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• FDA denied one-fourth (or 207) of the request for fast track designation, and the remaining 40 requests were either withdrawn by the sponsor or the drug application was inactivated, terminated, or cancelled before FDA could make a decision on the request.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.

By John A. Gilbert, Jr. & Larry K. Houck –

The Government Accountability Office (“GAO”) recently released a report examining issues related to state marijuana legislation and federal monitoring of such actions. GAO, State Marijuana Legalization: DOJ Should Document Its Approach to Monitoring the Effects of Legalization, GAO-16-1 (Dec. 2015). The report evaluates the extent to which the U.S. Department of Justice (“DOJ”) is monitoring the effects of state marijuana legalization in relation to DOJ policy as promised in the marijuana enforcement guidance memorandum from Deputy Attorney General James M. Cole in August 2013 (“Cole Memo”). The report also reviews the controls that Colorado and Washington have enacted to regulate recreational marijuana and the factors affecting Drug Enforcement Administration (“DEA”) field officials’ enforcement actions in states that have legalized marijuana for medical purposes.

In summary, GAO found that federal officials reported monitoring these state initiatives through prosecution of cases threatening federal enforcement priorities, consulting with state officials about federal concerns and collaboration among DOJ components (that is, DEA, ONDCP, etc.) in sharing data on marijuana enforcement areas. However, GAO found that DOJ did not document this monitoring process and recommends that DOJ conduct such monitoring to ensure that its efforts are addressing the intended goals and to better assist DOJ in identify state systems that are not adequately protecting federal enforcement priorities and take appropriate action.

The report provides background on marijuana in general and summarizes marijuana’s current status under federal and state law. The report also identifies the federal enforcement priorities articulated in the Cole Memo and provides a chronology of state action related to actions to legalize medical marijuana and recreational use. See our blog dated November 11, 2015. GAO notes that while 24 states and the District of Columbia have legalized marijuana and 15 states have legalized cannabidiol, an active ingredient in marijuana plants, for medical purposes, and 4 states and the District of Columbia have legalized marijuana for recreational use, marijuana remains a schedule I controlled substance under the federal Controlled Substances Act (“CSA”).

1. The GAO report provides a detailed description of the Colorado and Washington regulation of recreational marijuana but does not opine on the impact or effectiveness of these regulatory systems.  

GAO reviewed the laws and regulations governing recreational marijuana in Colorado and Washington to determine how those states regulate its production, processing and sale and interviewed state regulatory officials. GAO found the Colorado and Washington recreational marijuana regulatory schemes to be quite similar. Both states require licenses for marijuana production, processing, selling and testing. Both require applicant background checks of state residency, age and criminal history to determine licensing eligibility. Both states require recreational marijuana facilities to have specific physical security measures in place to prevent theft and diversion and that licensees implement inventory systems that allow state officials to track specific plants and products through the supply chain. Licensees must submit marijuana and marijuana-infused product samples to state-approved labs for testing. The states have established labeling and packaging standards. Colorado and Washington regulations set restrictions on consumer use of recreational marijuana, limiting who can possess, how much they can possess and where they can use it. The states require licensees to grant access to regulatory authorities to inspect facilities. Regulatory violations in both states can lead to progressive discipline with escalating penalties that could include monetary fines, suspension or cancellation of a license, and criminal charges.

Despite providing a detailed summary of these regulatory requirements, GAO did not opine on the effectiveness of the Colorado and Washington recreational marijuana regulatory systems.

2. GAO finds that DOJ has not documented monitoring of state marijuana legalization as outlined in the Cole Memo.

The Cole Memo set forth DOJ’s expectation that state and local governments implement strong and effective regulatory and enforcement systems to ensure that the laws and regulations do not undermine the eight federal enforcement priorities. The memo asserted that “[i]f state enforcement efforts are not sufficiently robust to protect” threats to the federal enforcement priorities, “the federal government may seek to challenge the regulatory structure itself in addition to continuing to bring individual enforcement actions, including criminal prosecutions.” Memorandum from James M. Cole, Deputy Attorney General, Guidance Regarding Marijuana Enforcement (Aug. 29, 2013). In determining how DOJ monitors the effects of state marijuana legalization laws relative to its marijuana enforcement policy, GAO reviewed DOJ documentation related to enforcement and monitoring efforts, and interviewed DOJ and other responsible federal officials.

