By Mark I. Schwartz –

Unlike solid oral dosage form drugs that don’t require sterilization, generally, parenteral drug products must be sterilized and, due to their nature, many parenteral drug products cannot be terminally sterilized. This leaves aseptic manufacturing. In the aseptic process, the drug product and the container/closure are first subjected to sterilization methods separately, and then are brought together. Given that, in these circumstances, there is no process to sterilize the drug product in its final container, the final product must be filled and sealed in an exceedingly high quality environment. See FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (Sept. 2004), at 2.

As an example of what can go wrong in an aseptic environment, at a recent FDA Team Biologics inspection at a facility in Europe, investigators noted in the 483 a wide variety of what they concluded were microbiological-based manufacturing issues, including: a viral contamination event; mold-like material in the fermentation and purification areas; inadequate CAPAs related to contamination events involving a spore-forming microorganism and one from the species Methylobacterium; as well as a CAPA from a contamination event related to a soil bacteria (Bacillus thurengiensis); cleaning and cleaning validation issues; and inadequate environmental and microbial controls. (The 483 also contained three purportedly significant labeling observations, which we won’t dwell on here, given the subject matter of the posting.)

Theoretically, any one of these events, assuming they actually occurred as suggested by the FDA investigators, could have resulted in product contamination and recall, though it is not even clear that the products manufactured during this timeframe were ever released from the facility.

Given that much can go wrong in an aseptic manufacturing process, and microorganisms are ubiquitous in our environment, many firms find that significant microbiological contamination issues occur at facilities engaged in such manufacturing. Indeed, FDA has stated that the vast majority of drugs recalled due to nonsterility or a lack of sterility assurance in the U.S. have been produced via aseptic processing. Id. at 3.

And certainly much is alleged to have gone wrong at the European site inspected by FDA’s Team Biologics late last year. However, our ability to understand precisely what transpired is hampered by the liberal redactions that FDA made to the 483 before it was cleared for release by the agency. Nevertheless, the following has been alleged: first, the purported inadequate microbial control supposedly consisted of a failure to perform bioburden and endotoxin testing at certain steps in the manufacturing process.

Regarding the corrective and preventative actions that “…were found to be inadequate…”, 21 CFR Part 211 does not even speak of corrective and preventative actions (i.e., CAPAs). So, the investigators’ conclusion that they were inadequate is somewhat of a red herring. Rather, 21 CFR 211.192 requires that “…[a]ny unexplained discrepancy…or failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated. . . . ” So a more appropriate observation by FDA would have been that these investigations had allegedly not been thoroughly investigated.

One of the purportedly inadequate investigations involved a water breach from a cooling system that leaked into the adjacent holding tank due to an improper weld. The cooling liquid was analyzed as part of the investigation and the soil bug, Bacillus thurengiensis, was recovered. Yet, FDA investigators claimed that no CAPAs had been initiated “…to clean, disinfect, sanitize, or sterilize the cooling system.”

Another purportedly inadequate investigation was opened as a result of a contact sample which allegedly grew 96 colony forming units (presumably well exceeding the action level), including a species of Methylobacterium and certain spore forming rods.

The viral contamination event is not well described by FDA in the 483 but, to the extent that it actually occurred, it likely contaminated the cell line, and apparently the firm was allegedly unable to detect where the virus had allegedly entered the manufacturing process. In addition, the FDA investigators criticized the firm because, allegedly, “…[a]dditional samples are not tested from the previous harvests in an effort to verify that virus is not present in low concentrations or non-uniformly throughout the fermenter.”

Next, cleaning and cleaning validation are significant programs at aseptic processing facilities. When either is inadequate the result is likely to provide evidence of microbiological contamination, because dirt and residue can be vehicles for, and oftentimes nutrition for, microbes. In this case, regarding cleaning validation, there was allegedly no procedure or requirement to repeat it or to re-evaluate it, even when circumstances may have warranted. Allegedly, a non-conformance was opened after two valves on a tank holding sterile product were observed to have a residue (believed to be an aggregated protein). Yet, allegedly, no samples were taken of the residue for definitive identification or for microbiological testing.

Regarding the cleaning operations, FDA concluded that equipment which had been previously cleaned, and verified as cleaned by an operator, was observed to allegedly contain a dried white residue. There was also allegedly inadequate cleaning of the fermentation and purification areas of the facility, where investigators noted “…[t]he trench next to the steam condenser in fermentation contained growth-like blobbed material as well as black mold-like material. One leg for the tank was observed to have black mold-like material on it.”

Finally, there were several alleged instances where equipment appeared to be wet and where the residual moisture was not evaluated for microbial contamination. Specifically, a tank was “…observed to contain a significant amount of residual liquid which covered more than 80% of the bottom of the vessel…” and in another situation, “…residual water was observed inside piping for tanks…and rouge was observed…[yet]…[t]here were no swabs taken inside the tanks or piping for microbiological testing. There was no bioburden or bacterial endotoxin testing of the remaining liquid. . . .”

Industry practice dictates, and FDA strongly recommends, that sterile drugs be manufactured using aseptic processing only when terminal sterilization is not feasible. Id. In other words, aseptic manufacturing is fraught with problems that are absent when manufacturing products that can be terminally sterilized. These inspectional observations would purport to buttress this proposition. Of course, biological products, like the drugs manufactured at this facility in Europe, cannot be terminally sterilized.

We’ll have to wait and see whether CBER determines that the observations in this 483 meet the threshold of regulatory significance to warrant a Warning Letter. Rest assured, you will be kept posted on all developments.  

By Ricardo Carvajal –

The prompt was an invitation to speak at the 21st Annual Tulane Environmental Law and Policy Summit on the pros and cons of genetically engineered food animals, in the wake of FDA’s approval of AquAdvantage salmon as a new animal drug (a topic we’ve addressed here, here, here, here, and here).  The panel featured a lively exploration of the issue from multiple perspectives, yielding perhaps only one point of agreement: the debate will continue, and is one to which any developer of such products had better be attuned.

A more traditional approach to food production was the subject of a panel on urban farming, a movement that has blossomed in a number of cities throughout the U.S. in response to demand for locally produced foods.  For the moment, the scale of production appears too small to face significant hurdles under Federal regulation, particularly requirements scheduled to take effect under FSMA.  That could change as investors start to ply the sector and finance development of larger scale production.  State and local requirements are another matter, especially those that govern zoning, land use, and product liability.  Solutions to those challenges have been found in a number of municipalities, and the movement can be expected to continue to grow in response to locavore demand.

Three detours were well worth any food and drug lawyer’s time.  The first was to the Audubon Butterfly Garden and Insectarium, which features a stunning collection of insects and related critters – many of importance in agricultural production.  When hunger strikes, the Insectarium houses Bug Appétit, a forward-looking snack bar that features culinary creations made from a variety of insects, and is in tune with the developing market for commercially produced insect-derived foods. 

The second detour was to the New Orleans Pharmacy Museum, which is devoted to the early history of pharmacology.  The site belonged to Louis Dufilho, reportedly America's first licensed pharmacist, and includes exhibits on a wide range of products and practices common in 19^th century – some of which helped to set the stage for passage and enactment of the 1906 Pure Food and Drug Law.

Finally, there’s the music – food and medicine for the soul?  One of its finest purveyors is Johnny Vidacovich, a New Orleans institution who maintains a performing schedule that would make many-a-youngster wilt – and who provided a fine cap to a very worthwhile 48 hours.

