By Jennifer D. Newberger –

On February 9, less than a year after issuing the draft, FDA issued a final guidance document confirming its exercise of enforcement discretion with respect to medical device data systems (MDDS), medical image storage devices, and medical image communications devices.  In line with the draft guidance, on which we blogged here, FDA has confirmed its intent not to enforce compliance with the regulatory controls previously applicable to the named devices.  This means manufacturers of those devices will not be required to register and list, or comply with the quality system regulation (QSR) or medical device and recall reporting.

Perhaps the most important takeaway from the guidance is that FDA has stated that it will also exercise enforcement discretion with respect to the named devices even if the device is intended for assessing the risk of cardiovascular disease or for use in diabetes management.  With the influx of apps and web services available to aid in diabetes management, FDA’s official position will be welcome news to many in the industry.

FDA also issued an updated version of its Mobile Medical Applications guidance, first released on September 25, 2013 (here), to incorporate the position outlined in the MDDS guidance.  For example, the September 25, 2013 mobile apps guidance indicated that an app that acted as an MDDS would be subject to registration and listing, QSRs, and medical device and recall reporting.  Since FDA has stated that it will not enforce regulatory compliance for MDDS products, the mobile apps guidance has been revised to reflect that position.

FDA has continued to indicate its intent to focus its efforts on higher risk technology products.  Hopefully, this trend will continue.

By Dara Katcher Levy –

Last Friday, FDA issued the latest in a series of draft guidance documents (here and here) that address alternate ways companies can disclose risk information in consumer-directed print Rx drug promotion.  The most significant difference between the 2015 and 2004 draft guidances is in scope; the 2015 document addresses not only consumer advertising but consumer print labeling. 

FDA regulations require that advertisements and promotional labeling be accompanied by different types of information.  Advertisements are required to have a “brief summary” of risk information accompany the ad.  Labeling is generally required to be disseminated with the full FDA-approved prescribing information (PI).  In the 2015 draft guidance, FDA recognizes that the lengthy, technical PI is difficult for consumers to comprehend and provides companies with a path forward to disseminating consumer-directed print labeling with an abbreviated statement of risk (referred to as the “consumer brief summary”) as opposed to the full PI.  This abbreviated option would not only benefit consumers with “better and more actionable information” (according to FDA) but can streamline the regulatory requirements for promotional materials with having the same consumer brief summary accompany both ads and promotional labeling.  Further, the consumer brief summary could potentially translate to a significant cost savings to companies that promote products with lengthy PIs that, to date, must be reprinted and disseminated in their entirety with promotional labeling.   

The proposal is an interesting shift for FDA:  In 2008, FDA issued a Warning Letter to Boehringer-Ingelheim for violations related to the promotion of Mirapex.  Among the issues cited was the “Failure to Provide Adequate Directions for Use” in that the full prescribing information was not provided with their consumer-directed promotional labeling in violation of 21 C.F.R. § 201.100(d).  In a footnote, FDA acknowledged that, “the pieces appear to have been disseminated with the patient package insert (PPI); however, as indicated above, the regulations require that any labeling which includes claims about a drug product must contain the contents of the full FDA-approved product labeling (PI). We remind you that this includes (but is not limited to) the full text of the Mirapex FDA-approved patient labeling or PPI, which must be reprinted immediately following the last section of the required FDA approved prescription drug labeling for Mirapex or, alternatively, accompany the Mirapex prescription drug labeling (PI).”  FDA did not comment on the adequacy of the PPI to convey appropriate safety information to consumers – rather, simply cited the regulatory requirement that the full PI must accompany the materials.  It appears that the PPI for most drugs would generally meet the requirements of the consumer brief summary as set forth in the new draft guidance, although FDA recognizes that there may be certain relevant drug risks not included in the PPI that might need to be added.

We note that the 2015 draft guidance does not simply provide an alternate approach, but actively discourages companies from meeting the current regulatory requirements.  FDA states that it “strongly recommends against providing the full PI,” when disseminating consumer-directed promotional labeling, and that companies should adopt the content and format recommendations in the guidance.  The suggestion is that the guidance supplants rule-making – an overt continuation of the Office of Prescription Drug Promotion’s trend toward regulating through the issuance of guidance documents and enforcement letters. 

Beyond the regulatory issues, companies should carefully consider the potential product liability implications involved with implementing FDA’s recommended approach in terms of “failure to warn” cases.  Although we recognize that the FDA recommendations are limited to direct-to-consumer promotion (and not the learned intermediary healthcare professional facing pieces), the approach may nonetheless increase a company’s vulnerability in this area.  Before determining whether to adopt the approach, companies should also consider consistency issues in the development and dissemination of promotional materials for their portfolio of products.  Any policy decisions should evaluate the inherent product liability risks represented by the most dangerous, or most litigated, drugs in their portfolio.        

By Jay W. Cormier & Allyson B. Mullen –

Two years ago, FDA promulgated the Part 4 regulations that specify how manufacturers of combination products are to comply with current good manufacturing practice (cGMP) when making products whose constituent parts are from more than one type of product. Recently, FDA issued a draft guidance document that put a bit more color on these regulations.

For those who are unfamiliar, each type of FDA-regulated product (e.g., drug, biologic, device, etc.) has its own set of regulations that govern what constitutes cGMPs. For single-category products, this makes sense – while the types of manufacturing issues that a medical device and, a biologic present do overlap, there are some differences in how to approach these issues, both technically and in the existing regulations. As if compliance with cGMPs isn’t difficult enough even for companies with big budgets, add in the wrinkle of manufacturing a product that, for example, is both a medical device and a drug at the same time, and things get messy in a hurry.

Part 4 was intended to come to the rescue. At a high-level, Part 4 is rather straight-forward. The analysis begins with the general rule that each constituent part of a combination product must be manufactured in compliance with its respective cGMP requirements. 21 C.F.R. § 4.3. For combination products that are either co-packaged (i.e., two or more separate products that are packaged together) or single-entity (i.e., comprised of parts that are physically, chemically, or otherwise combined into a single product) combination products, Part 4 provides an alternative to the general rule: a facility can elect to fully comply with the cGMP requirements for one of the constituent types and supplement certain specified provisions of the other constituent type cGMP requirements. See 21 C.F.R. § 4.4. Such a manufacturing facility has three options:

1. Fully comply with each of Parts 210 and 211 with respect to the drug constituent and with Part 820 for the device constituent;
2. Comply fully with Parts 210 and 211 for the combination product and with 21 C.F.R. §§ 820.20 (management responsibility), 820.30 (design controls), 820.50 (purchasing controls), 820.100 (CAPAs), 820.170 (installation), and 820.200 (servicing) for all constituent device parts; or
3. Comply fully with Part 820 for the combination product and 21 C.F.R. §§ 211.84 (component and container-closure testing), 211.103 (yield calculations), 211.132 (OTC tamper-evident packaging), 211.137 (expiration dating), 211.165-211.167 (final product release and stability testing), and 211.170 (reserve samples) for all constituent drug parts.

At 46 pages in length, the Draft Guidance helps to put some additional details onto this regulatory scheme. For readers who are interested in specifically how to apply device QSR provisions to drug components (when using option 2, above) or how to apply drug GMP provisions to device components (when using option 3, above), the majority of the Draft Guidance is dedicated to walking through each of these cross-product type issues. These summaries may be particularly helpful to companies that are unfamiliar with the cGMPs for the other regulatory product types (e.g., a device company that does not currently follow drug cGMPs). Rather than summarizing the many statements made by FDA on these specific issues, this post will provide a few highlights of the general concepts and clarifications provided by the Draft Guidance.

• Options 2 and 3, above, only apply to those manufacturing steps that occur after the first instance where the two separate product-type constituent parts are first co-packaged or combined into a single product. Prior to this point in time, the individual constituent parts are subject to their respective cGMP requirements.
• With respect to inspections, if a manufacturer elects one of these “streamlined” approaches (options 2 and 3), FDA recommends that the manufacturer notify FDA of which approach it intends to adopt in their premarket submissions as well as at the time that an inspection begins. A 510(k) premarket notification typically would not discuss manufacturing.
• A manufacturer may elect either streamlined approach for a co-packaged or single-entity combination product, without regard to which product center has been assigned as the lead review center or what primary mode of action has been designated for the combination product.
• Part 4 does not change FDA’s expectations for cGMP compliance for investigational products: drugs are generally exempt from cGMPs during Phase 1 studies and investigational devices are generally exempt from Part 820 with the exception of design controls.
• Part 4 does not change the analysis of whether a device component manufacturer is subject to Part 820 requirements. The guidance does a good job of explaining the difference between a device component (as defined in Part 820) and a device constituent part of a combination product.
• As with all other cGMP regulations, only those regulations that are applicable to the manufacturing operations must be followed.
• Specific procedures designed to implement one set of requirements (e.g., discrepancy investigations under 21 C.F.R. § 211.192) can be used to satisfy part or all of the relevant additional requirement s (e.g., CAPA requirements under 21 C.F.R. § 820.100).

