natural ingredients.” FDA is to issue final regulations for such claims not later than 30 months after the date of enactment of the Act.

By Wes Siegner –

In 2005, FDA published a Dietary Supplement Labeling Guide that, among other things, provided guidance on whether the words “Dietary Supplement” by themselves satisfied the requirement that the front panel of all dietary supplement products include a statement of identity.  FDA’s answer?  “No. This term by itself is not appropriately descriptive to be a statement of identity.”  FDA cited 21 CFR § 101.3(g) as authority for its position. 

As we have pointed out in a 2009 blogpost on this issue, FDA’s guidance position is in obvious conflict with the Federal Food, Drug, and Cosmetic Act (FDC Act), as well as with FDA’s preamble to the cited regulation, where FDA explained that the words “Dietary Supplement” are sufficient as the statement of identity for a dietary supplement.  That blogpost, titled “FDA Confirms that the Term ‘Dietary Supplement’ Is a Legal Statement of Identity for Dietary Supplement Products and that FDA Guidance to the Contrary is in Error; State Regulators may Remain Confused and Have Taken Enforcement Action,”  followed a struggle to resolve a multi-state investigation of a client over a variety of labeling issues, including accusations from the states that the company was violating FDA’s erroneous guidance.

We had hoped that our discussions with FDA leading to the prior blogpost might encourage FDA to fix the guidance and put an end to the matter.  We were wrong.  Recently we learned that plaintiffs’ lawyers are citing FDA’s erroneous guidance in class actions against dietary supplement manufacturers.  We learned of this problem when we were notified that the links in our 2009 blogpost to FDA’s erroneous guidance and an FDA press release cited in the blogpost were no longer functional. 

For those who continue to be plagued by FDA’s error, here we update those links:

• Dietary Supplement Labeling Guide: Chapter II. Identity Statement
• FDA 3/23/99 Press Announcement — Dietary Supplements Now Labeled With More Information Summary of Nutrition Labeling Rules for Dietary Supplements and Sample Labels 

FDA has developed “good guidance practices” and in 2011 issued a self-promotional report on FDA’s guidance practices titled “Food and Drug Administration Report on Good Guidance Practices: Improving Efficiency and Transparency.”  Pursuant to these “good guidance practices,” FDA frequently updates and revises its guidance documents.  Here however, after 10 years and even though senior FDA officials in FDA’s Food Center are (or were in 2009) aware of this significant error, FDA appears to have no desire to fix this mistake. 

All of which begs the question:  can incorrect guidance be “good guidance”?

By Kurt R. Karst –      

As the years go by and nostalgia creeps in, we reminisce about the past and how things were “back then” (which to this blogger means the 1980s and 1990s).  It’s not that things were necessarily better “back then,” they were just different.  Take a gander at the National Geographic Channel’s “The ‘80s: The Decade That Made Us” or “The ‘90s: The Last Great Decade?” as this blogger did this past weekend and you quickly get a sense of what we mean. Nostalgia and reminiscence will envelope you.  We’re not advocating a return to an era of big hair, shoulder pads, leg warmers and when David Hasselhoff ruled the airwaves, but there’s something heartwarming – something quaint – about those simpler times. 

As a food and drug attorney, I have plenty of opportunities to indulge in the past.  Take, for example, FDA Summary Basis of Approvals (“SBAs”).  (An SBA is defined in an FDA regulation as a “document that contains a summary of the safety and effectiveness data and information evaluated by FDA during the drug approval process;” however, the term is often used to refer more generally to what is known today as a “Drug Approval Package” or an “Action Package” (see FDA MAPP 4520.1).)  We recently had a reason to look over some old SBAs.  Maybe it’s the old typeface (from an old word processor), the magic marker redactions, the cut-and-paste data tables, the unreadable (and unsearchable) pages of text (stamped with “BEST POSSIBLE COPY”), the hand written notes (and signatures), or the hand-drawn and oddly artistic lettering of the cover pages separating each SBA section in many SBAs (see below), but there’s some level of comfort in seeing these things – particularly when compared to the regimented SBA structure and rules in place today. 

One SBA component to which this blogger has always paid close attention is the “Exclusivity Summary” (also sometimes referred to as the “Exclusivity Checklist”).  The earliest version of that document we have seen dates back to a July 1990 revision, but was apparently developed in the 1980s according to a recent FDA response to a series of Citizen Petitions (see here at page 7).  Since then, the document, known generically as “Form OGD-011347,” and which we understand was a sort of homemade piece, has evolved with technology, but only rarely with changes in the law.  (At one time, there was an html version of the document titled “Exclusivity Checklist” that was completed by FDA.)       

The one clear constant with the “Exclusivity Summary” are the three component parts, which are intended to track and simplify changes made to the law by the 1984 Hatch-Waxman Amendments:

PART I – IS AN EXCLUSIVITY DETERMINATION NEEDED?

PART II – FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES

PART III – THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS

Changes in the law and the need for greater granularity have resulted in small changes and updates to the “Exclusivity Summary.”  For example, the following question appeared in Part I as late as August 2000: “e) Has pediatric exclusivity been granted for this Active Moiety?”  Later, FDA added the following clarification after that question: “If the answer to the above question in YES, is this approval a result of the studies submitted in response to the Pediatric Written Request?”  (Emphasis in original.)