By Ricardo Carvajal & Jay W. Cormier –

In response to a Congressional directive buried in the 2016 Consolidated Appropriations Act (“the Appropriations Act”), FDA issued an Import Alert targeting “[a]ny shipment of suspected or known GE salmon or product composed in whole or in part of GE salmon” for further evaluation.  The Appropriations Act, at section 761, purports to prohibit FDA from admitting such products during fiscal year 2016 “until FDA publishes final labeling guidelines for informing consumers of such content,” and further directs FDA to “develop labeling guidelines and implement a program to disclose to consumers whether salmon offered for sale to consumers is a genetically engineered variety.”

Ominous as it may sound for a would-be importer of GE salmon, the immediate impact of FDA’s Import Alert is negligible.  As well known to all the participants in this long-running drama, AquaBounty Technologies, Inc. – the unstated target of the Congressional directive and the Import Alert – won’t have any GE salmon ready for market during fiscal year 2016. 

As to the Congressional directive to publish “final labeling guidelines,” FDA previously issued draft guidance providing for voluntary labeling of GE salmon, consistent with the agency’s conclusion that there is no material difference between food derived from AquAdvantage salmon and its conventional counterpart (see our prior posting here).  To the extent that Congress is directing FDA to require such labeling, FDA could do so only by changing its conclusion regarding materiality, or changing its longstanding interpretation of that concept as embedded in § 201(n) of the FDC Act.  The first course of action would appear to lack a scientific basis, and the second would have significant implications that go beyond food labeling and extend to labeling of other FDA-regulated product categories, including drugs and medical devices. 

Given the wording of the Appropriations Act, it appears that FDA could finalize the draft GE salmon labeling guidance in its current form.  The Appropriations Act does not explicitly direct that labeling be mandatory, nor does it provide a statutory basis for FDA to impose such a requirement.  Congress knows how to write legislation to that effect; to wit, Congress has attempted and failed no less than eight times since 2010 to pass such legislation (here, here, here, here, here, here, here, and here).

In summary, this is but one more play in a playbook evidently intended to derail the domestic marketing of GE salmon by any means – even means that are highly implausible.  The signal sent to a company that is considering developing a food derived from a GE animal can hardly be encouraging.  Simply put, meeting the rigorous scientific and regulatory criteria established by FDA might not be the most significant or unpredictable barrier to success.   

By Kurt R. Karst –      

Whether notice of commercial marketing given before FDA approval can be effective and whether, in any event, treating [Public Health Service Act (“PHS Act”) § 351(l)(8)(A) (42 U.S.C. § 262(l)(8)(A))] as a standalone requirement and creating an injunctive remedy that delays all biosimilars by 180 days after approval is improper.

Those are the questions presented by Sandoz Inc. (“Sandoz’s”) in a Petition for Writ of Certiorari submitted to the U.S. Supreme Court earlier this week on the last possible day permitted for such a petition.  The highly anticipated petition is the first time – but certainly won’t be the last time – the Supreme Court has been asked to take up an issue raised by the text of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  The Sandoz Petition appeals one aspect of a highly fractured July 21, 2015 opinion handed down by the U.S. Court of Appeals for the Federal Circuit in a dispute between Amgen Inc. (“Amgen’s”) and Sandoz over Sandoz’s ZARXIO (filgrastim-sndz), a biosimilar version of Amgen’s NEUPOGEN (filgrastim) (see our previous post here).  FDA licensed ZARXIO on March 6, 2015 under BLA 125553. 

The provision at issue – PHS Act § 351(l)(8)(A) – states that a biosimilar (or subsection (k) “applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k).”  A 2-1 panel majority of the Federal Circuit ruled that licensure of a biosimilar application is required before an “operative notice” of commercial marketing can be given.  Specifically, in overturning a lower court decision on this issue, the Federal Circuit stated:

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.

In a dissenting opinion, Judge Chen found the 180-day notice of commercial marketing provision to be optional, just like the BPCIA’s so-called “patent dance” provisions (which were also ruled on in the Federal Circuit’s opinion). 

The importance of final resolution of the meaning of the BPCIA’s 180-day notice of commercial marketing provision – either in the context of Sandoz’s Petition, if it is granted, or in another case that could ultimately reach the Supreme Court (there are at least three similar lawsuits pending around the country, including this one) – cannot be understated.  The Federal Circuit's ruling on the notice of commercial marketing provision, if it is upheld, could have everlasting effect on the biosimilars industry (more so that the Court's ruling on the optional nature of the statute’s patent dance provisions).  And reference product sponsors may find (and argue for) new ways to apply it, perhaps in the context of supplemental applications submitted to FDA seeking changes to a licensed Section 351(k) biosimilar product.  Such supplemental applications may seek changes to the manufacturing process of a biosimilar product, or to add into labeling an indication previously omitted because of unexpired patent or non-patent exclusivity (e.g., orphan drug exclusivity) protections on the reference product.  Why not argue for a 180-day notice in those situations as well?

Sandoz rolls through many of these concerns in the company’s Petition, so we’ll just let the company do the talking here:

In a fragmented decision, the Federal Circuit has disrupted the careful balance struck by Congress between competition and innovation.  If not reversed, the Federal Circuit’s ruling will delay access by patients to all biosimilars for six months longer than Congress intended.  The Federal Circuit reached that result by adding an extra-textual limitation to the BPCIA’s “Notice of commercial marketing” provision.  That provision calls for “notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k),” i.e., the abbreviated biosimilar pathway. 42 U.S.C. § 262(l)(8)(A) (emphasis added).  The Federal Circuit held that an applicant “may only give effective notice of commercial marketing after the FDA has licensed its product.”  App., infra, 20a (emphasis added).

A majority of the Federal Circuit panel then enforced that erroneous reading by divorcing that provision from the BPCIA’s patent resolution regime and replacing the remedies expressly provided in the BPCIA with a new remedy: “a 180-day injunction beyond the express twelve-year statutory exclusivity period.”  App., infra, 43a-44a (Chen, J., dissenting).  As Judge Chen recognized in dissent, the majority effectively awarded sponsors “an extra-statutory exclusivity windfall” of 180 days more than Congress expressly granted.  App., infra, 44a (Chen, J., dissenting).  The Federal Circuit’s decision cannot be squared with the BPCIA’s text and purpose, and it conflicts with this Court’s precedents. As the district court observed, if Congress had wanted to add six months to the statutory exclusivity period, “it could not have chosen a more convoluted method of doing so.”  App., infra, 76a.

By its plain terms, the notice of commercial marketing provision simply calls for 180 days’ notice before a biosimilar is marketed. Regardless of whether notice is given before or after FDA approval of the biosimilar, the notice would serve the statute’s purpose of giving the reference product sponsor at least 180 days to initiate suit.  But special notice after FDA approval would be superfluous, as FDA licensure is a public act.  The Federal Circuit reached its erroneous conclusion by reading too much into the word “licensed” in subsection (l)(8)(A).  That adjective merely refers to the biosimilar product that will be marketed, which will be licensed by the time of marketing.  Nothing in the text provides that an applicant must wait until the FDA publicly approves its biosimilar, then provide “notice” of its self-evident intent to market that approved biosimilar, and then wait six months more before marketing its product.