The Draft Guidance includes detailed hypotheticals for pre-filled syringes, drug-coated meshes, and drug-eluting stents. While these hypotheticals each only cover one of the available options under Part 4, they are illustrative of what FDA expects combination product manufacturers to do when designing and implementing their manufacturing processes.

As always, general agency guidance cannot anticipate every scenario used by industry, so while applying the Draft Guidance to many products may seem to be straightforward, undoubtedly there will be instances where reducing agency guidance to practice is anything but clear.

Comments on the Draft Guidance are due to FDA by March 30th.

By James E. Valentine* & Jim C. Shehan –

The 21^st Century Cures Act’s focus on patients is inescapable.  Title I of this nearly 400 page bill is entitled, “Putting Patients First By Incorporating Their Perspectives Into The Regulatory Process and Addressing Unmet Needs.”  When we reported on the 21^st Century Cures Initiative hearing on incorporating the patient perspective (see our previous coverage here), it was clear from stakeholder testimony and engagement by Energy & Commerce Committee members that such a legislative proposal would be included.

So what exactly do patients get in the proposed legislation?  Well, considering the entire document is devoted to the discovery, development, and delivery of new treatments and cures, potentially quite a lot (see our broader coverage of the Act here and its proposed expansion of clinical trials data sharing here).  But specifically, we’ve identified two provisions that are patient centric: (1) Patient-Focused Drug Development and (2) Expanded Access.  Neither are new concepts.  In fact, both are current programs at FDA.  So let’s break down what’s new.

Patient-Focused Drug Development

This provision, Section 1001, drafted by Health Subcommittee Chairman Joe Pitts (R-PA) and Representative Cathy McMorris Rodgers (R-WA), would build off FDA’s Patient Focused Drug Development.  FDA would be required to implement the structured benefit-risk framework it took on in PDUFA V, and develop processes for incorporating “patient experience data” into the framework to be used in its regulatory decision-making with respect to the benefits and risks of new drugs.

“Patient experience data” broadly includes information about the experience of patients with a disease, including specifically the impact of the disease on their lives and their caregivers.  This information can take the form of complete data and summaries and analysis of the data, and may be incorporated into “draft guidances” that patients groups submit to the agency. 

To facilitate “patient experience data” collection, the provision would have FDA publish guidance on (a) methodological considerations for collecting this information, (b) assessing patients’ beliefs of benefits and risks in the management of their disease, and (c) experimental designs for patient-reported outcomes.  FDA is also asked to include timeframes for review of documents containing this information and how it will use the documents and data.  Interestingly, the guidance would also cover establishing and maintaining patient registries designed to improve understanding the natural history of a disease.  A pre-draft workshop and post-draft public meeting would facilitate guidance development.

So in summary, this one provision endorses three tools for fostering patient participation in the regulatory process: patient registries, patient-reported outcomes, and “patient experience data,” including benefit-risk preferences.

Expanded Access

Another heavily patient centric section of Title I of the 21st Century Cures Act is Subtitle G, entitled “Expanded Access.”  This subtitle almost replicates H.R. 8505, the Andrea Sloan Compassionate Use Reform and Enhancement (CURE) Act, introduced at the end of last year by Representative Michael McCaul (R-TX) and blogged on by us previously.  Among changes worth noting, Subtitle G makes some slight changes to the scope of products covered, adding designated orphan drugs and dropping drugs approved under accelerated approval and drugs whose sponsors receive priority review vouchers.  Also, the task force assigned to look for ways to improve expanded access has grown from nine to thirteen members and is specifically asked to look at compliance with adverse event reporting requirements in expanded access programs.

There was another significant development in expanded access last week – FDA issued a draft guidance containing its new form for individual patient expanded access INDs.  Checking in at two pages and containing only eight sections that the patient’s physician needs to complete, the, new draft form, designated Form FDA 3926, appears to accomplish the FDA’s stated purpose  to “greatly simplify and accelerate the process by which a physician can request” expanded access.  The most significant pieces of information that physicians will need to provide are:

1. The patient’s initials;
2. Clinical information, including indication, brief clinical history of the patient, and the rationale for requesting the proposed treatment, including an explanation of why the patient lacks other therapeutic options
3. Treatment information, including the investigational drug’s name and treatment plan, that is, the planned dose, route and schedule of administration, planned duration of treatment, monitoring procedures, and planned modifications to the treatment plan in the event of toxicity.
4. A letter of authorization from the investigational drug’s manufacturer
5. Information about the physician’s qualifications;
6. The physician’s name, address and contact information;
7. A check box authorizing use of the form, which amounts to a request for a waiver of additional requirements under 21 C.F.R. Part 312; and
8. The physician’s signature and certification that treatment will not begin until 30 days after FDA receives the application unless there is earlier notification from FDA; that the physician will obtain informed consent; that IRB review of the expanded access use will be obtained; and that in the case of an emergency request treatment may begin without prior IRB approval provided the IRB is notified of the emergency treatment within 5 working days of treatment.

According to a post on FDA Voice, FDA expects that the new form can be completed within 45 minutes.  Comments on the guidance and the draft form may be submitted to FDA within 60 days.

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

By Kurt R. Karst –      

There was some big news out of FDA today.  Yes, there was the news that FDA Commissioner, Dr. Margaret Hamburg, one of the longest-serving FDA commissioners in the modern era (see here), has decided to resign her post effective next month.  But even bigger than that (at least for this blogger) was some other news.  For quite some time now this blogger has opened the pre-publication website of the Federal Register hoping to see posted a notice of FDA’s long-awaited proposed regulations to implement the December 8, 2003 Medicare Modernization Act (“MMA”).  We were disappointed when the proposed regulations – which have been in the works for many years – did not get published by the MMA’s 10th anniversary.  That was day 3,655 in our Hatch-Waxman diary (see our previous post here).  Fast-forward to day 4,079, February 6, 2015, and the proposed regulations will make their official debut in the Federal Register. 

The pre-publication version of the proposal is a massive 341 pages (and includes a slew of tables), while the official version printed in the Federal Register comes in at a cool 96 pages.  And this is only part one of what will likely be a two-part series.  Part two, which we don’t think will come out any time soon, will deal with forfeiture of 180-day exclusivity eligibility.  Part one largely deals with the MMA’s provisions concerning Paragraph IV notice, 30-month litigation stays, amendments to ANDAs and 505(b)(2) applications, the types of bioavailability and bioequivalence data that can be used to support ANDAs and 505(b)(2) applications, as well other changes “to facilitate compliance with and efficient enforcement of the FD&C Act.”  What does that last passage mean?  FDA provides an example: “we are proposing to clarify requirements for the NDA holder’s description of the patented method of use (the “use code”) required for publication in [the Orange Book] to avoid overbroad use codes that may delay approval of generic drugs.” 

We’re still poring over the behemoth of a proposal.  And because this is Hatch-Waxman we’re talking about, there’s a lot of nitty-gritty to consider.  Nevertheless, below are a few goodies to whet you Hatch-Waxman appetite (taken from FDA’s highlight summary).  We’re sure to have more to say on the proposal in the coming weeks.

Submission of Patent Information – In addition to revising and streamlining the requirements related to submission of information for certain patent types, FDA’s proposed rule tackles reissued patents and describes the Agency’s approach to treating original and reissued patents as a bundle of patent rights.  As FDA later explains in the proposal:

Proposed § 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) would provide that an NDA applicant or holder is required to include information on whether a patent submitted for listing is a reissuance of a patent previously submitted for listing for the NDA or supplement. . . .  [T]he timely filing of patent information for a reissued patent (including a reissued patent with a broadened scope of claims) does not alter the patent certification obligations of a 505(b)(2) or ANDA applicant whose application was pending when the original patent was filed by the holder of an approved application for listing more than 30 days after patent issuance (“late listed”).  In other words, if a 505(b)(2) or ANDA applicant is not required to provide a patent certification or statement to the original patent pursuant to § 314.50(i)(4) or § 314.94(a)(12)(vi) because the patent was late listed, the 505(b)(2) or ANDA applicant would not be required to provide a patent certification or statement to the reissued patent even if timely filed following reissuance.

In addition, to “restrain overbroad use codes,” FDA’s proposal “would expressly require that if the scope of the method-of-use claim(s) of the patent does not cover every approved use of the drug, the NDA holder’s use code must describe only the specific portion(s) of the indication or other method of use claimed by the patent.” 

Timing of Submission of Patent Information – FDA expressly describes the Agency’s current practice with respect to the late listing of patent information, and proposes “to expand the category of untimely filed patent information to include certain amendments to the NDA holder’s description of the approved method(s) of use claimed by the patent, if such changes do not relate to a corresponding change in approved labeling or are submitted more than 30 days after such labeling change.”  According to FDA, this revision “is intended to reduce delays in approval related to manipulation of patent use codes. . . .”