The text of Parts II and III of the “Exclusivity Summary” in place today is virtually identical to the text in place in 1990.  This is so notwithstanding significant changes in the law adding new types of exclusivity (e.g., GAIN Act exclusivity) or clarifying how exclusivity can be applied under certain circumstances (e.g., enantiomers of previously approved racemates), and an evolution in FDA’s interpretation of the law.  The current “Exclusivity Summary” (see here at pdf pages 23-30) takes none of this into account, leaving questions unanswered, or the need to add comments.  Take, for example, combination drug products.  FDA’s recent reinterpretation of the law (see our previous post here) provides that NCE exclusivity is now available for newly-approved combination drugs containing an NCE and a previously approved drug.  Despite this, the current “Exclusivity Summary” includes the same questions in place when FDA interpreted the law to preclude an award of NCE exclusivity for certain combination drugs containing an NCE:

2. Combination product.

If the product contains more than one active moiety (as defined in Part II, #1), has FDA previously approved an application under section 505 containing any one of the active moieties in the drug product? If, for example, the combination contains one never-before-approved active moiety and one previously approved active moiety, answer “yes.”  (An active moiety that is marketed under an OTC monograph, but that was never approved under an NDA, is considered not previously approved.)

                                                                                      YES /_/  NO /_/

If “yes,” identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s).

IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS “NO,” GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary should only be answered “NO” for original approvals of new molecular entities.) IF “YES” GO TO PART III.

In at least one instance, this required a FDA reviewer to clarify the award of NCE exclusivity:

NDA 205718 contains netupitant, a new chemical entity, in combination with palonosetron, a previously approved active moiety. Under the Agency’s new interpretation described in the Agency’s Guidance for Industry, New Chemical Entity Exclusivity for Certain Fixed-Combination Drug Products, a drug substance is eligible for 5-year exclusivity, provided it meets the regulatory definition of new chemical entity, regardless of whether that drug substance is approved in a single-ingredient drug product or in a fixed-combination with another drug substance that contains no previously approved active moiety, or in a fixed-combination with another drug substance that contains a previously approved active moiety. This NDA is thus eligible for 5-year new chemical entity exclusivity pursuant to the new interpretation.

Though quaint, the current version of the “Exclusivity Summary” is, like shoulder pads and big hair, outdated.  It needs a serious makeover to make the document useful.  At the very least, a revised “Exclusivity Summary” should include questions or information on all non-patent exclusivities available under the FDC Act.  For example, it should identify whether orphan drug designation and exclusivity was granted (and, in cases of clinical superiority, the basis for such a decision).  And in the case of generic drugs, it should identify whether 180-day exclusivity was granted or eligibility for such exclusivity forfeited. 

Why the “Exclusivity Summary” has gone without a makeover for so long while other important FDA forms, such as the Agency’s “RPM Filing Review” and associated “505(b)(2) Assessment,” have been revised significantly is unclear.  Until a significant change is made, the “Exclusivity Summary” is really just a relic of a bygone era – a reminder of the days when Hatch-Waxman was more simple. 

Hyman, Phelps & McNamara, P.C. (“HP&M”) is happy to announce that five of the firm’s attorneys have been named “Super Lawyers” in the Washington, D.C. area in the 2015 Washington DC Super Lawyers Magazine.  Super Lawyers is a rating service of outstanding lawyers from more than 70 practice areas who have attained a high-degree of peer recognition and professional achievement.  Super Lawyers are selected based on a multi-phased process that includes independent research, peer nominations, and peer evaluations.  Congratulations go to HP&M’s Robert A. Dormer, John R. Fleder, Jeffrey N. Gibbs, Frank J. Sasinowski and Jeffrey K. Shapiro, who are recognized in the Food & Drugs practice area (pages 39-40).

By Alexander J. Varond –

On July 10, 2015, the U.S. House of Representatives passed the 21st Century Cures Act.  In all, there were 344 “yes” votes and only 77 “no” votes, with half of the “yes” votes coming from Republicans and the other half coming from Democrats.  We have blogged on the 21st Century Cures Act here and here.  In addition, the House has provided a two-page summary and a section-by-section summary of the current legislation.

Although the overall 21st Century Cures Act is not the topic of this blog post, we give its passage in the House prominence here because it includes the most developed proposal for the renewal of FDA’s rare pediatric disease priority review voucher program (Pediatric PRV program).  We have blogged extensively on the Pediatric PRV program, including here and here.  Without congressional action, FDA will be unable to grant Pediatric PRVs after mid-March 2016 (see our post on the program’s sunset here).

Recall that the Pediatric PRV program was developed as a means to encourage the development of therapies to treat rare diseases that primarily affect children.  Since the program’s inception in 2012, three sponsors have received Pediatric PRVs.  Pediatric PRVs have been issued for: 

1. Vimizim (elosulfase alfa) for mucopolysaccharidosis type IVA (a rare, severely debilitating and progressive disease);
2. Unituxin (dinutuximab) for high-risk neuroblastoma (a rare pediatric cancer); and
3. Cholbam (cholic acid) for bile acid synthesis disorders due to single enzyme defects and for peroxisomal disorders (including Zellweger spectrum disorders) (both inborn errors of metabolism).