The Federal Circuit compounded this error by disconnecting Section 262(l)(8)(A) from the BPCIA’s patent resolution regime and by creating a new remedy nowhere provided by the BPCIA: an injunction against commercial marketing until 180 days after post-approval notice is given. If Congress had so intended, it knew how to stay FDA approval for 180 days; it also knew how to authorize injunctions to enforce the notice provision.  It did neither.  Instead, it provided sponsors with a powerful remedy: a patent suit for artificial infringement that could be brought even before FDA approval.  42 U.S.C. § 262(l)(9)(B), (C); 35 U.S.C. § 271(e)(2)(C).  Although Amgen brought such a suit, it made no attempt (and still has not) to seek an injunction based on any alleged patent infringement by Sandoz.

Without any such patent showing by Amgen, the plain terms of the BPCIA authorized Sandoz to make its biosimilar filgrastim product Zarxio® immediately available to cancer patients upon FDA approval: (1) Sandoz already had provided Amgen more than 180 days’ notice of its intent to market, giving Amgen time to bring suit (which it did) and seek a patent-based injunction (which it did not), and (2) any statutory exclusivity period had expired, as Amgen already had enjoyed 24 years of exclusivity.  See App., infra, 8a-9a.  Instead, due to the Federal Circuit’s erroneous interpretation of the notice of commercial marketing provision, competition was excluded from the market well beyond the exclusivity period granted by Congress, and cancer patients had to wait many months after FDA approval of Sandoz’s product for access to more affordable medicine.

Sandoz’s petition does not address one aspect of Judge Lourie’s opinion that has long intrigued us: his suggestion that an additional 180 days of marketing exclusivity is not necessarily a consequence of the Federal Circuit decision.  In that opinion Judge Lourie stated:

Furthermore, requiring FDA licensure before notice of commercial marketing does not necessarily conflict with the twelve-year exclusivity period of § 262(k)(7)(A).  It is true that in this case, as we decide infra, Amgen will have an additional 180 days of market exclusion after Sandoz’s effective notice date; that is because Sandoz only filed its aBLA 23 years after Amgen obtained FDA approval of its Neupogen product.  Amgen had more than an “extra” 180 days, but that is apparently the way the law, business, and the science evolved.  That extra 180 days will not likely be the usual case, as aBLAs will often be filed during the 12-year exclusivity period for other products.

It’s possible that Judge Lourie envisioned that FDA will provide tentatively or conditionally approve biosimilars during the reference product’s exclusivity period and that this tentative or conditional approval would then allow a notice of first commercial marketing to be provided under the statute.  It’s not clear that this is an interpretation of the statute that would withstand judicial review.  And absent FDA following up on Judge Lourie’s suggestion, we may not have an answer to that issue in the near-term.

What are the chances that the Supreme Court will take up the Sandoz Petition?  That’s difficult to say, of course.  And the recent passing of Justice Antonin Scalia adds more unknowns to the mix.

By James E. Valentine –

Last month, the U.S. Government Accountability Office (GAO), the independent, nonpartisan agency that provides auditing, evaluation, and investigative services to Congress, publicly released the findings of a report on FDA’s handling of drug postmarket safety oversight.  As reflected in the title of the report, “FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement,” the focus was on the safety of drugs brought to the market more quickly through use of FDA’s expedited programs (breakthrough therapy, accelerated approval, fast track, and priority review).  The GAO report was commissioned by Congresswoman Rosa DeLaura, D-Conn., following the release of another GAO report in October 2015 that implicated the safety oversight of medical devices approved by FDA. 

The report sought to examine the status of postmarket safety oversight of drugs approved using one or more of FDA’s expedited programs, which are programs to facilitate and expedite the development and review of new drugs.  This would have allowed GAO to determine the validity of Congresswoman DeLaura and consumer advocates’ concern that the use of expedited programs increases the risk of unforeseen safety issues once marketed (e.g., because there is less information due to fewer, smaller, or shorter clinical trials).  However, because “FDA lacks reliable, readily accessible data on tracked safety issues and postmarket studies needed to…conduct systematic oversight,” there was not reliable data to allow GAO to test this hypothesis.

In the absence of information on postmarket safety reporting and oversight, the GAO report instead independently examined the use of certain expedited programs. Here are some highlights of GAO’s findings:

Expedited Program Requests: Fast Track and Breakthrough Therapy Designation

• Of the 772 requests for fast track designation FDA received from October 1, 2006, through December 31, 2014, FDA granted about two-thirds (or 525) of them.
• FDA denied one-fourth (or 207) of the request for fast track designation, and the remaining 40 requests were either withdrawn by the sponsor or the drug application was inactivated, terminated, or cancelled before FDA could make a decision on the request.
• Since fiscal year 2011, the number of requests FDA has granted fast track designation has increased, from 54 requested granted in fiscal year 2011, to 89 granted in fiscal year 2014.
• In contrast, FDA denied more than half (or 120) of the 225 requests for breakthrough therapy designation that the agency received since that expedited program was established in July 2012 through the end of December 2014.

Expedited Program Requests: By Product Category

• Of the 525 requests for fast track designation that FDA granted from fiscal year 2007 through the first quarter of fiscal year 2015, the most common product categories to be granted fast track were:
  • Antiviral with 112;
  • Oncology with 81;
  • Neurology with 74;
  • Anti-infectives with 55;
  • Gastroenterology and inborn errors with 46;
  • Hematology with 34; and
  • Cardiovascular disease and renal with 32.
• The most common product categories among the 71 requests for which FDA granted breakthrough therapy designation from July 9, 2012, through December 31, 2014, were:
  • Oncology with 15;
  • Antiviral with 14; and
  • Hematology with 14.

Approvals Using Expedited Programs

• About a quarter of the 1,717 drug applications that FDA approved from October 1, 2006, through December 31, 2014, used at least one expedited program.
• Of 444 approved drug applications that used one or more expedited programs, 344 (77%) used one expedited program, 78 used 2 programs, 20 used 3 programs, and 2 used all four programs.
• Priority review was the most used program, with 408 of the 444 drug applications (92%) receiving priority review.
• FDA review time was an average of 8.6 months for marketing applications for drugs that used at least one expedited program compared with 12.1 months for marketing applications for drugs that did not.
• The most common product category for drug applications approved by FDA from October 1, 2006, through December 31, 2014, that used at least one expedited program was:
  • Oncology with 19% of applications;
  • Antivirals with 17% of applications; and
  • Hematology with 12 % of applications.

GAO Recommendations

While GAO confirmed that expedited programs play a significant role in the development and review of drugs (as demonstrated by the findings described above), GAO made two recommendations to FDA that would facilitate the future assessment of whether these programs pose additional postmarket safety risks to patients once they are on the market:

• Develop comprehensive plans, with goals and time frames, to help ensure that identified problems with the completeness, timeliness, and accuracy of information in its database on tracked safety issues and postmarket studies are corrected, and
• Work with stakeholders within FDA to identify additional improvements that could be made to FDA’s current database or future information technology investments to capture information in a form that can be easily and systematically used by staff for oversight purposes.

While, in FDA’s comments to the GAO recommendations, the Agency concurred with these recommendations, FDA clarified that FDA-approved drugs that used an expedited program do not necessarily require different postmarket safety monitoring than other drugs, noting that tracked safety issues and postmarket studies are utilized to monitor all drugs after they are approved by FDA. Therefore, it is unclear, even once it has implemented these recommendations, whether FDA will increase scrutiny of postmarket safety risks for those drugs approved using an expedited program.

