Attorney East Hampton

By Kurt R. Karst —

“Don’t test me!”— that’s a warning that I, along with my younger brother, Erik, heard more than once from our parents while growing up.  The warning would come up from time to time—but particularly during our teenage years—when teenagers do what they sometimes do: challenge authority or just forget some responsibility.  (Of course, I now recognize and understand this with two teenage boys in the hopper and a tween daughter not too far away from true teenage status.)  In any case, hearing “Don’t test me!” from my parents meant that they were serious and more than willing to impose a penalty for the infraction identified if it happened.  FDA has thrown down a similar gauntlet in the 180-day exclusivity arena.

Over the years here at the FDA Law Blog when putting together and updating our popular 180-Day Exclusivity Tracker (which tracks all grants and forfeitures of Paragraph IV 180-day exclusivity and Competitive Generic Therapy (“CGT”) 180-day exclusivity) we’ve found it a bit frustrating that the Orange Book does not always capture the running of a period of 180-day exclusivity.  And, in our experience, that’s happened because, despite boilerplate ANDA approval letter language that a company “[p]lease submit a correspondence to this ANDA informing the Agency of the date you begin commercial marketing,” some generic drug manufacturers have failed to notify FDA about the date of first commercial marketing of a drug product so that the Agency can update the Orange Book with the appropriate “PC” (Patent Challenge) exclusivity expiration date.  (Failure to notify has not been an issue with CGT 180-day exclusivity, but it’s worth noting that notice timing is important—see our previous post here.)

Back in October 2016 when FDA updated the Agency’s Hatch-Waxman regulations to incorporate some of the changes made by the 2003 Medicare Modernization Act (see our previous post here), the Agency added a new regulation: 21 C.F.R. § 314.107(c)(2).  That regulation, which concerns the timing of approval of “subsequent Paragraph IV ANDA” (i.e., an ANDA potentially blocked from final approval because of a first applicant’s eligibility for, or the running of, 180-day exclusivity) states:

A first applicant must submit correspondence to its ANDA notifying FDA within 30 days of the date of its first commercial marketing of its drug product or the reference listed drug.  If an applicant does not notify FDA, as required in this paragraph (c)(2), of this date, the date of first commercial marketing will be deemed to be the date of the drug product’s approval.

At the time FDA issued the regulation, we scoffed at it a bit.  Would FDA really carry through with this threat?  After all, the regulation right below it—“(3) If FDA concludes that a first applicant is not actively pursuing approval of its ANDA, FDA may immediately approve an ANDA(s) of a subsequent applicant(s) if the ANDA(s) is otherwise eligible for approval”—has been on the books for decades and FDA has never exercised that authority (see our previous post here about that regulation and the recently introduced BLOCKING Act).  So why would FDA decide to exercise its authority here?

Well, it turns out that despite going soft on the “active pursuit” regulation at 21 C.F.R. § 314.107(c)(3) for so many years, FDA almost immediately took a hard line on the new “deemed triggered” regulation at 21 C.F.R. § 314.107(c)(2).  In fact, FDA’s stance has punished some folks who perhaps should not have been punished in the first place.

The instances in which FDA has applied 21 C.F.R. § 314.107(c)(2) are difficult to find and require some hunting around for facts.  (And the lack of ANDA approval letters posted on Drugs@FDA does not help.)  In fact, the instances—of which there may be a handful—don’t appear to be documented at FDA in any exclusivity memoranda.  They just happen.

The first case we noticed occurred with the publication of the July 2017 Orange Book Cumulative Supplement.  There, FDA updated the Orange Book to reflect a period of 180-day exclusivity for ANDA 204065 for Desvenlafaxine Succinate Extended-release Tablets, 25 mg, 50 mg, and 100 mg.  That ANDA was approved on July 29, 2016.  The PC expiration date assigned to the 25 mg strength under ANDA 204065 was January 25, 2017, while the date assigned to the 50 mg and 100 mg strengths approved under ANDA 204065 was August 28, 2017.

At first glance, the different PC expiration dates don’t seem terribly out of order.  After all, there are many instances of staggered 180-day exclusivity expiration dates based on different commercial marketing dates.  But what stood out here was the date: January 25, 2017.  First, is it the only January 25, 2017 date listed in the Orange Book for any of the shared first applicants for any Desvenlafaxine Succinate Extended-release Tablets drug products.  The shared first applicants for the 50 mg and 100 mg strengths—ANDA 204003, ANDA 204028, ANDA 204082, ANDA 204083, ANDA 204095, and ANDA 204172—are, along with ANDA 204065, identified with a August 28, 2017 180-day exclusivity expiration date.  Second, the “Marketing Start Date” identified on DailyMed for the 25 mg strength approved under ANDA 204065 is March 1, 2017, and that date bears no 180-day relation to January 25, 2017.  Third, January 25, 2017 is exactly 180 days from July 29, 2016—the date of approval of ANDA 204065.