GAO found that DOJ monitors the effects of state marijuana legalization related to DOJ’s enforcement policy in two ways. First, DOJ continues to enforce the CSA by taking action against marijuana activity that threatens the eight federal enforcement priorities, and U.S. Attorneys in those states monitor whether the cases implicate the enforcement priorities and prosecute cases that do. Second, Office of the Deputy Attorney General (“ODAG”) officials reported that DOJ uses various sources of information to monitor the effects of marijuana legalization under state law, noting that “DOJ’s focus was on monitoring the effects that legalization has had relative to DOJ’s enforcement priorities, rather than evaluating specific requirements within states’ legalization laws or regulatory systems.” The report notes that ODAG officials did not state how they make use of information from various qualitative and quantitative sources including federal surveys on drug use, state and local research, and feedback from federal, state and local law enforcement, to monitor the effects of state marijuana legalization or how DOJ uses information to determine whether federal action is necessary to challenge a state’s regulatory system. ODAG officials reported that it had not documented their monitoring process and that they do not see a benefit in documenting how it would monitor the effects of state marijuana legalization on the Cole Memo guidance.

GAO concluded that “[d]ocumenting a plan specifying its monitoring process would provide DOJ with greater assurance that control activities – such as the ways DOJ is monitoring the effect of state marijuana legalization relative to federal enforcement priorities – are occurring as intended.” ODAG could gain institutional knowledge with respect to its monitoring plan by sharing it with officials from DOJ components who provide the data that the DOJ uses to monitor state legalization. GAO concludes that incorporating feedback from officials into its monitoring plan could assist ODAG to ensure that it is using the most appropriate data and better identify the state systems that do not effectively protect the federal enforcement priorities. 

3. DOJ’s marijuana enforcement priorities have affected DOJ and DEA marijuana enforcement efforts in states that have legalized medical marijuana.

GAO interviewed DEA and U.S. Attorney Office (“USAO”) officials in Colorado, Washington, Alaska, California, Maine and Oregon to determine the factors affecting their enforcement actions in states that have legalized marijuana for medical purposes. GAO also reviewed information in those states regarding enforcement actions, including letters sent to medical marijuana dispensaries and public case information from fiscal year 2007 through 2014, two years before DOJ’s first marijuana enforcement guidance and after the August 2013 guidance.

DEA and USAO officials reported that they continue to apply their limited resources to address the most significant threats within their jurisdictions. They sent warning letters to 1,900 owners and lien holders of medical marijuana dispensaries during fiscal years 2007 through 2013 in response to concerns about the growth of the medical marijuana industry. Officials in California, Oregon and Washington also reported conducting criminal investigations and prosecutions or civil suits with the letter campaigns. Some officials reviewed their open marijuana cases and closed cases that did not threaten the federal priorities. Moreover, a number of officials report that they now decline to consider some marijuana-growing cases for investigation and prosecution because they do not threaten the federal priorities. Officials in California, Colorado, Oregon and Washington that had sent warning letters to medical marijuana dispensaries have not sent warning letters since the Cole Memo because in part the guidance requires that they consider not the size or commercial nature of a dispensary alone, but rather whether it is implicating the enforcement priorities.

Recommendations

The GAO report recommends the Attorney General to direct ODAG to document a plan specifying DOJ’s process for monitoring the effects of marijuana legalization under state law in accordance with the Cole Memo, that identify the various data ODAG will use and its limitations, and how ODAG will use the information sources to determine whether state systems are effectively protecting the federal priorities. GAO also recommends that the Attorney General direct ODAG to use existing mechanisms to share DOJ’s monitoring plan with DOJ component officials responsible for providing information to DOJ about the effects of state legalization to ODAG, obtain their feedback and incorporate the feedback into its plan.