In collaboration with KPMG’s government pricing leaders, Hyman, Phelps & McNamara, P.C. (“HP&M”) will conduct a free webinar on the recently published Medicaid Rebate Final Rule (see our previous post here).  The webinar, titled “A Practical Guide the Medicaid Rebate Final Rule,” will be held on Friday, February 19 from 1:00 to 3:00 pm EST.  For information about the webinar and how to register for it, click here.  Speakers are HP&M’s Michelle Butler and Alan Kirschenbaum, and KPMG’s Jennifer Lospinoso and Timothy Nugent.

By Kurt R. Karst –      

Question: When was the first time FDA approved an ANDA containing a Paragraph IV certification to a patent listed in the Orange Book for DIPRIVAN (propofol) Injection, 10 mg/mL, approved under NDA 019627, and granted a period of 180-day exclusivity?

Buehler, Buehler?

If your guess is when Gary Buehler, R.Ph., was Director of FDA’s Office of Generic Drugs (“OGD”), you’re wrong. It was actually before Mr. Buehler was appointed Director of OGD in July 2001 (and perhaps while he was serving as OGD‘s Deputy Director in 1999).  When FDA first (and, to our knowledge, the last time, until recently) approved and ANDA for generic DIPRIVAN and granted a period of 180-day exclusivity, Roger L. Williams, M.D., then-Deputy Center Director for Pharmaceutical Science in CDER at FDA, signed the letter approving GensiaSicor ANDA 075102 (approved on January 4, 1999).  That exclusivity seems to have been triggered by commercial marketing, and expired on October 17, 1999.  That was a long time ago.  Bill Clinton was still President. 

Why all the history about the world of ANDA 180-day exclusivity as it existed prior to the December 2003 enactment of the Medicare Modernzation Act (“MMA”), when exclusivity was patent-by-patent and was triggered by the earlier of first commercial marketing or a final court decision of patent invalidity or non-infringement? After all, we now live in a post-MMA Hatch-Waxman world – and we have for some time now – where 180-day exclusivity is largely product-based, and where exclusivity, if eligibility for it is not forfeited, is triggered only through commercial marketing of the drug product. 

That’s all true . . . mostly.

As we noted in our “Bad Penny” post back in February 2014, pre-MMA 180-day exclusivity was not deleted from the law in 2003. Rather, it was put into hibernation for a set number of drugs (a list of which we provide in our previous post).  These days, pre-MMA 180-day exclusivity only comes out of hibernation every once in a while.  One day, it will make an appearance about as frequently as Brood X cicadas, a type of 17- year cicada.  And after that, it will be see about as often as a critically endangered animal.  Finally, pre-MMA 180-day exclusivity may one day become a mythological Hatch-Waxman creature, along the likes of Bigfoot or the Loch Ness Monster.

But we’re not quite there yet . . . .

Last week, after the January 2016 Orange Book Cumulative Supplement was published on FDA’s Orange Book website, we took a look at some of the new entries in the “Patent and Exclusivity Drug Product List.” One addition in particular stuck out like a sore thumb: a period of “PC” exclusivity (i.e., “Patent Challenge,” or 180-day exclusivity) for ANDA 205307 for Propofol Injection, 10 mg/mL, expiring on February 24, 2016. That period of 180-day exclusivity was not triggered by commercial marketing (ANDA 205307 was not even approved until December 22, 2015), but rather by an earlier final court decision with a holding on the merits on the exclusivity-bearing patent: U.S. Patent No. 8,476,010 (“the ‘010 patent”). That’s right!  We have a sighting of a relatively rare pre-MMA period of 180-day exclusivity.  And with a gap of about 17 years since the first period of 180-day exclusivity was granted for generic DIPRIVAN, it’s at least noteworthy. 

The exclusivity was triggered after Dr. Reddy’s Laboratories, Inc., a subsequent Paragraph IV filer to the ‘010 patent (ANDA 205067), filed a Complaint for Declaratory Judgment (after some previous patent infringement court proceeding) and obtained a Final Judgment on August 28, 2015 that the company’s proposed Propofol Injection drug product does not infringe the ‘010 patent. Add 180 days to that August 28, 2015 date and you come up with February 24, 2016.  That’s the date listed in the January 2016 Orange Book Cumulative Supplement for the expiration of 180-day exclusivity associated with ANDA 205307 (and the ‘010 patent).

So keep your eyes peeled folks. Pre-MMA exclusivity is still – or could be –lurking out there in the shadows of a number of old drug products.  When it does come up in the form of a newly listed patent, you have to be quick on the draw to get your certification in to FDA first.

By Mark I. Schwartz – [1]

According to our calculations, 2015 was a banner year, from CDER’s perspective, for foreign drug facilities receiving cGMP Warning Letters citing data integrity issues. While the overall number of cGMP Warning Letters issued by CDER was only 23 (compared, for instance, to 2011 with 42), the number with data integrity issues in 2015 was 18, equaling the number from 2012, and 15 of last year’s 18 were from inspections in either India or China, surpassing the prior high from those countries of 13, in 2014. 

Perhaps getting off to a slower start this year, on January 29th, CDER issued its first cGMP warning letter for a pharmaceutical facility in 2016, to Ipca Laboratories Ltd., (Ipca) in Mumbai, India, as a result of inspections at three of its manufacturing facilities: the Ratlam facility, the Pithampur facility, and the Piparia Silvassa facility.   The first of these facilities manufactures Active Pharmaceutical Ingredients (APIs), and hence the firm was cited for alleged violations under 21 U.S.C. 351(a)(2)(B), while the other two manufacture finished dosage form products, and hence were cited for alleged violations under 21 C.F.R. Parts 210 and 211. 

The investigators observed what was referred to as “systemic data manipulation and other CGMP violations and deviations” at the three sites. According to CDER, the quality system at the three sites did not adequately ensure the accuracy and integrity of the data generated at the facilities to support the safety, effectiveness, and quality of the drugs manufactured there. Intriguingly, the Warning Letter references an admission of data manipulation from an Ipca employee, as well as an anonymous email to management regarding the data manipulation.

The Ratlam Facility

1. The Failure to have Computerized Systems with Sufficient Controls to Prevent Unauthorized Access or Changes to Data

With regard to this alleged violation, CDER stated that: “[w]e found that controls on your computerized chromatographic instrumentation were not adequate to prevent analysts from manipulating processing parameters in order to obtain passing results. We also found that your computerized systems lacked controls to prevent the back-dating of test data.”

As evidence of alleged wrongdoing, among other things CDER cited to a 12 month commercial stability assay test for residual solvent in the API, performed by Gas Chromatography (GC), where standards and samples had allegedly been processed using different integration parameters, with no documented reason given. In addition, there were allegedly no controls in the software to prevent analysts from manipulating the integration settings in order to obtain passing results.

In what was an unusual twist for these sorts of inspections, the investigators spoke with an analyst who allegedly admitted that: “…if we find a failure, we set back the date/time setting and re-integrate to achieve passing results…”

2. Failure to Adequately Investigate and Resolve Critical Deviations

With this alleged violation, CDER is charging that the firm’s quality unit was aware of the lack of computerized controls to prevent data manipulation, and, despite that, they failed to take sufficient corrective action to prevent the recurrence of these problems. Indeed, CDER details the firm’s receipt of an anonymous email, dated August 5, 2013, which stated that: “…[t]here is no control of data in the department…Falsification is going on…Take action as early as possible…".