Correction or Change of Patent Information – Among other things, FDA wants to enhance its response to challenges to the accuracy or relevance of Orange Book patent information.  FDA’s current regulation at 21 C.F.R. § 314.53(f) to challenge Orange Book patent information is rather toothless.  “If, in response to such a challenge, the NDA holder confirms the accuracy of the information, fails to timely respond, or submits a revision to the use code that does not provide adequate clarity for FDA to determine whether the scope of a proposed labeling carve-out would be appropriate based on the NDA holder’s use code and approved labeling,” says FDA, then “we are proposing to review proposed labeling carve-out(s) for the 505(b)(2) application or ANDA with deference to the 505(b)(2) or ANDA applicant’s interpretation of the scope of the patent.”

Notice of Paragraph IV Certification (Timing) – FDA proposes to delineate the two limitations on the timeframe within which Paragraph IV certification notice can be provided to the NDA holder and patent owner: “(1) [t]he date before which notice may not be given (reflecting FDA’s long-standing practice) and (2) the date, established by MMA, by which notice must be given.”  In addition, FDA reiterates that pramature notice is inavalid “and will not be considered to comply with the FD&C Act’s notice requirement.”  The Agency is also proposing “administrative consequences” for ANDA applicants who fail to send Paragraph IV notice within the statutory timeframe.  Specifically, “[t]he date the ANDA was submitted would be deemed to be delayed by the number of days by which the time frame was exceeded, which may result in the applicant losing eligibility for 180-day exclusivity.”  This is a topic on which we previously posted.

In addition, FDA's proposal would, if implemented, get rid of those pesky “serial certifications” – a practice many ANDA applicants have used throughout the years in an attempt to secure first-filer status and eligibility for 180-day exclusivity by preemptively sububmitting a Paragraph IV certification each day (sometimes for several months) until (or in case) a patent is listed in the Orange Book.  According to FDA's proposal: 

We are proposing to establish a date (the first working day after the day the patent is published in the Orange Book) before which an ANDA applicant cannot send valid notice of a paragraph IV certification to a newly listed patent.  This approach is intended to promote equity among ANDA applicants seeking eligibility for 180-day exclusivity and to reduce the burden on industry and FDA associated with serial submissions and multiple notices of paragraph IV certifications related to a newly issued patent.

Notice of Paragraph IV Certification (Content and Methods) – FDA is proposing to expand the acceptable methods of sending Paragraph IV notice beyond the now archaic registered or certified mail routes to include “designated delivery services.”

Amended Patent Certifications – In an effort to codify FDA’s current practice of not removing a withdrawn patent from the Orange Book until the resolution of 180-day exclusivity issues, the Agency proposes to “clarify the requirements for a 505(b)(2) or ANDA applicant to amend a paragraph IV certification after a judicial finding of patent infringement to reflect statutory changes made by the MMA,” and to “clarify the circumstances and time frame in which a 505(b)(2) or ANDA applicant must submit an amended patent certification after an NDA holder has withdrawn a patent and requested removal of the patent from the Orange Book.”

Amendments or Supplements (Patent Certification Requirements) – FDA’s proposal would augment the current regulations on patent certification requirements for amendments and supplements (for both ANDA and 505(b)(2) applicants) by “requiring a new patent certification with an amendment to make other-than-minor changes in product formulation or to change the physical form or crystalline structure of the active ingredient.”  That is, FDA finally addresses the issue of when an applicant must recertification and renotification. 

Limitation on Submission of Certain Amendments and Supplements to a 505(b)(2) Application or ANDA – FDA’s proposal codifies the Agency’s current interpretation of the statutory prohibition on amending or supplementing an application to refer to a different listed drug (see our previous posts here, here, and here).  “We are implementing these parallel restrictions on submission of certain types of changes in an amendment or a supplement to a 505(b)(2) application or ANDA in a manner that is consistent with the statutory text and preserves a meaningful opportunity for a single 30-month stay,” says FDA. 

505(b)(2) Applications – Turning to an issue that is part of ongoing litigation (see our previous post here), FDA proposes “to require a 505(b)(2) applicant to identify a pharmaceutically equivalent product, if already approved, as a listed drug relied upon, and comply with applicable regulatory requirements.”  FDA later explains that:

If a pharmaceutically equivalent drug product has been approved before a 505(b)(2) application is submitted, then we consider the 505(b)(2) applicant to be implicitly relying on the approval of such drug product.  We are proposing to revise § 314.54(a)(1)(iii) to require that the listed drug or drugs identified as relied upon by a 505(b)(2) applicant must include any approved drug product that: (1) Is pharmaceutically equivalent to the drug product for which the 505(b)(2) application is submitted and (2) was approved before the 505(b)(2) application was submitted.

Date of Approval of a 505(b)(2) Application or ANDA – With respect to application approval and 30-month patent litigation stays, FDA, among other things in the proposal, codifies the MMA’s provisions on the type of court decisions that will terminate a 30-month stay.  FDA also brings up other scenarios in which a 30-month stay may be terminated (e.g., written consent to approval by the patent owner or exclusive patent licensee, a court order terminating the stay, or a court order of dismissal without a finding of infringement). 

Notification of Commercial Marketing – Under FDA’s proposal, an ANDA applicant’s failure to timely notify the Agency about the date of commercial marketing (and thus the trigger for the start of 180-day exclusivity) can have significant consequences:

A first applicant would be required to submit correspondence to its ANDA notifying FDA within 30 days of the date of first commercial marketing of the drug product.  If the first applicant does not notify FDA within this time frame, we are proposing to deem the date of first commercial marketing to be the date of the drug product’s approval.  This may have the effect of shortening the 180-day exclusivity period in a similar manner to the current regulatory consequence for failure to provide “prompt” notice of first commercial marketing.

Notification of Court Actions or Documented Agreements – In what appears to be an effort by FDA to be better informed of the patent infringement litigation landscape, the Agency proposes to “expand the scope of documentation that an applicant must submit to FDA regarding patent-related court actions and documented agreements to ensure that FDA is promptly advised of information that may affect the timing of approval of a 505(b)(2) application or ANDA.”  This includes a copy of any judgment (or settlement order or consent decree signed and entered) by a court (district court or mandate of the court of appeals) finding a patent invalid, unenforceable, or not infringed (or finding the patent valid and infringed).

By James C. Shehan –

The new Congress has been very busy introducing legislation that affects FDA and regulated industry, including the 21st Century Cures Act (see our previous post here); the Limited Population Pathway for Antibacterial Drugs Act (PATH) (here) and the Improving Regulatory Transparency for New Medical Therapies Act, which aims to speed up DEA’s scheduling of new drugs (see our previous post here).  While these bills have been favorably received by many in the regulated industry, there’s another recently introduced bill that has found a less welcoming reception among industry: the Medical Innovation Act of 2015 (“MIA”) (S. 320), introduced by Senators Elizabeth Warren (D-MA), Ben Cardin (D-MD), Sherrod Brown (D-OH), and Tammy Baldwin (D-WI).  (Senator Warren’s press release, floor introduction video, and a bill summary are available here.)  Characterized by the sponsors as a bill that would boost funding for critical medical research, MIA does indeed provide for substantial NIH and FDA funding, estimated at $6B per year.  But that funding is provided via a novel mechanism – drug companies that market blockbuster drugs and enter into certain settlements with the federal government would be required to pay portions of their net profits for a five year period to the two agencies, a mechanism Senator Warren likens to a “swear jar.”  Delving into the bill, we see some proposals likely to be opposed on both policy and legal grounds, and perhaps capable of generating some swearing by those subject to it.

Here’s how the bill works.  A “covered blockbuster drug” is defined as one for which a manufacturer realizes $1B in net sales (presumably global sales) and developed in whole or part through federal government investment in medical research.  Federal government medical research investment is to be determined by the HHS Secretary considering whether information included in any patents that claim the drug or a method of use for the drug  relate to (1) “prior science conducted, in whole or in part, by a person” funded by the federal government; (2) “a signaling pathway, cellular receptor, ion channel, protein, DNA or RNA sequence or mutation, virus, or any other scientific information discovered, in whole or in part”, through such funded research; or (3) “the manufacturing process or testing process of the covered blockbuster drug, technology derived, in whole or in part,” through such funded research.  Given the breadth of this definition, especially clause 2, it appears that many products will meet the definition.

“Covered manufacturers” are those who hold the NDA or BLA for the covered blockbuster drug or who are a licensed partner of the holder.  “Covered settlement agreement” is one between an agency and a covered manufacturer with a payment of at least $1M and related to an alleged violation of the anti-kickback statute, the False Claims Act, the Federal Food, Drug, and Cosmetic Act, or any other federal civil or criminal law.  This is a very broad definition but the bill contains an exception that narrows it – “covered settlement agreement” does not include any settlement that the HHS Secretary determines does not involve an alleged criminal violation and does not involve fraud resulting or potentially resulting in loss of taxpayer dollars or allegations of conduct having an adverse or potentially adverse impact on the public health. 

Covered manufacturers that enter into covered settlement agreements after the MIA is passed and that have net income of at least $1B will be required to pay1 the federal government each year for five years an amount equal to 1% of their net income multiplied by the number of covered blockbuster drugs sold by that manufacturer in that year. 