DOJ received a draft of the GAO report and concurred on November 13, 2015 with both recommendations. DOJ indicated that that ODAG will document a plan to identify the various data sources that assist DOJ and USAOs in making enforcement decisions that include individual criminal prosecution or civil enforcement in marijuana crimes. DOJ stated it will monitor this data and other sources of information to determine if states are protecting the federal enforcement priorities.

By Kurt R. Karst –

Those folks who have been following this blog for several years have a good sense about the depths of this blogger’s passion for the Orange Book. There’s the license plate (“ORNGBUK”), the trip to the summit of Mt. Kilimanjaro with the publication (yes, we got a few odd stares from other climbers), the new chapter in the book this blogger authors – Generic and Innovator Drugs: A Guide to FDA Approval Requirements – exploring nearly all of the Orange Book minutiae you can imagine, the various posts about Orange Book firsts and developments (here, here, and here for example), and, of course, the Hatch-Waxman/Orange Book trivia.  So it should come as no surprise that around this time each year, anticipation for FDA’s release of the annual edition of the Orange Book is at its highest.  (We’d call it a “Code Orange,” but we used that line in a another post about the Orange Book a couple of years ago – see here.)  

Why is the anticipation so high? We like perusing the Orange Book Preface each year to see what (if anything) has changed from the previous year.  Most years it’s merely a fun “where’s Waldo” type exercise (Hatch-Waxman style) looking for minor word changes or the Office of Generic Drugs’ sense of humor.  (For that sense of humor, take a look at Section 2.2 [DRUG PRODUCT ILLUSTRATION] of the Preface.  Applicants identified in the illustrations are – or were – members of FDA’s Orange Book Staff – e.g., GREENBERG PHARM; TIMOKIM LLC; JOHNSON MED; KENDRA PHARM.).  But sometimes we’ve seen new FDA policies announced in the Orange Book Preface (see our previous post here).  

The Preface to the 2016 and 36th Annual Edition of the Orange Book includes a lot of changes. Clearly, someone took a close look at the Preface to clean it up.  Many of the changes are just nips and tucks.  They start on the cover page, which now identifies the recently-established Office of Generic Drug Policy as the office housing the Orange Book Staff.  Other minor updates include corrections to grammar, word choice changes (e.g., “When the Citizen Petition is approved” to “If the citizen petition is approved”), and greater use of more contemporary terms (e.g., “authorized generic”).  

There are also a few moderate changes that have been made to the Preface. In a largely revised Section 1.12, titled “Changes to the Orange Book,” FDA reminds manufacturers that the Agency must be notified when the marketing status of a product changes.  Previously, FDA was more passive on this requirement, merely stating: “Applicant holders are requested to inform the FDA Orange Book Staff (OBS) of any changes or corrections.  Please inform the OBS when products are no longer marketed.”  In more active language, the Preface now states:

Applicants are requested to inform the FDA Orange Book staff of any changes or corrections, including any change in a product’s marketing status that would result in the product being moved to the Discontinued Drug Product List. FDA notes that 21 CFR 314.81(b)(3)(iv) requires an applicant to submit a notice to the Agency within fifteen working days of the withdrawal from sale of a drug product. 

Section 1.12 has also been updated to express FDA’s policy that the Agency does not intend to update listings with the evolution of product description conventions: 

To the extent that conventions for describing product identification information (i.e., active ingredients, dosage forms, routes of administration, product names, applicants, strengths) evolve over time, the Agency generally does not intend to revise such information for drug products already included in the List, but rather intends to apply the change prospectively to drug products added to the List.

This policy is also relayed in an addition to Section 1.2 discussed below. 