While the firm did perform an investigation as a result of this email, CDER’s Warning Letter makes clear it did not consider the investigation sufficient to detect or correct the data integrity issues. First, the GC investigation was limited to the review of audit trails for batches analyzed on only two GCs, over a very limited timeframe, and the firm came to the conclusion that there was no product impact, or patient risk associated with the “deficient data management and retention practices”. As a result, their CAPAs were not particularly effective, according to CDER.

Next, CDER looked at the High Performance Liquid Chromatography (HPLC) investigation that the firm had performed. Again, CDER concluded that the firm had reviewed the data for only a short period, and their investigation had concluded that good documentation practices were not being followed, and that the staff was insufficiently aware of the electronic records requirements under 21 C.F.R. Part 11. Again, in CDER’s view, it was clear that the investigation was inadequate. “…[A]lthough your own lengthy investigation did not capture critical deviations, our investigator’s limited review of this data during the inspection identified data manipulation, including deleted injections, re-injections, and missing injections.”

3. Failure to Follow and Document Laboratory Controls at the Time of Performance, and Failure to Document and Explain any Departures from Laboratory Procedures.

In addition to the data integrity issues previously outlined with GC and HPLC equipment, this section of the letter details CDER’s concerns with Ipca’s microbiology laboratory. “[O]ur investigators observed multiple examples of your firm’s practice of back-dating and falsifying laboratory data…. Without contemporaneous and accurate data, there is no way for you to ensure that your APIs meet specifications for the absence of objectionable microorganisms.”

Examples of alleged deviations here included temperature record logbooks that had allegedly been back-dated, and media growth promotion samples (i.e., plates) where the QC worksheets for these plates contained sample preparation and incubation information despite the fact that the plates had apparently not yet been tested.

The Pithampur Facility

4. Failure to ensure that laboratory records include complete data derived from all tests necessary to assure compliance with established specifications and standards. (21 C.F.R. 211.194(a))

Here investigators concluded that they found instances of analytical test results, but they did not find the original data. For example, incoming raw materials were tested by GC, and several initial injection results had allegedly been overwritten. They also concluded that they found multiple instances of trial injections of samples, where the final tests were recorded, but the original results had apparently not been.

Piparia Silvassa Facility

5. Failure to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards. (21C.F.R. 211.194(a))

Here too, the Quality Control laboratory had allegedly conducted trial injections of samples but failed to report and document all of the data that the lab had generated.

6. The firm’s laboratory controls failed to establish scientifically sound test procedures to assure that their drug products conform to appropriate standards of identity, strength, quality and purity. (21 C.F.R. 211.160(b))

The issue cited by CDER here involved the use of media with an inhibitor for gram positive bacteria (presumably for purposes of a growth promotion test) that none-the-less grew gram-positive microorganisms, specifically Staphylococcus aureus. According to the Warning Letter, the Quality Control laboratory confirmed the growth of the Staphylococcus aureus, but did not initiate any investigation, and proceeded to use the batch of media in the facility.

As with most of the other Warning Letters with purported data integrity violations, CDER requested a comprehensive investigation and evaluation, a risk assessment and a strategy to implement a global corrective and preventative action plan.

It will be interesting to see whether CDER concludes that these violations, together with CDER’s claims that the firm has performed insufficient remediation in response to the inspectional observations, warrant additional regulatory measures, such as import detention, of Ipca’s products at the three facilities.  (Ipca was previously placed on import restrictions for many of its drug products in early 2015, which restrictions are still in effect today.) Rest assured, we will continue to keep you updated in future posts.

[1] This post is our first of many drug cGMP compliance updates.  We will be providing regular updates of significant Form 483 inspectional observations, Warning Letters, policy pronouncements and yet other interesting information involving cGMP compliance matters emanating from CDER and CBER.

By Ricardo Carvajal & JP Ellison –

According to public communications by the restaurant chain Chipotle, the company has been served with subpoenas in a federal criminal investigation apparently arising out of one or more outbreaks of foodborne illness that appear to implicate certain of the company’s retail restaurants.  This type of investigation appears to be without precedent, but perhaps should not have come as a surprise.

Historically, FDA has not sought to directly regulate the retail food sector (restaurants, grocery stores, coffee bars, etc.), and has left that activity largely in the hands of state and local regulators. However, since 1993, FDA has played a significant role in helping to ensure food safety in the retail food sector through issuance and maintenance of the Food Code,  and by encouraging the adoption of that Code into state law.  The potential public health impact of retail food sector regulation has increased as consumption of away-from-home foods has increased – a trend of which FDA has been well aware.  More recently, FDA expanded its retail sector footprint to encompass menu labeling, in accord with a Congressional directive in the Patient Protection and Affordable Care Act.  All along, FDA has regulated many of the businesses that act as suppliers to the retail food sector, and is set to expand those activities pursuant to new regulations issued under the authority of FSMA.  Viewed in the context of those activities and developments, the current investigation appears less groundbreaking than might otherwise be the case.

At present, little is known about the nature and scope of the investigation or its targets, and any speculation should be tempered accordingly. One thing is clear: those in the retail food industry who might have thought that they were beyond some of the concerns burdening their manufacturing industry counterparts have experienced an adjustment of their reality.

By Kurt R. Karst –  

We love precedents – particularly unusual precedents that are wrapped up in drug approval histories. A couple of years ago we learned about a new precedent concerning the “date of approval” of a drug product.  That term is defined in an FDA regulation (21 C.F.R. § 314.108(a)) to mean:

the date on the letter from FDA stating that the new drug application is approved, whether or not final printed labeling or other materials must yet be submitted as long as approval of such labeling or materials is not expressly required. “Date of approval” refers only to a final approval and not to a tentative approval that may become effective at a later date. [(Emphasis added)]

Way back in April 2014, FDA issued a Consolidated Response to two Citizen Petitions (Docket Nos. FDA-2013-P-1397 and FDA-2013-P-0884) submitted to the Agency in 2013 by Eisai Inc. (“Eisai”) and UCB, Inc. (“UCB”) arguing that FDA erroneously triggered the periods of 5-year New Chemical Entity (“NCE”) exclusivity for Eisai’s BELVIQ (lorcaserin HCl) Tablets (NDA No. 022529) and FYCOMPA (perampanel) Tablets (NDA No. 202834), and UCB’s VIMPAT (lacosamide) Tablets (NDA No. 022253) before the drugs were scheduled by the Drug Enforcement Administration under the Controlled Substances Act (“CSA”), and thus, before commercial marketing could occur at that time (prior to the enactment of the Improving Regulatory Transparency for New Medical Therapies Act – see our previous post here).  Buried in the Petition Response (at footnote 92), FDA states that the Agency “is aware of one situation, which did not involve scheduling [of a controlled substance under the CSA], in which this narrow exception [(highlighted in the definition above)] has been applied.” 

The drug at issue in footnote 92 was RAZADYNE ER (galantamine hydrobromide) Extended-release Capsules, approved under NDA 021615. In that case, “the letter announcing the approval of the NDA contemplated the later submission of a trade name that FDA would have to review and approve prior to marketing, and FDA determined that the approval date was the date when the trade name was approved,” explained FDA.  We dug into the precedent, which came up again in litigation Eisai brought against FDA (see our previous posts here and here), as well as in a Citizen Petition (Docket No. FDA-2014-P-1615) Spectrum Pharmaceuticals, Inc. (“Spectrum”) submitted to FDA concerning the company’s FUSILEV (levoleucovorin) for Injection drug product approved under NDA 020140, and which petition FDA later denied (see our previous post here). 