(See our posts on each of these grants here, here, and here.)

Industry has taken considerable interest in the Pediatric PRV program.  After all, the most recent priority review voucher sold for an incredible $245 million dollars.  Here is a rundown of the publicly announced sales of priority review vouchers to date: 

Table 1: PRV Sales Data

Despite significant interest in the Pediatric PRV program, thereis concern related to the program’s unpredictable availability.  Stated another way, companies do not know whether the Pediatric PRV program will be reauthorized or how long it will be authorized for.  This uncertainty has had a considerable chilling effect.

A Change in the Proposed Legislation.  The most recent version of the 21st Century Cures Act pegs the sunset of the program to the date on which a sponsor files its marketing application (so long as the drug is also designated as a drug for a rare pediatric disease prior to the sunset date).  In the past, a sponsor’s marketing application had to be approved by the sunset date.  This small change is significant—it creates more certainty because it does not subject sponsors’ eligibility to unpredictable delays in the review process.

Below, we catalogue the current law and recent proposals for reauthorizing the program.

Table 2:  Pediatric PRV Sunset Provisions (Current Law and Recent Proposals)

A Proposal for a Different Sunset Date.  Short of significantly increasing the duration of the program or making it permanent, it would be helpful if future legislation used a different sunset date.  As the status quo demonstrates, timing on the reauthorization of the program is unpredictable and unpredictability can be costly.  Therefore, instead of designating an arbitrary sunset date (e.g., December 31, 2018), the sunset date of the Pediatric PRV program could be tied to the sunset date of the Prescription Drug User Fee Act (PDUFA) authorization (e.g., September 30, 2022).  

By tying the sunset of the Pediatric PRV program to the sunset date of PDUFA authorization, the Pediatric PRV program would have a predictable platform on which it could be reauthorized.  With the predictable timing of PDUFA reauthorization, the timing of the Pediatric PRV program’s reauthorization would also be more predictable.  As a result, sponsors could plan better and invest more in developing the therapies that the program intends to encourage—therapies for rare pediatric diseases.

By James C. Shehan –

On July 9, 2015, Representatives Matt Salmon (R- AZ), Paul Gosar (R-AZ) and Marlin Stutzman (R-IN) introduced H.R. 3012, the Right to Try Act of 2015. The bill seeks to expand the access of terminally ill patients to experimental drugs in a novel way, by prohibiting the federal government, including FDA and DEA, from taking action to stop such access.

The bill is short and straightforward.  It simply states that, notwithstanding any law, including the Federal food, Drug, and Cosmetic Act, the federal government shall not take “any action to prohibit or restrict the production, manufacture, distribution, prescribing, dispensing, possession, or use of an experimental drug, biological product, or device that – (1) is intended to treat a patient who has been diagnosed with a terminal illness; and (2) is authorized by, and in accordance with, State law.  An “experimental product” is defined as one that “has successfully completed a phase 1 clinical investigation,” remains under investigation in an FDA-approved clinical trial, and is not FDA “approved, licensed, or cleared.”   The term “terminal illness’’ is defined as the meaning given to such term under relevant State law.

The legislation is viewed by at least one of its sponsors, Rep. Stutzman, as complementary to state right to try laws.  These laws (see our previous post here) also allow doctors, patients and companies to bypass FDA’s regulations.  But given the reluctance of companies to violate regulations that require prior FDA approval of expanded access, these laws are not being regularly used. 

Whether this bill if passed would change this situation is unclear.  On the one hand, it bars FDA from doing something that it almost never does – denying access to an experimental drug to a terminally ill patient.  On the other hand, by preventing FDA from taking any action to stop access, it potentially undermines FDA’s entire expanded access regulatory regime.  Although the bill does not mention the companies that make experimental products, the bill could be interpreted as prohibiting FDA from taking enforcement action against anyone who ignored the expanded access regulations, including the companies.  Whether FDA would agree with that interpretation and whether companies would decide to not seek FDA approval in the face of such ambiguity remains to be seen. 

By Etan J. Yeshua –

Last week, FDA announced that it will be extending by one year the compliance date for its menu labeling rule.  This means that restaurants and other establishments covered by the rule, and by the menu labeling provisions of the Affordable Care Act (ACA), now have until December 1, 2016 to post calories and other information on their menus and menu boards, provide full written nutrition information in-store, and come into compliance with the rule’s other requirements.  The Agency also announced that it plans to issue a draft guidance document to provide “answers to some of the more frequently asked and crosscutting questions that the agency has received” about the rule.  The announcement followed requests by some in industry and on Capitol Hill for such a delay and for additional guidance.

Earlier, FDA had rejected requests for delaying enforcement past December 1, 2015.  In its proposed rule, FDA specified that the final rule would become effective six months from the date of its publication.  When the final rule was published on December 1, 2014, the Agency said it agreed with comments it received that called for a later enforcement date, and it announced a one-year compliance window, ending on December 1, 2015.  In that preamble, the Agency said it believed a compliance date longer than one year was unnecessary: “We disagree that an effective date over 1 year (such as 18 months or 2 years, as suggested by [some] comments) is necessary.  Many comments seeking a longer effective date focused on the need to train employees.  Such training does not need to wait until all implementation activities are complete.”  The Agency added that “we have no information that could assist us in considering whether or how much additional time might be appropriate.”