Funds equivalent to the payments would be allocated by the HHS Secretary every year between NIH and FDA to “meet urgent needs in medical research.”  NIH’s funding would be used to support “research that fosters radical innovation,” “research that advances fundamental knowledge,” “research related to diseases that disproportionately account for Federal health care spending” and “early career scientists.”  FDA’s funding would be used to support its implementation of Section 1124 of FDASIA and other research to promote the public health and advance innovation in regulatory decision-making.  Between NIH and FDA, funds would be allocated according to the ratio of discretionary Congressional funding that each receives in that year.  MIA also contains mechanisms to prevent the funds from being used to replace budget cuts.

Among possible concerns about the bill is that it punishes settlements instead of fault.  Indeed although the bill summary states that it applies to companies that “[b]reak the law and enter into a settlement” with the government, by its text it applies to settlements and alleged violations, not actual violations of the law.  Indeed, somewhat perversely, the payments would not be owed by companies that went to trial and were actually found guilty of breaking the law. 

The bill may also be subject to legal as well as policy challenges as imposing an unconstitutionally excessive fine, given that the payments are not linked to any degree of culpability but instead to the size of corporate profits. 

Coverage of the bill in the media has been limited.  But PhRMA is reported to have offered the following point of view: “Pursuing misguided policies that siphon funding from the groundbreaking medical research happening in the biopharmaceutical industry will have devastating consequences for patients and society.  The proposed legislation would result in fewer medicines for patients and lost jobs at a time when our economy can least afford it.” 

Introduced by minority party Senators and lacking bipartisan support, unlike the other bills referenced at the start of this blog, it’s difficult to see this bill gaining much traction.  But if the situation changes, we are likely to blog on it. 

By Kurt R. Karst –      

There’s no two ways about it: We love data.  And it doesn’t really matter what FDA-related topic those data concern: citizen petitions (here and here), drug patent settlement agreements (here), user fees (here), orphan drugs (here), or just general FDA regulation (here).  We find it all rather interesting.  After all, data can provide an informative picture of the FDA sandbox in which we play, and data are often predictive of the future. 

As this blogger fingered through the pages of the final Cumulative Supplement to the Orange Book from December 2014 (yes, the paper version of the publication is still used!), I stopped at a section I had seen may times before, but to which I had not paid a lot of attention: Section 1.6, titled “Report Of Counts For The Prescripton Drug Product List.”  It’s buried deep in the bowels of each Orange Book Cumulative Supplement  (but is not included in each annual edition) and is probably ignored by most folks.  Here’s how that section is described in the December 2014 Orange Book Cumulative Supplement:

This report provides summary counts derived from the product information in the Prescription Drug Product List and the current Cumulative Supplement.  Products included in the counts are domestically marketed drug products approved for both safety and effectiveness under section 505 of the Federal Food, Drug, and Cosmetic Act.  Excluded are approved drug products marketed by distributors; those marketed solely abroad; and those now regarded as medical devices, biologics or foods.

The baseline column (Dec 201[3]) refers to the products in the Prescription Drug Product List.  For each three-month period, a column of quarterly data is added which incorporates counts of product activity from the previous quarter(s) with those in the baseline count.

That description sounds pretty humdrum, and the numbers provided for each category and subcategory seem just as uninteresting – at least until they’re put into historical perspective.  And that’s just what we did.  We went back to the 1987 Orange Book (7th edition) – the first year after FDA transitioned from a fiscal year to a calendar year Orange Book publication schedule – and pulled the numbers from each December from 1986-2014 for two categories of drug product information: Drug Products Listed and Number of Applicants ("NoA").  We also looked at the following subcategories under the Drug Products Listed category: Single Source, Multisource, Therapeutically Equivalent ("TE"), and Not Therapeutically Equivalent ("Not TE").  Here’s the table we put together with the information we culled: 

The numbers from the table above are even more illuminating when put into graphic format.  Below are several tables, first showing graphically the numbers for all of the categories in the table above, and then breaking out some of the categories (by number or percent).

The historical Orange Book data show some interesting trends – many of which seem self-evident.  First, the number of marketed drug products has grown significantly in nearly 30 years – increasing by more than 80%.  Second, generic penetration post-Hatch-Waxman continues to grow.  According to the IMS Institute for Healthcare Informatics and the Generic Pharmaceutical Association (here and here), 86% of prescriptions dispensed in the United States in 2013 were for generic drugs. That figure is pretty close to the 84.1% figure above for multisource drugs listed in the “active” (i.e., Prescription Drug Product List) section of the Orange Book.  Similarly, the number of therapeutically equivalent (i.e., “A-rated”) drugs continues to grow – from 65.2% in 1986 to 83.2% at the end of 2014.  Meanwhile, the number of drug products not therapeutically equivalent (i.e., “B-rated”) continues to decrease – from 10.8% in 1986 to just 0.8% in 2014.  This significant (more than 86%) decrease may be due to the fact that post-Hatch-Waxman, drug products approved under an ANDA are not “B-rated.”  Prior to Hatch-Waxman, and as a result of the Drug Efficacy Study Implementation program, FDA approved many ANDAs with a “B” therapeutic equivalence rating.  Finally, the number of applicants increased by more than 178%.  Although there’s been a lot of consolidation among companies over the past decade, and some companies may have multiple subsidiaries, that’s a pretty significant increase in the spread of companies, and seems to show the continuing development of a robust pharmaceutical industry.  

Viewed as a whole, the data convey a clear message (at least to this blogger): the Hatch-Waxman Amendments, now in their 31st year post-enactment, have been a great success.  The two competing goals of the legislation – to spur new pharmaceutical development and to encourage greater access to generic drugs – have thus far been met.  That’s an important message to keep in mind as Congress considers proposals (see here, here, and here) that some folks argue might upset the balance created back in 1984. 

Attached here is the obituary of Frank Hurley, as issued by his company RRD International.  Frank was a Co-Founder of RRD as well as its Chairman and Chief Scientific Officer.  The obituary’s rich detail correctly describes his professional reputation as the premier innovator in his field, whose expertise made possible the development of products that advanced the cause of medicine.  Moreover, the obituary notes the personal qualities that made him so well loved and, now, so greatly missed by so many.

We at Hyman, Phelps & McNamara, P.C., join with Frank’s family, his colleagues at RRD, and his countless friends in mourning his passing.  Some of us have known and worked with Frank since he founded his first company, BRI International, Inc., in 1971.  On the professional level, Frank was simply the best at what he did, providing expert advice that was always clear, insightful, and useful.  As a husband and a father, he was the best.  On the personal level, Frank was a great companion in good times and bad – thoughtful, good-humored, and generous.  We will miss him greatly.

By John R. Fleder & Riëtte van Laack –

On Friday, January 30, almost nine months after the oral argument, the U.S. Court of Appeals for the D.C. Circuit issued its Opinion in POM Wonderful Inc. v. FTC.  We have previously blogged on this case (see here and here).  Although the Court provided some very limited relief to POM Wonderful, LLC. and the other petitioners (collectively “POM”) from a 2013 FTC cease-and-desist order, the FTC Chairman has already described the court ruling as “a victory for consumers.”

In 2010, the FTC filed an administrative complaint against POM alleging that a series of advertisements for POM’s products violated the FTC Act.  The FTC alleged that POM’s advertising constituted claims that the products could treat, prevent, or reduce heart disease, prostate cancer, and erectile dysfunction. According to the FTC, those claims were false and misleading because POM did not have valid and adequate scientific evidence to substantiate its claims.  After extensive administrative proceedings, in 2013, the FTC ruled that POM violated the FTC Act and issued a cease and desist order prohibiting POM from making health benefit claims for its products without competent and reliable scientific evidence.  Specifically, the FTC’s Order barred POM from making disease claims (claims that its products treat, prevent, or reduce a disease), unless such claims are supported by at least two randomized, controlled, human clinical trials (“RCTs”).

POM sought judicial review of the FTC’s Order in the D.C. Circuit.  POM made a broadside attack on that Order, claiming it lacked substantial evidence and violated POM’s First Amendment rights.

The Court initially concluded that POM’s ads “mischaracterized the scientific evidence concerning the health benefits of POM’s products.”  Slip. Op. at 2.  The Court ruled that there was no basis for setting aside the FTC’s conclusions that many of POM’s ads made misleading or false claims.  Id. at 3.  This conclusion was not altered by the fact that POM had spent more than $35 million on pomegranate-related medical research, sponsoring more than one hundred studies at forty-two different institutions.  Id. at 4.

Many may wonder if the FTC and the D.C. Circuit would not accept as adequate that quantity of product-specific research, how can any company convince the FTC or a court that the company had adequate substantiation?  Here, what probably sank POM were the explicit claims that POM made that the Court said were false and misleading.

Advertisers often try to avoid arguments that their ads are misleading by qualifying the ads through words that present less than an unqualified claim.  That strategy did not work here.  POM argued that it had properly qualified its claims by using words such as “promising” “initial” and “preliminary.”  The FTC and the Court rejected this argument.  The D.C. Circuit seemed to adopt the FTC’s conclusion that those words did not neutralize the claims made when the positive results to consumers were otherwise described in unequivocally positive terms.  Id. at 21.