FDA initially approved NDA 021615 for RAZADYNE ER on December 22, 2004. The drug, however, was approved without a proprietary name after FDA rejected name proposals because of concerns about medication errors.  The NDA sponsor ultimately (i.e., 101 days after the December 22, 2004 approval, or April 1, 2005) found a proprietary name that passed muster at FDA and then asked the Agency to revise the NDA approval date.  FDA acquiesced and issued a letter in June 2006 with the following rationale: 

FDA’s December 22, 2004 action letter stated that, because of medication errors associated with the use of the trade name Reminyl for the approved galantamine hydrobromide immediate release product, J&J would not market the extended release product until a new trade name had been reviewed and approved by FDA. 

We have reviewed your letter and the NDA record, and concluded that the action letter of December 22, 2004, should be considered an approvable letter as described in 21 CFR 314.110. In light of the concerns about medication errors expressed in that letter, it is reasonable to conclude that Razadyne ER was not approved until April 1, 2005, when the Agency completed its review of the proposed new trade name, found it acceptable, and conveyed this information to J&J.

As a result, FDA also amended the Orange Book to reflect the new NDA approval date, and then reset the period of 3-year exclusivity for RAZADYNE ER to expire on April 1, 2008, instead of on December 22, 2007.

It turns out that RAZADYNE ER is not the only drug product to have its approval date revised.

One day while perusing an old edition of the Orange Book we came across an apparent discrepancy between the date of approval of an NDA listed in the Orange Book versus the date of approval identified on FDA’s Drugs@FDA website. The drug, GLUCOPHAGE (metformin HCl) Tablets, 500 mg and 850 mg, is approved under NDA 020357.  But is the “date of approval” of NDA 020357 March 3, 1995, as shown on Drugs@FDA, or an earlier date, as reflected in older editions of the Orange Book? 

Both strengths of GLUCOPHAGE approved under NDA 020357 were first added to the Orange Book with the December 1994 Cumulative Supplement showing an approval date of December 29, 1994, and an NCE exclusivity expiration date of December 29, 1999 (pages 40 and 79). The December 29, 1994 approval and December 29, 1999 NCE exclusivity expiration dates also appear in the 1995 annual edition (15th edition) (page 3-193 and AD32).  This all seems to make sense.  After all, the FDA letter approving NDA 020357 is date-stamped “DEC 29 1994”.

Fast-forward to 1997, and to the April Orange Book Cumulative Supplement in particular, which shows the following additions and deletions to the Prescription Drug Product List and to the Patent and Exclusivity Data Addendum for NDA 020357:

Why were the dates changed to March 3, 1995 and March 3, 2000? 

Apparently when the GLUCOPHAGE NDA was “approved” on December 29, 1994, it was not approved with agreed upon prescribing information – which was referred to back then as a Patient Package Insert (“PPI”). Instead, the NDA was approved with a commitment from the then-NDA sponsor, Lipha Pharmaceuticals, Inc. (“Lipha”), not to market GLUCOPHAGE until a PPI was agreed to by FDA.  

How do we know about this commitment?

We hunted down a letter from Lipha, dated December 29, 1994, which states, in relevant part: “In accord with our telephone conference of December 29, 1994 with [FDA], we agree that Glucaphage® will not be marketed in the United States without an accompanying Patient Package Insert (PPI). The language of this PPI will be mutually agreed upon by FDA and Lipha Pharmaceuticals, Inc. in the immediate future.” That PPI was presumably approved on March 3, 1995, making that date the official “date of approval” of NDA 020357 for GLUCOPHAGE.  

Given that GLUCOPHAGE was approved with a period of 5-year NCE exclusivity, and, unlike RAZADYNE ER, could be eligible for a Patent term Extension (“PTE”), we wondered (for the sake of completeness) whether or not the revision of the December 29, 1994 approval date for NDA 020357 to an official “date of approval” of March 3, 1995, also affected the PTE calculus. Unfortunately, we cannot find any evidence that a PTE was submitted for a patent covering GLUCOPHAGE. 

Both the RAZADYNE ER and GLUCOPHAGE approval date reset precedents are now artifacts of history . . . so why dredge up old history?  There's the obvious answer: “Because precedents can be important to making and supporting a case for some FDA action.”  But there's more.  Knowing that a second example exists with the approval of GLUCOPHAGE might mean that there are other, more recent examples out there not yet uncovered that may have more immediate implications if found. 

By Kurt R. Karst –

Now that the dust from 2015 has settled, we’re able to take a look at and evaluate the year that was in orphan drug designations and approvals. Our annual review has become quite popular.  We often see the numbers we provide repeated on various websites and cited in published reports (e.g., here).  As we noted last year, in 2014 FDA’s orphan drug program shattered records in each of the three categories we track: orphan drug approvals, orphan drug designations, and orphan drug designation requests submitted to FDA’s Office of Orphan Products Development (“OOPD”). In 2015, FDA’s orphan drug program continued to break new ground with massive numbers of orphan drug designations and orphan drug designation requests. Orphan drug approvals (which include not only approvals of NDAs for new molecular entities and BLAs for original biological products, but also applications approved for new orphan uses of previously approved drugs and biologics – so-called “repurposed drugs”) dipped slightly from 2014, but 2015 was still the second best year for orphan drug approvals since the enactment of the Orphan Drug Act.

In 2015, FDA’s OOPD received an avalanche of 472 requests for orphan drug designation (5 more than the record set in 2014), and designated an amazing 354 products as orphan drugs (about a 22% increase over 2014). There were 5 or 7 fewer orphan drug approvals in 2015 compared to 2014, depending on whether or not you accept the 2014 number in FDA’s Orphan Drug Designations and Approvals Database or the 2014 number provided by OOPD in a report last year (we use the OOPD report number instead of the database number for 2014).  (There are also other FDA databases and reports – here and here – that show differing numbers, making it difficult to identify a true count.)  For 2015, we added one orphan drug approval for Cysteamine Bitartrate (NDA 203389) to our count because that approval does not seem to be captured in the OOPD database.  Since 1983, FDA has approved about 552 orphan drugs, has granted 3,633 orphan drug designations, and has received 5,210 orphan drug designation requests.   

Below are three tables – one for each metric we track – showing the year-by-year numbers since 1983. A few of the numbers we provided last year changed slightly as FDA has updated the Agency’s designation and approval database.  The most current numbers are in the tables below.

With the growing number of designation requests submitted to FDA’s OOPD each calendar year (about 1.9 per day in 2015 based on a 251-day working year), as well as all of the other programs OOPD is responsible for implementing (e.g., the Humanitarian Use Device Program, the Pediatric Device Consortia, the Orphan Drug Grants Program, and designation requests under the Rare Pediatric Disease Priority Review Voucher Program), you might think that the staff in OOPD has grown accordingly.  You would be wrong.  Despite the massive increase in workload and added responsibilities, OOPD’s staff has remained at about 25 employees for many years now.  Moreover, funding for OOPD has remained relatively flat over the past few years.

While OOPD is a pretty lean, mean working machine, resources can be stretched only so thin. We’re already starting to see some of the strains of the increasing workload on OOPD.  Usually OOPD sets an internal target date for responding to orphan drug designation requests at about 60-90 days from receipt of a request.  We understand that the target date is now at around 90-120 days.  Those folks in charge of the purse strings should really consider dedicating greater funding to OOPD.  But that may not happen soon.  Earlier today we learned that FDA's Fiscal Year 2017 Budget Request is $26,099,000 in budgeting authority for OOPD (see here at pages 105-113).  That figure mirrors the actual Fiscal Year 2016 enacted level.