Since then, there have been repeated calls for FDA to delay enforcement and/or to revise or clarify certain of the rule’s requirements.  For example, in May 2015, 32 U.S. Senators sent a letter to FDA requesting a one-year delay citing “outstanding questions regarding the details of how the final rule will be applied to certain covered entities” and the need for “clear and consistent guidance” as well as “adequate time to understand and come into compliance with the regulations.”  In addition, legislation that would both delay enforcement of the rules and revise the statutory requirements of the ACA’s menu labeling provisions has been introduced in Congress.  More recently, language was added to a draft House Appropriations bill (pages 84-85) and report (page 67) that “directs the FDA to implement the final rule no earlier than December 1, 2016, and at least one-year following agency publication of related guidance to newly regulated stakeholders.”  Some in industry have been calling for a delay as well, and in its announcement last week, FDA cited its “extensive dialogue with chain restaurants, covered grocery stores and other covered businesses.”

FDA noted that specific information in four requests it received from “large retailer and trade and other associates” justified the compliance date extension:

[T]he requests describe steps involved in developing software, information systems, and other technologies for providing nutrition information in ways that better correspond to how foods are offered for sale in covered establishments and allow for more efficient and product specific nutrition labeling. In addition, the requests describe steps involved in training staff, implementing standard operating procedures, and developing and installing updated and consistent menu boards across all locations within a chain. Most requests sought to extend the compliance date by 1 year. In light of these requests, we have decided to extend the compliance date for the final rule to December 1, 2016.

By Alexander J. Varond –

FDA recently issued its final rule on permanent discontinuance or interruption in manufacturing of certain drug or biological products.  To those familiar with the proposed rule issued in 2013, a review of the final rule will not bring many surprises.  We discussed the proposed rule and FDA’s “Strategic Plan for Preventing and Mitigating Drug Shortages” here.

The final rule requires “all applicants of covered approved drugs or biological products—including certain applicants of blood or blood components for transfusion and all manufacturers of covered drugs marketed without an approved application—to notify FDA electronically of permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (or a significant disruption in supply for blood or blood components) of the products in the United States.”

Ongoing Effort to Address Drug Shortages

The rule represents the latest step in an ongoing effort to address drug shortages in the United States.  Recall that President Obama, in 2011, issued an Executive Order to address the issue.  We blogged on that here.  That same year, the Government Accountability Office released a report finding that FDA needed increased authority to address the growing problem of drug shortages.  We blogged on that here.  Congress then amended the Federal Food, Drug, and Cosmetic Act (FDCA) (via FDASIA), in 2012, and further addressed the drug shortage issue.  Our summary of FDASIA can be found here.

FDASIA amended the FDCA to give FDA the authority to require all manufacturers of certain drugs to notify FDA six months in advance of a permanent discontinuance or interruption in manufacturing.  It also required FDA to maintain a list of drugs in shortage.  This is FDA’s shortage list in its current incarnation.  Finally, FDASIA gave FDA the authority to apply its drug shortage provisions to biological products.  FDA’s final rule implements FDASIA’s changes and substantively modifies 21 C.F.R. §§ 310.306, 314.81(b)(3)(iii), and 600.82.

Recent Statistics on Drug Shortages

FDA notes in its preamble to the final rule that although the number of drug and biological product shortages quadrupled from approximately 61 in 2005 to more than 250 shortages in 2011, the number of shortages has decreased in the last several years.  The preamble reports the following figures:

Table 1:  Drug Shortages

Thus, it appears that the increase in early notifications to FDA that began as a result of the 2011 Executive Order (Executive Order 13588) has enabled FDA to work with stakeholders to prevent shortages.  FDA reports the following statistics:

Table 2:  Drug Shortages Prevented

According to FDA, these shortages were prevented by using such tools as, working with manufacturers to resolve manufacturing and quality issues, expediting FDA inspections and review of submissions to prevent shortages, identifying and working with manufacturers willing to initiate or increase production to cover expected gaps in supply, and exercising regulatory flexibility and discretion under certain circumstances.

Final Rule

The final rule requires that a covered entity notify FDA in writing of a permanent discontinuance of manufacture or interruption in manufacturing that is likely to lead to a meaningful disruption in the supply of a product that is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition.  Radiopharmaceuticals are excluded from these requirements.  Notably, a meaningful disruption does not include interruptions such as routine maintenance “so long as the manufacturer expects to resume operations in a short period of time.”

The final rule defines “life support or life sustaining” as “essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life.”  “Intended for use in the prevention or treatment of a debilitating disease or condition” is defined as “intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-to-day functioning.”  In the preamble to the final rule, FDA notes that this definition is different than the Agency’s definition of “medically necessary,” which it uses in its Manual of Policies and Procedures on shortages.

The rule defines “product” in a way that significantly increases the frequency with which covered entities must notify FDA.  That is, a covered entity must notify FDA of a discontinuance or interruption for specific strengths, dosage forms, and routes of administration.  FDA provides an example:

[I]f Applicant X experiences an interruption in manufacturing of the 50-milligram (mg) strength of a drug product that would be subject to § 314.81(b)(3)(iii), but the 100-mg strength continues to be manufactured without delay, under the rule, Applicant X must notify FDA of the interruption in manufacturing of the 50-mg strength if the interruption is likely to lead to a meaningful disruption in the applicant’s supply of the 50-mg strength.