The 2015 Preface (as well as previous editions) included Section 1.3, titled “Statistical Criteria for Bioequivalence,” that went on for about two pages. That section, renamed “Further Guidance on Bioequivalence,” in the 2016 Preface is now significantly shorter, and merely states: “FDA’s regulations and guidance documents provide additional information regarding bioequivalence and bioavailability, including methodologies and statistical criteria used to establish the bioequivalence of drug products.”  In a footnote, FDA notes the revision and includes links to the Agency’s regulations and guidance documents for additional information regarding bioequivalence and bioavailability requirements.

Aside from the minor and moderate changes, there are a couple of more significant changes FDA made to the Orange Book Preface in 2016.

First, in Section 1.2, titled “Therapeutic Equivalence-Related Terms,” FDA adds the term “Strength” and a definition:

Strength. Strength refers to the amount of drug substance (active ingredient) contained in, delivered, or deliverable from a drug product.  Note that if the criteria the Agency establishes for determining and expressing the amount of drug substance in a product evolves over time, the Agency generally does not intend to revise the expressions of strength for drug products already included in the List, but rather intends to apply the criteria prospectively to drug products added to the List.

The strength of drug products in the List is generally expressed in terms of the amount of drug substance (active ingredient) in the drug product, but is sometimes expressed in terms of the amount of the active moiety. For example, certain drug products included in the List include a designation of “EQ” next to their expression of strength.  This “EQ” designation generally is used in connection with salt drug products to indicate that the strength of such drug product is being expressed in terms of the equivalent strength of the active moiety (e.g., “EQ 200MG BASE”), rather than in terms of the strength of the active ingredient.

The description of salt drug products reflects the 2013 adoption of the USP Salt Policy, which is discussed in an FDA guidance.  FDA also cleans up the description of an “AP” therapeutic equivalence rating insofar as how the strength of parenteral drug products is expressed.

The most significant change to the 2016 Orange Book Preface appears to be in Section 1.10, titled “Change of the Therapeutic Equivalence Evaluation for a Single Product.” The change concerns the assignment of therapeutic equivalence ratings to drug products approved under 505(b)(2) NDAs.  At the end of Section 1.10, FDA adds a new paragraph:

We recognize that certain drug products approved in 505(b)(2) applications may not have therapeutic equivalence codes, and that FDA may undertake therapeutic equivalence evaluations with respect to such drug products. A person seeking to have a therapeutic equivalence rating for a drug product approved in a 505(b)(2) application may petition the Agency through the citizen petition procedure (see 21 CFR 10.25(a) and CFR 10.30).

You may recall that in recent years there’s been a decent amount of controversy over the issue of therapeutic equivalence rating assignment to 505(b)(2)-approved drug products, from citizen petitions (see our previous post here), to a lawsuit against FDA that was later dropped (see our previous post here).  In addition to substitutability, the assignment of therapeutic equivalence ratings to drug products approved under 505(b)(2) NDAs has an effect on whether or not a manufacturer is subject to annual PDUFA user fees.  

Is FDA’s pronouncement that the citizen petition process may be utilized for therapeutic equivalence rating assignment purposes an indication that FDA will no longer make therapeutic equivalence rating decisions for 505(b)(2)-approved drug products on its own initiative? Or maybe it’s that FDA will not make such determinations in non-obvious and difficult cases absent a citizen petition.  (Of course, what constitutes non-obvious or difficult will differ from one person to another.)  We’ll see.  

In the past, FDA has made the calls in complicated 505(b)(2) situations. . . . sometimes leading to inconsistencies in how (or if) 505(b)(2) drug products are rated. For example, FDA rated as “BX” three strengths of SEROSTIM (NDA 020604) with respect to corresponding strengths of other Somatropin Recombinant Injection drug products notwithstanding differences in labeled indications between the drug products. In other cases, however, products one would think might have a “B” therapeutic equivalence rating are not rated at all. For example, VELETRI (epoprostenol sodium) 1.5 mg Injection (NDA 022260) is not rated to the listed drug relied on for approval, FLOLAN Flolan (epoprostenol sodium) 1.5 mg Injection (NDA 020444). VELETRI is a 505(b)(2) by virtue of a formulation with a so-called non-exception excipient – arginine – that makes the product more stable upon reconstitution and administration. The improved stability of the product led to different labeled storage conditions, and apparently to FDA’s decision not to assign a “B” rating among the two drug products, notwithstanding pharmaceutical equivalence and bioequivalence.