In November 2013, the Drug Quality and Security Act (“DQSA”) was signed into law in an effort to increase the quality of the United States drug supply. The law contains two separate acts: the Compounding Quality Act (Title I), and the Drug Supply Chain Security Act (Title II). As industry implements new requirements, questions on office use, traceability, serialization, preemption, and licensing persist.

On February 23, 2016, the Food and Drug Law Institute (“FDLI”) will hold a one-day conference in Washington, D.C., titled “Drug Quality and Security in 2016,” to discuss the ongoing implementation of both DQSA titles and recent FDA guidance. Hyman, Phelps & McNamara, P.C.’s Karla L. Palmer will lead a breakout session on the DQSA’s Compounding Quality Act, during which she will review recently released guidance for compounders under FDC Act § 503A and § 503B and related topics (see our previous post here).

A copy of the FDLI conference agenda and information on registration is available here.  FDA Law Blog readers can get a 15% discount off the registration fee by using the following discount code: 16DQSA.

By Kurt R. Karst –  

The ink from President Obama’s signature on Public Law No. 114-89, the “Improving Regulatory Transparency for New Medical Therapies Act” (or “IRTNMTA”), was hardly dry when the company that led the charge to change the law, Eisai Inc. (“Eisai”), asked the Patent and Trademark Office (“PTO”) in a submission made last month (Docket No. FDA-2014-E-0072) to consider how the new law applies and might affect Eisai’s request for a Patent Term Extension (“PTE”) for U.S. Patent No. 6,949,571 (“the ‘571 patent”) covering Eisai’s FYCOMPA (perampanel) Tablets (NDA 202834). Under one PTE calculation, the term of the ‘571 patent would extend until September 4, 2025.  But with the IRTNMTA, argues Eisai, the term of the ‘571 patent should extend until October 12, 2026.

As we previously reported, the cumbersome (both in acronym and in substance) IRTNMTA amended the FDC Act, the PHS Act, the PTE statute, and the Controlled Substances Act (“CSA”) to provide, among other things, that the “date of approval” of an NDA, NADA, or Section 351(a) BLA for a controlled substance awaiting a scheduling determination by the DEA (or the “covered date” for PTE submission purposes) is the later of the date of NDA, NADA, or Section 351(a) BLA approval, or “the date of issuance of the interim final rule controlling the drug.” 

Why were these changes necessary? As we previously explained, the IRTNMTA remedies an unfairness created by bureaucratic red tape.  Until the enactment of the IRTNMTA, drug products containing controlled substances could be approved by FDA, but could not be marketed until the DEA issued a final determination scheduling the controlled substance under the CSA (and appropriate labeling changes were made reflecting the scheduling determination).  In some cases that meant that a company was  unable to market its drug product after FDA approval – sometimes for more than a year – while the 5-year period of New Chemical Entity (“NCE”) exclusivity has ticked away.  By resetting the date of approval of a drug product containing a controlled substance requiring scheduling to be the later of the date of application approval or the date of issuance of the interim final rule scheduling drug, a company will not be punished by a scheduling delay.  (Eisai sued FDA over the issue of the start date of NCE exclusivity, but lost – see our previous post here.)  

The question presented by Eisai is one of applicability of the IRTNMTA: does the new law have prospective application for pending (and timely submitted) PTE applications for patents covering a drug that is a controlled substance? The answer to that question is “yes” says Eisai, based on a January 29, 2014 PTE application for the ‘571 patent that was submitted to the PTO within 60 days of the effective date of the DEA’s scheduling of FYCOMPA under the CSA:

The new statute is currently effective, and, as applied to the ’571 patent, would be prospective: the application for a PTE for the ’571 patent is currently pending, and neither the PTE nor the regulatory review period for Fycompa® has yet been determined; moreover, its effect as to Fycompa® and the ’571 patent would not occur until September 2025- nearly 10 years in the future. Therefore, FDCA § 505(x), 21 U.S.C. § 355(x) and the amendments to 35 U.S.C. § 156, apply to the pending applications for a PTE for the ’571 patent; and FDA and the PTO should apply those new provisions to determine Fycompa®’s “date of approval, ” FDCA § 505(x)(2), 21 U.S.C. § 355(x)(2), and its “covered date”, 35 U.S.C. § 156(i)(2). As relevant here, new FDCA 505(x), 21 U.S.C. § 355(x), and new 35 U.S.C. § 156(i) are essentially interchangeable.  In view of the manifest purpose of the new statute, Fycompa®’s date of approval is the “date of issuance,” FDCA § 505(x)(2)(B), 21 U.S.C. § 355(x)(2)(B), 35 U.S.C. § 156(i)(2)(D), of the DEA’s regulation scheduling Fycompa®, i.e., the effective date of that regulation. Fycompa®’s date of approval is to be used in determining whether the Applicant’s second pending application (submitted on January 29, 2014) was submitted within the time period specified in Section 156(d)(1) as amended, and in determining the regulatory review period under Section 156(g)(1)(B) and (i) and, consequently, the length ofthe PTE under Section 156(c) and (g)(6).

Treating DEA’s regulation scheduling Fycompa® as the functional equivalent of an interim final rule under FDCA § 505(x), 21 U. S.C. § 355(x), would serve the manifest purpose of that statutory provision. That use of the DEA regulation is necessary and appropriate for applying the new statute to the pending applications.

The remainder of Eisai’s 51-page submission is spent providing legal justification for the company’s position on obtaining a longer PTE than compared to the PTE that would be due without application of the IRTNMTA. It may be some time before the PTO digests Eisai’s submission and makes a determination; however, if the PTO rules against Eisai, then we may see a new line of legal challenge for this drug.  

By Allyson B. Mullen –

On January 26, FDA issued the draft guidance “Design Considerations and Pre-market Submission Recommendations for Interoperable Medical Devices.” A copy of the draft guidance can be found here. The draft guidance addresses design and premarket issues related to the interoperability of devices, which it defines as the “ability of two or more products, technologies or systems to exchange information and to use the information that has been exchanged.”  Exchange of information is defined as the “transmission, reception or both, that may be accomplished by means of wired or wireless methods that may exist on a local network, or through the internet.”  The guidance indicates that it is addressing more than unidirectional sending of patient data, and includes complex interactions including control of medical devices.

FDA states that in order to ensure the safe performance of the interoperable devices, the manufacturers must establish appropriate functional, performance, and interface requirements. Failure to do so may lead to device malfunction, patient injury, and possibly death according to the draft guidance, which gives as an example the transmission of patient weight in kilograms when the receiving device assumes the weight is in pounds. 

The draft guidance includes three major topic areas: (1) design considerations for interoperable devices, including testing and risk management of interoperable devices; (2) content of premarket submissions for interoperable devices; and (3) labeling considerations for interoperable devices.

Design Considerations.  The draft guidance provides recommendations to be incorporated during the design and development of interoperable devices, including identifying the purpose of the electronic data interface and anticipated users, performing appropriate risk management and verification and validation testing, and adequately labeling of the device. As part of the risk management activities, the draft guidance suggests that manufacturers consider data security, including cybersecurity of interoperable devices.  FDA recently issued a draft guidance on postmarket considerations for device cybersecurity.  Our blog post on this draft guidance can be found here. 