Thus, when determining whether an interruption in manufacturing is likely to lead to a meaningful disruption in supply, triggering the notification requirement, a manufacturer or applicant may only consider whether the manufacturing disruption will affect the manufacturer’s own ability to meet demand for its product – even if the manufacturer has such a small market share that its disruption is unlikely to affect the market as a whole.

The final rule applies to the following covered entities:

• All applicants with an approved NDA or ANDA for a covered drug product;
• All applicants with an approved BLA for a covered biological product, other than blood or blood components;
• Applicants with an approved BLA for blood or blood components, if the applicant is a manufacturer of a significant percentage of the U.S. blood supply; and
• All manufacturers of a covered drug product marketed without an approved NDA or ANDA in its entirety to covered drug products marketed without an approved NDA or ANDA).

With regard to timing, notifications must be submitted electronically to FDA:

• At least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing; or
• If 6 months’ advance notice is not possible because the permanent discontinuance or interruption in manufacturing was not reasonably anticipated 6 months in advance, as soon as practicable thereafter, but in no case later than 5 business days after the permanent discontinuance or interruption.

Such notifications must include the name of the product and applicant, whether the notification relates to a permanent discontinuance or interruption, a description of the reason for the permanent discontinuance or interruption, and an estimated duration of the interruption.

Covered entities that fail to submit adequate notification will be issued a noncompliance letter from FDA informing the entity of its failure to adequately notify FDA.  The covered entity will then have an opportunity to respond.  If FDA does not find that the covered entity had a reasonable basis for failing to adequately notify FDA, the Agency will make the letter and the applicant’s response to the letter public.  As we noted when the proposed rule was issued, while the Agency’s ability to publicize violations is generally one of its most powerful and well-utilized enforcement tools, it may be comparatively weak in this context, where the unfavorable publicity seems unlikely to expose a violative company to private litigation in the absence of extenuating circumstances.

By Ricardo Carvajal –  

The White House Office of Science and Technology Policy (OSTP) directed the three federal agencies charged with ensuring the safety of biotechnology products (FDA, USDA, and EPA) to undertake a review intended to “improve the transparency, predictability, coordination, and, ultimately, efficiency of the biotechnology regulatory system.”  The review will consist of three elements: an update to the Coordinated Framework for the Regulation of Biotechnology to “help clarify which biotechnology product areas are within the authority and responsibility of each agency;” development of a “long-term strategy to ensure that the system is prepared for the future products of biotechnology;” and the conduct of “an expert analysis of the future landscape of biotechnology products” by the National Academies of Sciences, Engineering, and Medicine.   

As noted by OSTP, the Coordinated Framework was established in 1986 and hasn’t been updated since 1992.  In explaining the need for a review, OSTP pointed to changes in the biotechnology product landscape, a proliferation of regulations and guidance documents by FDA, USDA, and EPA, an apparent lack of public understanding with regard to safety evaluation of biotechnology products, and unnecessary burdens on small companies.  Among other things, OSTP directs the agencies to take measures to ensure that the Coordinated Framework is periodically reviewed and updated going forward.

OSTP’s directive can be expected to have an impact on regulation of bioengineered foods, but not on human drugs and medical devices because those products “are not the focus of the activities described” in the OSTP memorandum.  Given ongoing controversy over certain aspects of regulation of biotechnology, most notably in the area of labeling, there should be significant interest in the OSTP-directed review.  Public meetings are anticipated in the fall, and interested parties are encouraged to sign up to be notified of further developments. 

By Kurt R. Karst –      

One of the more memorable lines from the original Star Wars Trilogy is uttered in Return of the Jedi when Luke Skywalker surrenders himself to Darth Vader on the Forest Moon of Endor.  Luke tries to convince Vader to return to the Light Side of the Force, saying that he feels the “good” within Vader.  Vader, however, rebuffs the attempt at conversion, saying “You don’t know the power of the dark side!  I must obey my master.” 

Putting aside the light versus dark allegory, those lines sum up quite well the power of pediatric exclusivity (and its statutory master), particularly as it relates to Orange Book-listed patents.  And it’s a power that is often overlooked . . . at least initially, until the full force of pediatric exclusivity comes to bear on an ANDA or 505(b)(2) applicant.   Indeed, we’ve seen a few instances over the past year where pediatric exclusivity has crept up on an unsuspecting applicant to block final approval of an ANDA.  Consider, for example, the cascading periods of pediatric exclusivity applicable to various patents that were (and some that still are) listed in the Orange Book for NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg.  Although there is no 180-day exclusivity block on ANDA approval, only one ANDA sponsor, Ivax Pharmaceuticals, Inc., currently has approval of an application – ANDA 078003.  FDA approved that application after the sponsor obtained a waiver of pediatric exclusivity from the NDA sponsor, and which pediatric exclusivity became operative upon expiration of a patnet to which it attached (see our previous post here).   Other ANDA sponsor have apparently not been as fortunate. 

In light of this incident and others, we thought it would be a good time to review a couple of the ins and outs outs of pediatric exclusivity.  We also refer to several of our previous posts on some interesting pediatric exclusivity topics – here, here, and here. 