The Court next rejected POM’s argument that it was unnecessary for POM to have one or more RCTs to substantiate disease claims.  The Court cited the FTC for an explanation of the importance of control groups, and having double-blinded studies, concluding that “it is less likely that participants or investigators will consciously or unconsciously take actions potentially biasing the results.  Id. at 25-26.

Next, the Court rejected POM’s argument that requiring RCTs to substantiate disease related claims about food products was too onerous.  Id. at 27-28.  Indeed, the Court acknowledged that RCTs may be costly but ruled that “if the cost of an RCT proves prohibitive, petitioners can choose to specify a lower level of substantiation for their claims.”  Id. at 28-29.

As noted above, the Court rejected POM’s argument that it had effectively qualified its claims through words such as “preliminary.”  However, the Court softened the blow of that finding by making another important finding that should be of use to many advertisers in future cases: “An advertiser thus still may assert a health-related claim backed by medical evidence falling short of an RCT if it includes an effective disclaimer disclosing the limitations of the supporting research.”  Id. at 29.  We expect that faced with the option of conducting expensive RCTs or including an effective disclaimer, many advertisers will choose the latter.  However, whether the FTC or a reviewing court accepts the disclaimer as adequate will be closely watched in future cases.

The Court reaffirmed the general principle that there is no First Amendment protection for misleading advertising.  The D.C. Circuit seemed to have no difficulty summarily concluding that the FTC correctly determined that many of POM’s ads were deceptive.  Id. at 34-35.

The Court next reviewed whether the First Amendment permitted the FTC’s decision to require RCTs.  It is at this point in the Court’s Opinion where the worm started to turn a bit on the FTC.  The Court employed the general test for commercial speech set out by the Supreme Court in the Central Hudson case.  It first ruled that the FTC’s Order requiring an RCT satisfied the First Amendment because the FTC had a substantial interest in ensuring the accuracy of commercial speech and the FTC had adequately demonstrated that requiring an RCT was no more extensive than necessary to serve the stated FTC interests.  Id. at 37-38.  Therefore, the Court rejected on constitutional grounds, POM’s argument that the FTC could not impose “a general RCT-substantiation requirement for disease claims.”  Id.

However, the Court concluded that the FTC’s Order against POM was unconstitutional to the extent it mandated two (as opposed to one) RCTs “as an across-the-board requirement for any disease claim.”  Id. at 38.  It ruled that the FTC failed to justify a “categorical floor of two RCTs for any and all disease claims.”  Id.  In reaching this conclusion, the Court noted, among other things, that FDA seemed to only require one RCT (at least in certain circumstances).  In addition, it noted that even the FTC itself had not consistently required two, or in some cases even one, RCTs.  Id. at 39-44.  Nevertheless, the Court ended its decision by stating that the FTC is not necessarily barred in future cases from imposing a two-RCT substantiation requirement.  Id. at 45.

So what conclusions can we derive from this decision?  One weekend probably does not allow us enough time to do justice to that question.  However, it is quite likely that this ruling was a compromise reached by the three judge panel.  As noted earlier, it took almost nine months for the Court to render its decision.  One can fairly guess that the panel had substantial internal debates about the RCT issue and may have compromised by allowing for one RCT but generally drawing the line there.  Indeed, the writers of this analysis are hard-pressed to understand how the Constitution allows for the government to require one RCT, but prohibits the FTC from requiring two RCTs, at least in this case.

The Opinion is filled with enough qualifiers and explanations to make it almost impossible to set forth any clear principles from this case.  Perhaps the only clear ruling is the Court’s reaffirmation of the principle that regardless of the substantiation an advertiser has, the advertiser is not permitted under the FTC Act or the Constitution to engage in deceptive advertising.  The ruling is evidence that the two-RCT substantiation requirement is challengeable.  This combined with two of the five Commissioners questioning the two-RCT substantiation requirement in recent FTC consent orders, suggests that we may well see fewer two RCT orders in the future.

This decision is unlikely to be the end of this litigation.  First, POM can seek rehearing from the three judge panel that decided this case and/or from the entire D.C. Circuit sitting en banc.  Given the unanimous ruling of the Court, it is unlikely that the D.C. Circuit will alter this ruling.  In addition, POM can seek Supreme Court review of the decision.  Because the D.C. Circuit’s ruling has many qualifiers, it may be very difficult for POM to articulate a basis warranting the Supreme Court to take the case.

As we previously noted, in the FTC’s Complaint filed in 2010, the FTC reserved the right to file a court action seeking restitution and other remedies after it issued a cease and desist order and the order becomes final.  Unless, POM can rally from a double digit deficit in the ninth inning of this game, we expect the FTC will file that court action.  As a result, one must wonder if the time has come for POM to seek a settlement with the FTC to avoid a restitution court action that could potentially cost the company many millions of dollars.

By James E. Valentine* & Anne Marie Murphy –

The first month of 2015 has seen two policy proposals that would expand clinical trials data sharing.  On January 14, the Institute of Medicine (“IOM”) released its report on “Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risks,” recommending an approach to clinical trial data sharing that parallels the clinical trial life cycle.  While IOM does not have authority to enforce these recommendations, its report may set expectations for stakeholders for the responsible sharing of clinical trial data.  Meanwhile, the House Energy & Commerce Committee released a discussion draft of 21st Century Cures Act (see our previous post here), which includes provisions on “Improving Clinical Trial Data Opportunities for Patients.”  A report from the Senate Health, Education, Labor & Pensions Committee, titled “Innovation for Healthier Americans,” also includes provisions on clinical trial reform.  These proposals come just two months after NIH issued its proposed rule for clinical trials registration and results reporting for ClinicalTrials.gov (see our previous posts here and here). 

IOM’s Recommendations for Clinical Trial Data Sharing

The IOM report sets out a plan that would allow for the sharing of clinical trial data.  Doing so presents risks, burdens, and challenges, particularly on regulated industry.  The report takes into consideration the benefits, risks, and challenges of data sharing for key stakeholders, including study participants, sponsors, regulators, investigators, research institutions, journals, and professional societies.  IOM sets out four broad recommendations for clinical trial data sharing:

1. Data sharing should be the expected norm with commitments from stakeholders to move toward this goal;
2. Various types of clinical trial data should be shared no later than the times specified in the report (see timeframes in the figure below);
3. Holders of clinical trial data should operationally mitigate the risk and enhance the benefits of sharing sensitive clinical trial data; and
4. A multistakeholder body with global reach and broad representation should be convened to address challenges with data sharing.

A key concern addressed by IOM is the risks associated with sharing clinical trial data, particularly participant data and clinical study reports.  The report recommends addressing this through controls on data access in ways that would not compromise the usefulness of the data sharing for the generation of additional scientific knowledge.  Appreciating that de-identification and data security alone do not always provide adequate protection, IOM determined that data use agreements could be a vehicle for reducing these risks and disincentives for sharing clinical trial data.

Additionally, IOM developed an approach to clinical trial data sharing for various key points along the clinical trial life cycle (see figure below), endorsing specific timeframes and providing recommended formats for sharing clinical trial data.

(Source: IOM)

21st Century Cures’ Proposed Improvements

The draft 21st Century Cures Act includes a subtitle devoted to “Building a 21st Century Data Sharing Framework.”  Two of the provisions offered by Representatives Morgan Griffith (R-VA), Leonard Lance (R-NJ), and Larry Bucshon (R-IN) directly relate to FDA-regulated clinical trials.  These provisions, Sections 2081 and 2082, seek to (a) establish a data sharing framework to enable patients and physicians to better identify ongoing clinical trials and (b) facilitate further research using clinical trial data. 

Section 2081 would amend Section 402(j) of the Public Health Service Act (42 U.S.C. § 282(j)) to have NIH standardize data on ClinicalTrials.gov to allow for easier use of the data by the public and make registration and results information easily comparable.  It would also require a data format that employs comprehensive health care terminology, so that it is compatible with electronic health records and can match to diagnosis or procedure coding systems (e.g., the International Classification of Diseases or the Current Procedural Terminology).  The focus of this section is recruitment information, such as eligibility criteria.  The provision would also require NIH to convene a public meeting to seek advice on these enhancements, including on usability, functionality, and search capability.  The deadline for implementation of these requirements would be one year after the date of enactment.

Section 2082 would lead to the development of a clinical trial data system for purposes of allowing registered users to conduct further research using clinical trial data that would serve as a guide for future medical product development.  FDA and NIH would enter into a collaborative agreement (to be known as the “Clinical Trial Data System Agreement”) to implement systems that would make standardized, de-identified clinical trial data available.  The systems would consist of solely government-sponsored trials of medical products that are approved or have discontinued development.  Certain highly qualified individuals at educational institutions or nonprofits could apply to enter into a cooperative agreement with the agencies so long as they are not involved in the sponsoring or conduct of clinical trials and agree to disseminate results of their research.  These individuals would serve as neutral third parties, working with industry, academic institutions, and FDA, and would protect confidential information contained in the system.