By Allyson B. Mullen –

On January 15, FDA issued the draft guidance “Postmarket Management of Cybersecurity in Medical Devices.”  This draft guidance is the postmarket counterpart to the draft premarket guidance that FDA released in 2013, which we previously posted on here and here. 

Without finalizing the draft premarket guidance, FDA has turned its attention to postmarket cybersecurity, likely because as the draft guidance states “cybersecurity risks to medical devices are continually evolving.” Thus, to comprehensively protect devices against cybersecurity threats, FDA believes that manufacturers must assess cybersecurity during design and development and during postmarket surveillance. 

Like the draft premarket guidance, which was picked up by the Wall Street Journal, the draft postmarket guidance was also the focus of a Wall Street Journal article just after it was released.  Two-and-a-half years after issuance of the draft premarket cybersecurity guidance, Wall Street and investors are still interested in the cybersecurity of medical devices, but what does this new guidance mean for industry?  A lot.  FDA expects manufacturers to implement a comprehensive cybersecurity program throughout the entire device life cycle (pre- and postmarket).

The draft guidance recommends that manufacturers engage in what it calls “good cyber hygiene,” performing “routine device cyber maintenance, assessing postmarket information, employing a risk-based approach to characterizing vulnerabilities, and timely implementation of necessary actions can further mitigate emerging cybersecurity risks and reduce the impact to patients.” The guidance also encourages manufacturers to comply with the voluntary NIST standard, “Framework for Improving Critical Infrastructure Cybersecurity,” and participate in an Information Sharing Analysis Organization (ISAO), such as the National Health Information Sharing & Analysis Center, with which CDRH has entered into a Memorandum of Understanding.  The draft guidance provides an appendix with additional details regarding the recommended elements of a comprehensive cybersecurity program. 

The draft guidance emphasizes that in order to effectively mitigate cybersecurity risks the manufacturer should have a risk management program that incorporates both premarket and postmarket phases. The risk management program should use a tool that is appropriate for scoring and rating cybersecurity vulnerabilities such as the “Common Vulnerability Scoring System,” and it should have a process for assessing the potential health impact (e.g., ISO 14971).  The end result should be a conclusion as to whether each cybersecurity risk is controlled (i.e., “sufficiently low (acceptable) residual risk”) or uncontrolled (i.e., “unacceptable residual risk that the device’s essential clinical performance could be compromised”).  If a risk is deemed to be uncontrolled, FDA expects that additional risk control measures will be applied.  The draft guidance provides examples of both controlled and uncontrolled risks. 

The draft guidance states “for the majority of cases, actions taken by manufacturers to address cybersecurity vulnerabilities and exploits are considered ‘cybersecurity routine updates or patches,’ for which the FDA does not require advance notification or reporting under 21 CFR part 806.” The guidance indicates that a “routine update or patch” is one that is intended to “increase device security and/or remediate vulnerabilities associated with controlled risk” and does not affect a software’s “essential clinical performance.”  Essential clinical performance is defined by the guidance as “performance that is necessary to achieve freedom from unacceptable clinical risk.”  Interestingly, FDA’s final guidance regarding distinguishing a recall from a product enhancement (which we previously posted on here) did not acknowledge that companies making routine updates or patches to address known vulnerabilities with acceptable (low) levels of risk in its software would not require reporting under Part 806.  Although the guidance speaks directly to cybersecurity vulnerabilities, we expect – or at least would like to think – this line of reasoning would also be applied to other known vulnerabilities with acceptably low levels of risk at the time of software release. 

With regard to PMA devices, changes made to mitigate cybersecurity vulnerabilities should be reported in periodic annual reports to FDA. The draft guidance provides suggested content for such reports. 