FDC Act § 505A provides an additional six months of patent and non-patent exclusivity to pharmaceutical manufacturers that conduct acceptable pediatric studies of new and currently-marketed drug products identified by FDA in a Written Request for which pediatric information would be beneficial.  Pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity (e.g., five-year, three-year, and orphan drug exclusivity) an application holder may have under the FDC Act, provided that the exclusivity is granted with not less than nine months of term remaining.  Pediatric exclusivity does not extend the term of a patent itself, but only the period during which FDA cannot approve an ANDA or a 505(b)(2) application that includes a Paragraph II certification (patent has expired), a Paragraph III certification (date on which a patent will expire), or a Paragraph IV certification that concerns a patent that a court has determined is valid and would be infringed.
 
An important aspect of pediatric exclusivity is that it provides additional marketing exclusivity not just for the pediatric indications or formulations, but for all protected indications and formulations of that sponsor’s drug.  Thus, pediatric exclusivity attaches to the patent and non-patent marketing exclusivity for any of the sponsor’s approved drug products (including certain combination products) that contain the active moiety for which pediatric exclusivity was granted, and not to a specific drug product.  See National Pharmaceutical Alliance v. Henney, 47 F. Supp. 2d 37 (D.D.C. 1999) (here).

Where folks most often get tripped up with pediatric exclusivity is the applicability of the exclusivity after patent expiration (i.e., a Paragraph II certification).  A Paragraph II certification exists either because an applicant specifically certified as such, or because FDA has administratively converted a certification to a Paragraph II certification upon patent expiration.  FDA’s ability to make such conversion has been upheld in court.  See Mylan v. Thompson, 332 F. Supp. 2d 106 (D.D.C. 2004) (here), aff’d, 389 F.3d 1272 (D.C. Cir. 2004) (here); Ranbaxy Lab., Ltd. v. FDA, 307 F. Supp. 2d 15 (D.D.C. 2004) (here), aff’d 96 Fed. Appx. 1 (D.C. Cir. 2004).  Now add in 180-day exclusivity and things can really get complicated, particularly when 180-day exclusivity “overlaps” with patent expiration.  That is, when the period of 180-day exclusivity extends only to patent expiration (cutting that exclusivity short) and butts up against pediatric exclusivity applicable to a patent subject to a Paragraph II certification preventing subsequent ANDA applicants from obtaining final approval.  

FDA first encountered this fact pattern back in 2007 in the context of ANDA approval of generic versions of Pfizer’s NORVASC (amlodipine besylate) Tablets, and in light of pediatric exclusivity applicable to Orange Book-listed U.S. Patent No. 4,879,303 (“the ‘303 patent”).  It led to a flurry of activity, including litigation against FDA, citizen petitions, and more.  It was the first “big case” we covered on this blog (see our previous posts here, here, here, here, and here).  

In an April 18, 2007 Letter Decision (Docket No. FDA-2007-N-0090; Docket Legacy No. 2007N-0123), FDA laid out not only when a court decision becomes final in the context of a patent infringement action (i.e., upon issuance of the mandate), but what such a decision means in the context of the pediatric exclusivity statute.  In doing so, FDA explained how an ANDA applicant subject to pediatric exclusivity applicable to an expired patent can “beat” what is otherwise ironclad exclusivity.  You can read the opinion for greater context, but here’s the important part:

This is the first time that FDA has been called upon to determine whether an ANDA applicant is subject to the innovator’s pediatric exclusivity when the ANDA applicant has received a favorable court decision in its paragraph IV litigation but has not yet obtained final approval when the patent expires [(here, because of another applicant’s 180-day exclusivity)]. . . .

In considering [the Mylan and Ranbaxy decisions] regarding the switch to paragraph II certifications with today’s decision regarding the non-applicability of pediatric exclusivity to applicants who prevail in patent litigation, FDA determines as follows.  When the ‘303 patent expired on March 25, 2007, all of the unapproved ANDAs were required to change (or deemed to have changed) to paragraph II certifications and became subject to Pfizer’s pediatric exclusivity at that time.  That is their status during the period before the mandate issues.  However, FDA believes that the language of the statute manifests a clear Congressional intent that pediatric exclusivity not block the approval of an ANDA where the ANDA applicant has prevailed in the paragraph IV patent litigation and therefore creates an exception to the application of the Hatch-Waxman certification provisions.  Thus, if and when the mandate finalizing the panel’s March 22 decision issues in the Apotex case, Apotex’s ANDA will not be blocked by Pfizer’s pediatric exclusivity.

FDA followed up that initial Letter Decision with a couple of other letters (here and here) applying the Agency’s Letter Decision in light of developing facts.  Ultimately, the ‘303 patent was delisted from the Orange Book, thereby removing the pediatric exclusivity barrier to ANDA approval. 

So, at the end of the day, what are the options for an ANDA applicant to overcome pediatric exclusivity applicable to an expired patent that is blocking final approval?  There aren’t many options, and they can take some time to work through, but there are at least three: (1) obtain a wavier from the NDA sponsor; (2) obtain a final court decision of patent invalidity or non-infringement; or (3) successfully pursue Orange Book delisting of the blocking patent.