Three Frameworks Moving Forward

Although they have no direct link to NIH’s rulemaking, it is unclear how either the IOM recommendations or provisions in the 21st Century Cures Act may influence NIH’s proposed framework.  For example, the IOM report recommends making lay summaries of results available to trial participants and summary level results be made available publicly.  Whether such non-technical and technical summaries should be required is being explicitly considered under the NIH rulemaking.

Both IOM and Congress’s policy proposals have generated additional attention on the benefits and risks of sharing clinical trial information; meanwhile, NIH is continuing to collect comments on its proposed rule through February 19. 

By Karla L. Palmer –

A very busy House Energy and Commerce’s Subcommittee on Health (chaired by Joe Pitts (R-PA)) held a hearing earlier this week to review six bi-partisan bills intended to benefit veterans, address the prescription drug abuse crisis, secure access to medical care, and improve certain provisions of the Controlled Substances Act.  Several witnesses testified in support of the bills.  A link to the bill summaries, witness list and testimony is available here. Two of the bills should seem familiar and of particular interest to those following DEA matters.

The first, H.R. 4299, titled “Improving Regulatory Transparency for New Medical Therapies Act,” was first introduced in March 2014 (see our previous post here).  The current version would amend 21 U.S.C. § 811(a); specifically, any request by the Secretary of HHS to control a drug or substance not previously scheduled, “shall be commenced not less than 120 days after receipt of written recommendations by the Secretary.”  The bill continues, “the final rule [scheduling the drug] shall be issued not later than 60 days after the date on which both the public comment period has closed and the substance is the subject of an approved new drug application.” Recall that DEA’s delay in scheduling new drugs made headlines (as reported here and here), when Eisai (maker of seizure treatment medication FYCOMPA) sued DEA after a delay in excess of a year in scheduling FYCOMPA.  Eisai later sued FDA over a related issue involving the start of new chemical entity exclusivity (see our previous poet here).  Dr. Nathan Fountain, on behalf of the Epilepsy Foundation of America, yesterday testified that DEA’s scheduling of new molecular entities lacks transparency and timeliness. He noted that the time period between drug approval and scheduling has increased over the years almost five times (from an average of 49.3 days to an average of 237.6 days).  Dr. Fountain urged that passage of the bill would permit innovative treatments to reach the market and provide a clear timeline for availability. 

Seeking to ensure timely manufacturing of study drugs, H.R. 4299 would permit drug manufacturers to more quickly obtain a DEA registration when using controlled substances in only clinical trials.  The DEA would be required – in accordance with to-be-enacted regulations — to grant a manufacturer registration or serve an order to show cause on the applicant not later than 180 days after receipt of an application (and all other information the Attorney General deems necessary to make a determination).  One question remaining is what exactly is “all other information the Attorney General deems necessary to make a determination,” and, whether a claim that DEA has not received such information — whatever that information may be — could significantly delay the circumvent the 180-day deadline. 

The second DEA-related bill addresses the definition of “imminent danger” in the context of immediate suspension orders, and would provide for greater oversight of DEA’s activities.  Note that Immediate Suspension Orders permit DEA to bypass the typical Show Cause process and suspend a DEA registration without notice or a hearing.  H.R. 471, titled “Ensuring Patient Access and Effective Drug Enforcement Act of 2015,” is purportedly based on former H.R. 4079, which passed the House last year.  The new bill is similar to S. 2862 (see our previous post here).

New H.R. 471 would modify the definition of “imminent danger to the public health and safety” to mean that, “in the absence of an immediate suspension order, controlled substances: (1) will continue to be intentionally distributed or dispensed (a) outside the usual course of professional practice or (b) in a manner that poses a present or foreseeable risk of serious adverse health consequences or death; or, (2) will continue to be intentionally diverted outside of legitimate distribution channels. 

S. 2862 differs from from H.R. 471 in at least two material respects: First, it tied imminent danger to dispensing and distribution by a registrant “who knows or should have known through fulfilling the obligations of the registrant under the Act, or has reason to believe that” dispensing is outside the usual course of professional practice….”  In other words, the suspension would be tied to the registrant with knowledge of the wrongful activity.

Second, the new bill does not seem to tie “imminent danger” to a “registrant’s” knowledge.  And, it defines “imminent danger” as those situations when controlled substances will “intentionally be distributed or dispensed …” or will “continue to be intentionally diverted outside legitimate distribution channels.” The bill is unclear about whose “intent” counts for the purpose of the “imminent danger” determination – is it a registrant, a downstream user, an upstream supplier?    

Like proposed legislation introduced last year (see our previous post here), the bill also proposes to amend 21 U.S.C. § 824 to provide a registrant facing revocation or suspension of a DEA registration the opportunity to submit a corrective action plan within 30 days after receipt of an order to show cause.  The new provision would require DEA to review a corrective action plan to determine whether to dissolve, modify or continue with show cause.  The bill states that the corrective action provisions do not apply to immediate suspension orders. 

Lastly, the bill contains reporting requirements concerning the effect of DEA enforcement activities on patient access to controlled substances and diversion.  The report must be prepared in consultation with patient groups, pharmacies, manufactures and other entities throughout the pharmaceutical manufacturing and distribution chain. 

By Jennifer D. Newberger –

The question of what constitutes an accessory has never been well answered.  In a December 1996 guidance document, Medical Device Quality Systems Manual: A Small Entity Compliance Guide, FDA said that accessory devices are devices “packaged, labeled, and distributed separately to a hospital, physician, etc., for health-related purposes.”  Apart from this, no definition of this statutory term was ever provided.   Despite the lack of a definition for accessories, FDA historically classified accessories either by classifying the accessory in the same class as the parent device, or by issuing a separate classification regulation. 

On January 20, 2015, FDA issued a draft guidance document putting forth a definition for accessory, and proposing a new way of classifying accessories.  The draft guidance defines an accessory as a “device that is intended to support, supplement, and/or augment the performance of one or more parent devices.”  This definition is further parsed as follows:

• “A device supports the performance of a parent device by enabling or facilitating that device to perform according to its intended use.”
• “A device supplements the performance of a parent device if it adds a new function or a new way of using the parent device, without changing the intended use of the parent device.”
• “A device augments the performance of a parent device by enabling the device to perform its intended use more safely or effectively.”

These distinctions are likely to be difficult to apply in practice.  To provide more clarity, FDA gave some examples, some of which seem questionable.  For example, FDA states that a rechargeable battery intended to operate when paired with an automated external defibrillator (AED) is an accessory to the AED because it is intended to support the AED by enabling it to defibrillate.  It would not seem that a battery that is required for the operation and function of the parent device would be considered an accessory, but rather part of the parent device itself.

As an example of an accessory that “supplements” the parent, FDA cited a pulse oximeter that allows a multi-parameter monitor to display oxygen saturation but does not change its intended use:  to record and display multiple physiological parameters.  While multi-parameter monitors are cleared to display specific parameters, including oxygen saturation, they are rarely cleared for use with specific devices.  Additionally, a pulse oximeter is a finished device with its own regulatory classification that requires 510(k) clearance.  It is therefore not evident that a pulse oximeter would appropriately be considered an “accessory” to a multi-parameter monitor.  In light of the examples provided, the definition of an accessory would seem to include a larger number of devices than previously believed to be accessories, and could presumably include any device that, for any purpose, is intended to be used with another device.

In addition to questionable examples of accessories, the draft guidance proposes that manufacturers consider submitting de novo classification petitions for device accessories.  The intent behind the proposal may be well-founded:  some accessories may have a lower risk profile than their parent, and therefore may warrant being regulated in a lower class.  The application, however, seems flawed.  First, as noted above with respect to the AED battery, some “accessories” are key to the functionality of the device, and it is debatable whether FDA would clear or approve a submission that did not include a key part of the product. Second, the utility of the de novo process for accessories would be limited because it would apply only to accessories “of a new type.”  Finally, it is not clear in what circumstances use of de novo for an accessory would be appropriate or practical.  FDA proposes this approach in very high-level, theoretical terms, but provides no examples of when de novo classification for an accessory may actually be suitable.

While it is welcome to, at long last, have FDA provide a definition of an accessory, the examples provided do not seem to fit the traditional understanding of an accessory.  Furthermore, the proposal to utilize the de novo pathway is likely to be beneficial only in limited circumstances that are not entirely evident.  Thus, while the draft guidance does provide a definition, it will not likely alter the way in which accessories are cleared. 

By Kurt R. Karst –      

For months we have been waiting with bated breath for the promised January 2015 release of a discussion draft of legislation to implement the 21st Century Cures Initiative, which was launched in April 2014 by now-Chairman of the House Energy and Commerce Committee Representative Fred Upton (R-MI) and Committee Member Representative Diana DeGette (D-CO).  That wait came to an end on January 27, 2015 when an announcement was posted on the Committee website stating: “21st Century Cures Legislative Phase Now Underway.”  The Committee released a nearly 400-page discussion draft of the 21st Century Cures Act, a 13-page section-by-section summary of the draft bill, a 7-page white paper, and a 1-page discussion document.   