One key question left to be answered is how FDA will enforce this draft guidance. Unlike the draft premarket guidance where FDA can review a device’s cybersecurity information during 510(k) or PMA review, the postmarket guidance merely sets out recommendations for new and existing devices once they are on the market.  FDA will be left to enforce these recommendations during device facility inspections.  The draft guidance appears to imply that a failure to comply with the guidance would be violation of the Quality System Regulation (QSR).  The draft guidance states “it is essential that manufacturers implement comprehensive cybersecurity risk management programs and documentation consistent with the Quality System Regulation (21 CFR part 820), including but not limited to complaint handling (21 CFR 820.198), quality audit (21 CFR 820.22), corrective and preventive action (21 CFR 820.100), software validation and risk analysis (21 CFR 820.30(g)) and servicing (21 CFR 820.200).”  While we do not expect to see this guidance cited in any FDA Form 483 observations – or at least not in the short term – it is likely that investigators will at some point start looking for the elements described in this guidance when they inspect device manufacturer’s quality systems. 

By Alan M. Kirschenbaum, Michelle L. Butler & David C. Gibbons –

The February 1st Federal Register contains CMS’s final rule implementing changes to the Medicaid Drug Rebate Program (MDRP). The rule had been released for prepublication review on January 21. This rule, which has an effective date of April 1, 2016, will require pharmaceutical companies to make substantial changes in their MDRP policies, procedures, calculation methodologies, and systems within a very short time frame. To help our readers understand the final rule and how to implement it, HP&M today released a memorandum summarizing the rule, which is available here.

Also, in collaboration with KPMG’s government pricing leaders, HP&M will conduct a free Webinar entitled “A Practical Guide the Medicaid Rebate Final Rule” 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.

The final rule goes a long way toward clarifying ambiguities in the Affordable Care Act amendments to the Medicaid Rebate statute and CMS’ 2012 proposed rule, and contains a number of favorable changes from the proposed rule. Among the highlights are the following (page numbers refer to our summary memorandum):

• Wholesaler sales: For the treatment of wholesaler sales in AMP, CMS has retreated from its proposal to require a so-called buildup method, and instead is permitting manufacturers to use the traditional presumed inclusion approach. (P. 3)

• Line Extensions: CMS has withdrawn its complex proposed methodology for determining line extensions of solid oral dosage form single source and innovator multiple source drugs, and is instead soliciting additional comments on this subject. A drug will not be considered a line extension of a drug marketed by another manufacturer unless there is a corporate relationship. (Pp. 20-21)

• Territories: The MDRP will be extended to the U.S. Territories beginning April 7, 2017, and sales to customers located in the Territories will be includable in AMP and best price. (P. 2)

• 5i AMP: Exclusions from AMP for 5i drugs are added to the regulation, specifically identifying government sales, bona fide service fees, and other excluded transactions. (Pp. 11-14)

• Entities conducting business as retail community pharmacies:   CMS has withdrawn its proposal to include in AMP sales to entities that “conduct business as retail community pharmacies,” such as specialty pharmacies, home infusion pharmacies, and home health care providers. (P. 5)

• Best price definition: CMS is narrowing the scope of customer categories included in best price so that it is consistent with the statutory definition. For example, sales to patients are not included in best price. (P. 14)

• 340B sales and best price: All prices to 340B covered entities are excluded from best price, not just “prices charged under the 340B program,” as proposed. (P. 15)

• “Original NDAs”: Although an “original NDA” is defined to mean an NDA as in the proposal, certain drugs approved under an NDA may be eligible for a “narrow exception” to the definition of an innovator drug, with approval from CMS. (Pp. 18-19)

• Federal Upper Limits: FULs for multiple source drugs will be calculated as 175% of the weighted average of the A-rated drugs, as proposed, except that a FUL will not be lower than the National Average Drug Acquisition Cost (NADAC) published by CMS. (P. 26)

• Actual acquisition cost: Beginning April 1, 2017, states must base their fee-for-service Medicaid ingredient cost reimbursement to pharmacies on actual acquisition cost, determined using pharmacy surveys or other reliable data. (P. 25)