The draft guidance recommends that manufacturers perform testing that appropriately demonstrates the electronic data interface and exchange interactions perform as intended both on the device itself and when incorporated into the intended interoperable system. It provides several examples of tests to consider. 

Content of Premarket Submissions.  The draft guidance also provides suggested premarket submission content that is specific to interoperable devices and goes beyond the standard content described in other FDA guidance documents (e.g., the 510(k) RTA Checklist). The recommended content includes specific device description information, including the purpose of the interface and technical details of the data exchange.  A risk analysis is also recommended.  Risk analyses, although generally prepared during device design and development, are not typically provided in premarket submissions. 

The draft guidance also provides specific suggestions for the verification and validation section of premarket submissions. In addition to test results, FDA recommends that manufacturers clearly specify the other devices with which the subject device is intended to be used.  If there is a class of devices with which the subject device is intended to be used, the submission should explain why the testing is appropriate for the entire class of devices. 

This position is consistent with FDA’s current expectations for devices that are intended to be used together (not specifically interoperable devices). We note that, while FDA leaves open the possibility of testing a device to include an entire class of devices, in our experience, FDA has been unwilling to permit references to a class of products in device labeling and has limited labeling to devices for which data has been provided showing that they work together. 

Labeling.  Finally, the draft guidance provides a detailed list of suggested labeling content for interoperable devices. The draft guidance appears to focus primarily on ensuring that the user is provided with appropriate information regarding the purpose, use, and limitations of the devices and data exchange interface.  The draft guidance recommends that manufacturers perform human factors testing to validate labeling.  While not expressly referenced in the premarket submission section of the guidance, it is likely that FDA would expect the results of human factor testing to be included in a premarket submission.

Although the draft guidance is not yet final or legally binding, it is possible that FDA reviewers may be looking at interoperability during their premarket review of device submissions. Accordingly, applicants would be well advised to be prepared to answer questions regarding interoperability of their devices sooner rather than later.

By Melisa M. Moonan –

FDA has been flooding the zone with new guidance documents. Earlier this week, FDA finalized the human factors guidance, “Applying Human Factors and Usability Engineering to Medical Devices, Guidance for Industry and Food and Drug Administration Staff” (Feb. 3, 2016). At the same time, the agency issued a complementary draft guidance, “List of Highest Priority Devices for Human Factors Review, Draft Guidance for Industry and Food and Drug Administration Staff” (Feb. 3, 2016).  

We will cover the final human factors guidance is an upcoming post. In this post, we focus on the complementary draft guidance, which is intended to help with the question of when human factors data must be included in a premarket submission. Until now, it has always been something of a mystery as to when such data are required and when they are not.

The draft guidance identifies a specific list of devices for which FDA would definitely expect human factors data:

• Ablation generators (associated with ablation systems, e.g., LPB, OAD, OAE, OCM, OCL)
• Anesthesia machines (e.g., BSZ)
• Artificial pancreas systems (e.g., OZO, OZP, OZQ)
• Auto injectors (when CDRH is lead Center; e.g., KZE, KZH, NSC )
• Automated external defibrillators (e.g., MKJ, NSA )
• Duodenoscopes (on the reprocessing; e.g., FDT) with elevator channels
• Gastroenterology-urology endoscopic ultrasound systems (on the reprocessing; e.g.,
• ODG) with elevator channels
• Hemodialysis and peritoneal dialysis systems (e.g., FKP, FKT, FKX, KDI, KPF ODX,ONW)
• Implanted infusion pumps (e.g., LKK, MDY)
• Infusion pumps (e.g., FRN, LZH, MEA, MRZ)
• Insulin delivery systems (e.g., LZG, OPP)
• Negative-pressure wound therapy (e.g., OKO, OMP) intended for use in the home
• Robotic catheter manipulation systems (e.g., DXX)
• Robotic surgery devices (e.g., NAY)
• Ventilators (e.g., CBK, NOU, ONZ)
• Ventricular assist devices (e.g., DSQ, PCK)

FDA indicates that it will expect a human factors report (as described in Appendix A of the Final Human Factors Guidance) for the listed devices unless the submission is for a modification to an approved or cleared device that does not affect usability, i.e., no change to users, use environment, user tasks, or user interface. Alternatively, a submission can provide a detailed rationale for why human factors data are unnecessary based on a risk analysis showing that the severity of potential harm from user error is not serious.

In providing the list, FDA utilized the following standard to identify the device types for which it expects submission of such human factors data: “Device types that have clear potential for serious harm resulting from use error.” FDA states that the draft list was derived by the agency from MDRs and recall information, and the list does reflect recent and historical agency concerns such as AEDs, infusion pumps, and reprocessing methods. However, there is not a detailed analysis as to how FDA applied the standard when generating the list.

Accordingly, we hope the agency will further clarify the terms “clear potential” and “serious harm” in the final guidance, particularly as they relate to established regulatory standards and definitions regarding product risk, such as those for reporting adverse events and malfunctions in the MDR regulation, 21 CFR Part 803, and for reporting recalls in the Corrections and Removals reporting regulation, 21 CFR Part 806.

Of perhaps greater concern, FDA states that additional device types may be identified in various ways, including through guidance, special controls, and classifications, as well as by individual reviewers on a case by case basis. The latter method is troubling. The welcome transparency provided by this draft guidance could be swallowed whole by case by case reviewer decisions to request human factors data for device types that are not on the list.

FDA has attempted to put guardrails around this possibility in two ways. First, the draft guidance puts the onus on manufacturers to proactively submit human factors data when their risk analysis indicates that user error (whether by failing to perform tasks, or by performing them incorrectly) could result in serious harm.

Second, the agency proposes that reviewer requests for such data could be made only if one or more of a group of factors apply. FDA lists certain factors where it states the factor also must be accompanied by a potential for serious harm resulting from use error, and other factors where it appears to presume that the potential for serious harm is inherent.

The factors where a potential for serious harm from user error must be present are:

• The submission is a PMA or a De Novo Petition
• The submission includes a change of intended users, e.g., from professional to lay use
• The device was modified or differs from the predicate in any of the following ways:

• The user interface has been modified (even if simplified)
• User tasks have been added or changed
• The severity of possible harm resulting from use error has increased
• The device will be used in a new use environment (e.g., in a home or vehicle)

The factors for which such potential for serious harm appears to be presumed are:

• The user interface was modified to satisfy a special control or recommendation (in a device-specific guidance document) related to its use. This factor makes sense if such controls and recommendations were promulgated primarily based on a potential for serious harm resulting from use error.

• The device type has been associated with recalls, adverse events, problem reports or complaints for which the cause has been attributed to use error or use error is the only explanation. This factor does not make sense unless the recalls considered are associated with a risk to health and “adverse events” means MDR reported events that have been vetted by the agency and confirmed to represent a potential device use issue. Inclusion of complaints does not make sense, as any complaint associated with use error resulting in serious harm would fall under MDR reported events. It is unclear what is meant by “problem reports,” but those too should meet the criteria for MDR reportability and be vetted by the agency to determine whether they represent a potential device use issue.  

We strongly encourage FDA to provide transparency and opportunity for comment for non-listed device types before permitting reviewer requests for human factors data on a case by case basis. Perhaps the agency could periodically propose any updates to the list under good guidance practices. At a minimum, such requests should require approval by the reviewer’s supervisor. Otherwise, there is a clear potential for surprise requests that could unfairly delay clearances and approvals.

Comments are due within 90 days from February 3rd to Docket No. FDA-2015-D-4599.