The release of the discussion draft was immediatly acknowledged by several organizations, including the Advanced Medical Technology Association, the National Health Council, United for Medical Research, Research!America, the Biotechnology Industry Organization, and the Pharmaceutical Research and Manufacturers of America, and by some Members of Congress (here and here).  Most folks still need time to digest the discussion draft, but don’t seem to be dissatisfied with the first draft; however, there is a growing opposition to the draft bill.  The Generic Pharmaceutical Association issued a press release stating that the organization “is deeply disappointed in [the] discussion draft” and that “in its current form, the bill would upset the important balance between creating competition and encouraging innovation in the pharmaceutical marketplace, putting savings at risk and limiting access to affordable medicines for millions of American patients.”  In addition, Representative DeGette and Representative Frank Pallone (D-NJ), Ranking Member of the Energy and Commerce Committee, expressed their disappointment with the draft.  In a press release, Representative DeGette said: “While I don’t endorse the draft document, I know that with continued engagement, we can reach a bipartisan consensus to help advance biomedical research and cures.”  Meanwhile, Representative Pallone said in a press release that he is “disappointed that the discussion document released today by Chairman Upton does not reflect true bipartisan collaboration,” and that “[i]n its current form, I am concerned that the nearly 400 page draft could create more problems for our health care system than it solves.”

Like many others, we’re still poring over the draft bill, some sections of which include a placeholder for draft text that will be added in the coming weeks, but we found some time to put together a post on the draft legislation.  We’re certain to have additional posts on the bill – or on specific sections of the bill – in the weeks and months ahead as we learn more and as the 21st Century Cures Act takes greater shape while it moves through the legislative process.     

The 21st Century Cures Act is chock-full of proposals, some of which are new and some of which are old (i.e., based on or inspired by previously introduced legislation), from various stakeholders.  As noted in the Energy and Commerce Committee’s discussion document:

Over the course of the last year, patients, providers, innovators, regulators, and researchers from around the country have provided a wide range of specific ideas on how Congress can help accelerate the discovery, development, and delivery of promising new treatments and cures for patients and maintain our nation’s standing as the biomedical innovation capital of the world.  While it remains a work in progress, the legislative language included in the discussion document is based on such ideas, including proposals authored by both Republicans and Democrats.

The 21st Century Cures Act discussion draft has 5 titles.  Each title includes a series of proposals covering a wide range of drug, biologic, and medical device topics – from various “push” and “pull” incentives (see here and here), to orphan drugs, to clincial trial requirements, to social media, to controlled substances, to reimbursement, to . . .  well, you get the idea: there’s a lot in the draft bill!   Here’s the title framework from the discussion draft:

TITLE I – PUTTING PATIENTS FIRST BY INCORPORATING THEIR PERSPECTIVES INTO THE REGULATORY PROCESS AND ADDRESSING UNMET MEDICAL NEEDS

TITLE II – BUILDING THE FOUNDATION FOR 21ST CENTURY MEDICINE, INCLUDING HELPING YOUNG SCIENTISTS

TITLE III – MODERNIZING CLINICAL TRIALS

TITLE IV – ACCELERATING THE DISCOVERY, DEVELOPMENT, AND DELIVERY CYCLE AND CONTINUING 21ST CENTURY INNOVATION AT NIH, FDA, CDC, AND CMS

TITLE V – MODERNIZING MEDICAL PRODUCT REGULATION

Some of the interesting items this blogger tagged while going through the draft legislation are identified below (with subtitle or section and page number references to the discussion draft); but note that because of this blogger’s penchant for all things related to drug regulation (and especially the Hatch-Waxman Amendments, the Orange Book, and the Biosimilars Act), the items tagged below reflect my interest in those topics over other topics (though that doesn’t mean other topics aren‘t interesting . . . just that they’re probably more interesting to others with different predilections and expertise in those matters).

Title I of the draft bill includes an array of proposals intended to incorporate patient perspectives into the regulatory process and to help address their unmet medical needs.  This goal would be accomplished in part by requiring that a “structured risk-benefit assessment framework” be built into the new drug approval process that includes the development and use of patient experience data to facilitate a balanced risk-benefit consideration, and the development and implementation of “a consistent and systematic approach to the discussion of, regulatory decisionmaking with respect to, and the communication of, the benefits and risks of new drugs” (Section 1001; pages 8-15). 

Other sections of Title I further provide for surrogate endpoint qualification and use, and the qualification of other biomarkers (Subtitle B 1021; pages 15-28); modify the breakthrough therapy evidentiary standard and other provisions in FDC Act § 506 (Subtitle C; pages 29-34); foster the development of new antibiotics along the lines of the Antibiotic Development to Advance Patient Treatment Act (“ADAPT Act”) (see our previous post here) and the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms Act (“DISARM Act”) (Sections 1061-1064; pages 34-72); require greater transparency for expanded access programs (Subtitle G; pages 82-91); and allow for streamlined data review so that the sponsor of an approved prescription drug can submit “qualified data summaries” in a supplemental application for approval of a “qualified indication” (i.e., “an indication for the detection, diagnosis, prevention, treatment, or cure of cancer,” or other types of indications identified by FDA) (Subtitle J; pages 94-98).  The bill's provisions on antibiotic development may be considered in tandem with a proposal that will be included in the President’s 2016 Budget.  The White House laid out that multi-pronged proposal to combat antibiotic resistance in a fact sheet released on January 27th.   

As expected (see our previous post here), several provisions in the draft bill (Title I) would also create new patent and non-patent exclusivity opportunities.  Continuing a trend of “exclusivity stacking” started in 1997 with the creation of 6-month pediatric exclusivity, the draft Cures Act would extend a period of 3-year new clinical investigation exclusivity by 2 years if the NDA sponsor provides documentation to FDA demonstrating that:

(I) the new clinical investigations essential to the approval of the application or supplement and conducted or sponsored by the person submitting the application or supplement support the approval of a new indication or use for the drug that is the subject of the application or supplement; or

(II) the drug that is the subject of the application or supplement has been reformulated or redesigned so that the drug can reasonably (as determined by the Secretary in consultation with the person submitting such application or supplement) be expected—

(aa) to promote greater patient adherence to an approved treatment regime relative to the previously approved formulation or design of the drug;

(bb) to reduce the public-health risks associated with the drug relative to the previously approved formulation or design of the drug;

(cc) to reduce the manner or extent of side effects or adverse events associated with the previously approved formulation or design of the drug;

(dd) to provide systemic benefits to the health care system relative to the previously approved formulation or design of the drug; or

(ee) to provide other patient benefits that are comparable to the benefits described in items (aa) through (dd).

We can envision several instances in which this provision (Subtitle M; pages 118-122), if enacted, might come into play, including with the development of abuse-deterrent formulations of opioids. 

Another exclusivity stacking provision would provide a 6-month extension to the 5-year new chemical entity, 3-year new clinical investigation, and 7-year orphan drug exclusivity periods available to drug products approved under the FDC Act (and to patents listed in the Orange Book for a drug), and to the 4-year and 12-year reference product exclusivity and 7-year orphan drug exclusivity periods available to biological products licensed under the PHS Act if a sponsor obtains approval of a drug or biological product for a “new indication for use of the drug to prevent, diagnose, or treat [a designated] rare disease or condition.”  This provision (Subtitle N; pages 123-131) appears to be intended to address the situation where a product shows potential to prevent or treat both a prevalent and an orphan disease, but it is developed first (and perhaps only) for the prevalent disease.  As a result, many patients with orphan diseases don’t have viable access to potentially beneficial drugs because the drugs are approved only for the prevalent disease.  Indeed, there are numerous examples of drugs approved for a prevalent indication that are also used as an effective off-label treatment for patients with orphan diseases.  Clonidine is one such example.  It is approved for the treatment of high blood pressure, a prevalent disease, but clonidine can also be used to treat Tourette’s Syndrome, an orphan disease.  Clonidine, however, has never been developed for that orphan use.  The 6-month incentive provided by this provision in the draft bill would target a situation like that. 

The draft Cures Act also includes provisions (Subtitle L; pages 101-118) modeled after the Dormant Therapies Act of 2014 (S. 3004), which Senator Orrin Hatch (R-UT) introduced last December.  The Dormant Therapies Act is a redo of the Modernizing Our Drug & Diagnostics Evaluation and Regulatory Network Cures Act (“MODDERN Cures Act”), which was introduced in 2013 (H.R. 3116) and 2011 (H.R. 3497).  Among other things, the draft Cures Act would create a new guaranteed 15-year “protection period” for certain drug and biological products designated and approved as dormant therapies.  As part of the deal, however, companies must agree to waive patent rights. 

In what is a rather innovative way to approach the concept of “wildcard exclusivity” (see our previous post here) the draft Cures Act would amend the Generating Antibiotic Incentives Now Act (“GAIN Act”) (FDC Act § 505E), which amended the law to include a 5-year marketing exclusivity add-on for a drug product designated and approved by FDA as a Qualified Infectious Disease Product, to allow a sponsor to convey a portion of its exclusivity (currently pegged at 12 months) to apply with respect to one or more other drugs (Section 1063; pages 59-68).  Such conveyance – which could include the sale of exclusivity from one company to another company – would also apply to Orange Book-listed patents.  But there’s a catch!  In addition to certain cutoff periods for conveyance, the sponsor of an application to which exclusivity has been conveyed must make donations to the National Institutes of Health and to a “bona fide, independent patient assistance program.”  The amounts of the donations are still being ironed out, but donation amounts would not exceed 5% of sales of the recipient drug in the United States for a defined period and for a yet-to-be-determined total donation. 