By Kurt R. Karst – 

The Orphan Drug Tax Credit (“ODTC”) is not an incentive you hear about all too often, but it’s been around for quite some time – since the enactment of the Orphan Drug Act of 1983 – and is a strong incentive for companies to develop products for rare (i.e., “orphan”) diseases and conditions.  So when Congress considered repeal of the ODTC last year (see here and here) in June 2015 by the Biotechnology Industry Organization (“BIO”) (soon to be renamed the Biotechnology Innovation Organization) and the National Organization for Rare Disorders (“NORD”), and titled “Impact of the Orphan Drug Tax Credit on treatments for rare diseases,” the industry groups quantify the benefits of the ODTC, which has amounted to $750 million in awarded tax credits between 1996 and 2011 (as illustrated below in Figure 7 from the report). 

By way of background, a tax credit for certain clinical testing expenses for an orphan drug incurred in that taxable year is permitted under the Internal Revenue Code and under the Internal Revenue Service’s implementing regulation at 26 C.F.R. § 1.28.  The tax credit permits a firm paying United States taxes to credit against its federal income tax 50% of “qualified clinical testing expenses” relating to orphan drug development.  To qualify for the credit, the clinical testing must, under 26 U.S.C. § 45C: (1) be conducted under an IND; (2) relate to a drug and indication that has received an orphan drug designation from FDA; (3) occur after FDA designation as an orphan drug and before FDA approval; and (4) be conducted by or on behalf of the taxpayer to whom the orphan drug designation applies. 

Expenses eligible for the credit include both in-house testing expenses, such as wages and non-depreciable supplies, and contract research expenses (i.e., amounts paid to persons other than employees to conduct the research).  Under 26 U.S.C. § 39(a), companies can carryback unused tax credits “to each of the 1 taxable years preceding the unused credit year,” and can carryforward unused tax credits “to each of the 20 taxable years following the unused credit year.”  Although the law sets a baseline that “[n]o tax credit shall be allowed . . . with respect to any clinical testing conducted outside the United States,” there’s an exception when “testing is conducted outside the United States because there is an insufficient testing population in the United States . . . .”  (A regulation – at 26 C.F.R. § 1.28-1(d)(3)(ii)(B) – defines “insufficient testing population” to mean “[t]he testing population in the United States is insufficient if there are not within the United States the number of available and appropriate human subjects needed to produce reliable data from the clinical investigation.”)

The key findings from the BIO/NORD report are that:

• Without the ODTC, it is estimated that investment in orphan drugs would have been smaller by a third both historically and in the future;
• In the absence of the ODTC, 67 orphan drugs, or 33%, would likely not have been developed over the past 30 years; and
• Going forward, if the ODTC were repealed, it is estimated that 57, or 33%, fewer new orphan drugs would be approved over the next 10 years.

These findings and others are illustrated throughout the report, and, in particular, in Figures 9, 10, and 11 (reproduced below). 

Things appear to be quiet thus far in 2015 insofar as efforts to repeal the ODTC are concerned.  But if there is a renewed effort, the BIO/NORD report may be an important advocacy piece to sustain the tax credit.

The American Conference Institute (“ACI”) will hold its 26th FDA Boot Camp conference in Boston, Massachusetts from September 30 to October 1, 2015.  A copy of the conference program can be obtained here.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will co-chair the event with Kleinfeld, Kaplan & Becker, LLP’s Scott M. Lassman.  The conference will include presentations from a virtual “who’s who list” of FDA regulatory experts on myriad topics, including the approval process, pre-approval concerns, product labeling, clinical trials, adverse events reporting, and patent and non-patent marketing exclusivity issues.

ACI will also hold its 3rd annual Paragraph IV Disputes Master Symposium in Chicago, Illinois from September 30 to October 1, 2015, with a post-conference workshop on October 2nd.  A copy of the conference program can be obtained here.  The conference features presentations from preeminent patent litigators representing brand-name and generic drug manufacturers, leading in-house counsel, and esteemed jurists and government representatives who will discuss, analyze, and interpret the latest controversies affecting Paragraph IV litigation.  Hyman, Phelps & McNamara, P.C.’s James C. Shehan will be speaking at the conference. 

FDA Law Blog is a media partner for both conferences.  As such, we can offer FDA Law Blog readers a special $200 discount off the current price tier.  The discount code is: FDA200.  We look forward to seeing you at the conferences.

By James E. Valentine* –

The enactment of FDASIA, including the fifth reauthorization of PDUFA, really put patient engagement on the radar beyond some of the traditionally active disease communities (e.g., HIV/AIDS, cancer, neurological diseases).  FDASIA’s section 1137, the provision on Patient Participation in Medical Product Discussions, led FDA to seek input on “strategies to solicit the views of patients during the . . . development process and consider the perspectives of patients during regulatory discussions” (see our prior coverage here).  Meanwhile, CDER and CBER have been busy fulfilling their commitment to host at least 20 Patient-Focused Drug Development (PFDD) meetings on specific disease areas during fiscal years 2013-2017.

On July 2, 2015, CDER/CBER will announce the selection of the final set of disease areas to cover as part of the PFDD initiative under PDUFA V:

• Alopecia areata
• Autism
• Hereditary angioedema
• Non-tuberculous mycobacterial infections
• Patients who have received an organ transplant
• Psoriasis
• Neuropathic pain associated with peripheral neuropathy
• Sarcopenia

With the addition of these eight meetings, FDA is on target to have held 24 in total—four more than the minimum of 20 that the Agency committed to under PDUFA V. 