Other topics of interest in other titles of the discussion draft include:

• Provisions concerning genetically targeted platform technologies for rare diseases under which accelerated approval is available based on the extrapolation of evidence that is reasonably likely to predict clinical benefit of a product (Section 2051; pages 150-153); 
• Revisions to human subject research regulations (Section 3001; pages 223-231); 
• The requirement that FDA “establish and implement a framework through which sponsors of drugs, biological products, or devices may submit to the Secretary a proposal for the incorporation of adaptive trial designs, Bayesian methods, or other alternative statistical methods into proposed clinical protocols and marketing applications for drugs, biological products, or devices” (Section 3021; pages 232-235);
• Changes to the Tropical Disease Priority Review Voucher provisions of FDC Act § 524 that broaden the voucher program to infectious diseases (Section 4045; pages 267-271); 
• In what seems likely be a nod to President Obama’s announcement at the 2015 State of the Union Address of the creation of a new precision medicine initiative, the Cures Act includes a placeholder for text on “Precision Medicine” (Section 2301; page 223);
• FDA succession planning (Section 4121-4122; pages 280-282); and
• A lot, lot more . . . . 

We’ll end this post with one more exclusivity provision included in the draft Cures Act.  Unlike all of the other exclusivity provisions in the draft bill, this last provision applies to generic drugs and biosimilars.  Tucked away in Title V of the draft legislation (Section 5001; pages 347-349), it gives FDA the authority to designate a drug or biological product as an “American-manufactured drug.”  Such a designation means, with certain limitations, that 180-day exclusivity applicable to generic drugs and the 1-year, 18-month, or 42-month period granted (as applicable) to an interchangeable biosimilar biological product will be extended.  The amount of that extension is still being debated, however.

As Porky Pig would say at the conclusion of a Looney Tunes cartoon, “That’s All Folks!” 

By Kurt R. Karst – 

Earlier today (January 26, 2015), FDA announced the first approval of an ANDA for a generic version of AstraZeneca Pharmaceuticals LP's (“AstraZeneca's”) NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg.  But it wasn’t Ranbaxy Laboratories, Ltd./Ranbaxy, Inc. (“Ranbaxy”) that scored the approval for its long-pending application (ANDA 077830); it was Teva Pharmaceuticals USA subsidiary Ivax Pharmaceuticals, Inc. that scored the approval of its application (ANDA 078003).  Generic NEXIUM is expected by some folks to be one of the most lucrative generic launches in years.

The fact that purported first-filer Ranbaxy was not the recipient of the ANDA approval could mean only one thing for the company: that FDA determined that Ranbaxy forfeited eligibility for 180-day exclusivity.  (FDA's approval of ANDA 078003 also appears to indicate that before approving the application, AstraZeneca waived successive and overlapping periods of pediatric exclusivity expiring on May 25, 2015 and August 3, 2015 and associated with U.S. Patent Nos. 5,690,960 and 5,714,504, respectively, that would otherwise have prevented ANDA approval until later this year.)  Indeed, in a Notice of Administrative Action filed in the U.S. District Court for the District of Columbia in pending litigation concerning the stripped tentative approvals for both generic NEXIUM and VALCYTE (valganciclovir) Tablets, 450 mg, FDA states:

Defendants . . . hereby withdraw their argument that Ranbaxy’s claims in this matter regarding generic esomeprazole are unripe and lack final agency action.

Today, FDA determined that Ranbaxy had forfeited its eligibility for 180-day exclusivity for esomeprazole because it failed to obtain tentative approval of its ANDA within 30 months after the date on which the ANDA was submitted and that failure was not caused by a change in or a review of the requirements for approval, and notified Ranbaxy of this determination.

The failure-to-obtain-timely-tentative approval basis for generic NEXIUM is the same basis FDA used to determine that Ranbaxy forfeited eligilbity for 180-day exclusivity for generic VALCYTE (see our previous post here), and that led Ranbaxy to sue FDA over the decision and the stripped tentative approvals (see our previous post here).  Both Dr. Reddy’s (represented by Hyman, Phelps & McNamara, P.C.) and Endo intervened in the case.  A merits decision in the case has been pending since Judge Beryl A. Howell issued a Minute Order earlier this month vacating a hearing scheduled for January 9, 2015.  Late on January 26th, Ranbaxy filed a Motion for Expedited Ruling on Pending Motions.

FDA also states in the court filing that the Agency responded to and denied a 2012 Citizen Petition (Docket No. FDA-2012-P-0661) related to generic esomeprazole.  In that petition, Sandoz Inc. (“Sandoz”) asked FDA to determine whether Ranbaxy forfeited 180-day exclusivity eligibility for generic NEXIUM as a result of FDA’s February 5, 2008 tentative approval of the application (which was later stripped).  The ANDA was received as of August 5, 2005, so February 5, 2008 was the 30-month anniversary date of submission.  Although FDA has previously indicated through at least one approval precedent (see our previous post here) that a tentative approval on the 30-month anniversary date is timely tentative approval for 180-day exclusivity forfeiture purposes, FDA’s denial of the Sandoz petition appears to be the first instance in which the Agency has publicly described its rationale.  

By Kurt R. Karst –      

It’s been a little more than 2.5 years since Section 505(w) was added to the FDC Act by Section 1134 of the 2012 FDA Safety and Innovation Act (“FDASIA”).  Section 505(w), titled “Deadline For Determination on Certain Petitions,” requires FDA to issue a final, substantive determination on a petition submitted pursuant to 21 C.F.R. § 314.161(b) – a so-called  “discontinuation petition” – “no later than 270 days after the date the petition is submitted.”  The provision, which many believe was included in FDASIA to make the bill compliant with the Statutory Pay-As-You-Go Act of 2010 (see our FDASIA Summary here), applies to any discontinuation petition submitted to FDA on or after July 9, 2012.  Unlike Section 505(q) petitions, which FDA must respond to within 150 days of receipt, FDA is not required to report to Congress on the Agency’s track record in responding to discontinuation petitions.  (Last December, we reported on FDA’s most recent Report to Congress on 505(q) petitions.)  So we took it upon ourselves to assess – and grade – FDA on the Agency’s efforts to meet the statutory deadline.  After all, when FDA is not subject to any oversight, the Agency has been known to slip on meeting statutory deadlines.  Just consider FDA’s 30-plus-year track record in meeting (or not) the 90-day statutory deadline for ruling on ANDA suitability petitions.  This blogger analyzed that record in an article for the William Mitchell Law Review’s Hatch-Waxman 30th anniversary edition, titled “Letting the Devil Ride: Thirty Years of ANDA Suitability Petitions Under the Hatch-Waxman Act.”

As we noted when the provision that would become FDC Act § 505(w) was initially proposed under FDC Act § 505(j)(4)(I), FDA may refuse to approve an ANDA if the Agency determines that the Reference Listed Drug (“RLD”) was withdrawn from sale for reasons of safety or effectiveness.  In addition, FDA can withdraw (or suspend) approval of an ANDA if the RLD is withdrawn from sale for reasons of safety or effectiveness (FDC Act § 505(j)(6)).  In that case, the RLD is removed from the Orange Book (FDC Act § 505(j)(7)(C)).

The Hatch-Waxman Amendments didn’t specify any procedure for FDA to follow in determining whether a drug that is withdrawn from sale by its manufacturer is withdrawn for safety or effectiveness reasons.  So FDA took it upon itself to create such a procedure, which is laid out at 21 C.F.R. § 314.161.  Prior to FDASIA’s enactment, FDA’s timeframe for responding to withdrawal petitions was all over the map; however, that’s probably because the Agency generally responded to discontinuation petitions only when it was necessary to do so (i.e., when FDA was nearing an ANDA approval decision).

By our tally, 41 discontinuation petitions were submitted to FDA since the July 2012 enactment of FDASIA and the end of 2014.  (As a side note, the first such petition, from August 2012, was the topic of a lawsuit against FDA – see our previous posts here and here.)  Of those 41 petitions, 3 (7.32%) were withdrawn before an FDA decision was published, and 3 (7.32%) are pending and within the 270-day deadline.  That leaves 35 petitions for which there is either a timely or untimely FDA decision.  So how did the Agency do?  As shown in the table below, FDA has timely responded to nearly 86% of Section 505(w) petitions.  That puts FDA in solid  “B” grade territory.

As you can calculate from the docket-specific information below that we compiled, most of the missed deadlines were not too far off the 270-day mark.  So, if we’re grading on a curve (vis-à-vis other statutory deadlines for FDA action), then perhaps FDA’s B” grade can be bumped up to a “B+” or “A-”.