The PFDD meetings have helped advance a systematic approach to gather patients’ input on their condition and treatment options, and provide what FDA has deemed “the therapeutic context” for weighing benefits and risks of investigational products for the given disease.  This is accomplished through the inclusion of information synthesized from the PFDD meetings in the first two rows of the structured benefit-risk framework (sB/R) (see below).  The framework was rolled out in March 2015 in CDER’s review of NME NDAs and Original BLAs.   

However, it appears one industry trade group sees this sB/R framework as a platform with greater utility.  In a white paper released in June 2015 by the Biotechnology Industry Organization (BIO) (soon to be renamed the Biotechnology Innovation Organization), the industry group recommends that the perspectives of patients be a standard component of decisions that are made during discussions behind closed doors between sponsors and FDA.  As BIO sees it, the sB/R framework holds the potential to serve as the bridge between patient input and regulatory decisions.  But in order for this to work, patient input should begin when initiating a development program, and the sB/R framework needs to be used early and often in considerations by both sponsors and FDA.

The BIO white paper provides a comprehensive set of recommendations for incorporating patient feedback into the sB/R framework and using the framework during key points of a product’s lifecycle to ensure transparency on the key areas of judgement for regulatory decision-making.  Here are a few recommendations this blogger found noteworthy that bring the patient perspective earlier in the development lifecycle:

Early Stage Development (Pre-IND to Phase 1)

In the early stages of development, a sponsor has the ability to describe the development rationale for a new medicine in the context of the benefit-risk framework and use this information to screen compounds.  To obtain input from patients, BIO recommends that sponsors consider organizing meetings with a representative group of patients and caregivers, including patient advocacy groups (PAGs), to engage in a dialogue around the burden of the condition and the current armamentarium of treatment options.  This information would be summarized in the first to lines of the sB/R framework.  This early stage, qualitative activity appears similar in scope to the discussions at FDA-hosted PFDD meetings.

In addition, BIO recommends that sponsors employ methods to gather robust and representative data that could be used in regulatory decision-making, such as patient surveys and stated choice studies, to assess patient preferences and perspectives on benefit-risk considerations and integrate this information into the framework summary.

To date, this quantitative approach to incorporating the patient perspective has been endorsed by FDA only for the review of medical devices (see our coverage on Patient Preference Information draft guidance here).  However, patient advocacy groups have taken their own initiative to collect patient preference information for use in drug review (e.g., Parent Project Muscular Dystrophy’s risk tolerance survey) and CDER officials have suggested that “more systematic collection of patients’ experience” would be considered in future iterations of PFDD. 

BIO postulates that, in sum, incorporating these patient perspectives in submissions to FDA (e.g., briefing materials for milestone meetings) will assist the sponsor and FDA in developing an aligned sense of the status quo.  It may also provide an opportunity to identify and discuss potential differences in opinion between the two parties early in development.

Mid-to-Late Stage Clinical Development (Phase 2 to Pre-NDA/BLA)

Here, the targeted benefit-risk profile of an investigational drug continues to be investigated and refined so the focus shifts to designing registration trials that ideally reflect an alignment between the sponsor’s and FDA’s perspectives on the clinical context.  BIO sees a role for the sB/R framework to facilitate this evolving dialogue.

In preparation for the end-of-phase 2 meeting, BIO recommends that sponsors obtain further patient preference input from patient organizations in the context of data emerging over the course of development.  This would allow sponsors to gain insight into evolving views of the drug candidate.  BIO suggests measures such as non-disclosure agreements to protect any confidential commercial information.  This qualitative and quantitative patient feedback would be summarized in the bottom three rows of the sB/R framework, as well as the summary assessment.  This recommendation is novel in that it expands the inclusion of patient input beyond the contextual information contained in the first two rows of the framework, now including product-specific input. 

BIO suggests including the updated sB/R framework in the end-of-phase 2 meeting document to serve as an early opportunity for FDA to hear the voice of the patient as it relates to the specific drug candidate benefit and risk attributes, as well as Phase 3 clinical trial development considerations (e.g., size and complexity, recruitment and enrollment strategies, use of endpoints, the clinical outcome measure).

Other opportunities to share the patient perspective, as well as to concisely summarize available data and other factors considered by the sponsor, through the sB/R framework include at pre-NDA/BLA and other late stage meetings and at advisory committee meetings.  BIO also requests that FDA integrate the sB/R framework in the decision memo at the time of approval to communicate the reasoning behind the Agency’s decisions, such as which benefits, risks, or other factors were considered and how they were weighed.  In the event of a Complete Response Letter, BIO requests that FDA provide the sponsor with the framework as documentation of those same factors, but not to release that information to the public.

Shifting to PDUFA VI

While BIO’s recommendations could be implemented at any time, to establish buy-in by FDA, there is an opportunity to present and discuss such proposals during the negotiations for the next reauthorization of PDUFA.  FDA is hosting a public meeting on July 15 to initiate the reauthorization process.  Once under way, there will be opportunities for industry and other stakeholders, including patient advocacy groups, to participate in the process.  A second iteration of PFDD is bound to be a hot topic.

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