The second case we noticed also occurred with the publication of the July 2017 Orange Book Cumulative Supplement.  There, FDA updated the Orange Book to reflect a period of 180-day exclusivity for ANDA 204029 for Clofarabine 20 mg/mL (1 mg/mL).  That ANDA was approved on May 9, 2017.  The PC expiration date assigned to the ANDA was November 5, 2017, which is 180 days after the May 9, 2017.  According to DailyMed, the “Marketing Start Date” for Clofarabine 20 mg/mL (1 mg/mL) approved under ANDA 204029 was May 10, 2017, which would have resulted in a November 6, 2017 180-day exclusivity expiration date.

The third case we’ve been able to uncover is a doozy and shows how FDA’s interpretation and application of the “deemed triggered” regulation at 21 C.F.R. § 314.107(c)(2) can have unintended consequences for other ANDA applicants.  But just as my parents would say “Too bad!” in response to my brother any his cry of “That’s not fair, Mom/Dad!” when being roped into punishment for one of my infractions, FDA’s response—insofar as how the Agency has interpreted and applied the regulation—seems to be of a similar flavor.

In the January 2019 Orange Book Cumulative Supplement, FDA updated the Orange Book to reflect a period of 180-day exclusivity for ANDA 208327 for Abiraterone Acetate Tablets, 250 mg, that expires on April 29, 2019.  FDA approved ANDA 208327 on January 7, 2019, and, according to DailyMed, the “Marketing Start Date” was January 7, 2019.   So what gives?  Based on the timing of approval of ANDA 208327 and the publication of the January Orange Book Cumulative Supplement, something does not add up.

In this case, there were multiple first applicants eligible for 180-day exclusivity for Abiraterone Acetate Tablets, 250 mg.  Subtracting 180 days from the April 29, 2019 exclusivity expiration date identified by FDA yields October 31, 2018.  It just so happens that FDA approved four ANDAs on that date: ANDA 208453, ANDA 208339, ANDA 208446, and ANDA 208432.  According to DailyMed, product was not marketed under those ANDAs until November 21, 2018 (ANDA 208446 and ANDA 208432) and November 23, 2018 (ANDA 208453 and ANDA 208339), so one might expect 180-day exclusivity to expire on May 20, 2019, which is 180 days from November 21, 2018.  But one of those first applicants apparently failed to timely notify FDA of commercial marketing under their ANDA.  That caused FDA to set the shared 180-day exclusivity period for all first applicants to 180 days after that applicants October 31, 2018 ANDA approval date.  In others words, one slacker first applicant can spoil 180-day exclusivity for all diligent first applicants.  That’s an interpretation and application of the “deemed triggered” regulation that’s going to sit well with folks and that might just come under some scrutiny.

The Food and Drug Law Institute (FDLI) is holding a conference devoted to digital health regulatory issues:  Medical Devices: FDA Regulation in the Era of Technology and Innovation. Hymn, Phelps & McNamara’s Jeffrey K. Shapiro is the Chair.  The conference will be held in South San Francisco on June 6, 2019.  The keynote address will be delivered by Bakul Patel, Associate Director of Digital Health at FDA’s Center for Devices and Radiological Health (CDRH).  The conference will examine FDA’s efforts to adapt medical device regulation to modern day digital health technology and the practical impact on firms that must interact with FDA.  Learn more (and register) here.  (Use code “CaMedDev” for a special 15% discount.)

By James E. Valentine & Frank J. Sasinowski —

On March 25, 2019, FDA issued a draft guidance, “Rare Diseases: Natural History Studies for Drug Development,” to help inform the design and implementation of natural history studies that can be used to support the development of drugs and biological products for rare diseases (hereinafter “Rare Disease Natural History guidance”).  This is the latest in a number of draft rare disease-focused guidance documents released by FDA (e.g., on common issues in drug development in February 2019 here and human gene therapies in July 2018 here).

The existence of a stand-alone guidance document on this topic demonstrates FDA’s recognition of the important role natural history studies play in rare disease drug development, which is understandable given that natural history has been underutilized as well as underappreciated when used.  In addition, when natural history has played a key role its use has often not been thoroughly described or explained so that its use as a precedent was muted.

Informing Drug Development

The Rare Disease Natural History guidance endorses use of information from these studies as primarily helpful informing the design and conduct of adequate and well-controlled clinical trials of investigational drugs that can support review and eventual approval decisions.  This includes identifying the appropriate patient population to study.  The guidance notes that a natural history study may uncover important, detectable physiologic changes that are important predictors of disease progression or are clinically important in their own right.  In addition, a natural history study can be useful in understanding patient subgroups and identifying which may benefit from a particular clinical trial.  These things together can inform decisions on inclusions/exclusion criteria, the stage of the disease to treat, the duration of the trial, the frequency of data collection, and endpoints.

Specifically related to endpoints, FDA endorses natural history studies as a way to identify and develop two types: (1) clinical outcome assessments (COAs) and (2) biomarkers.   COAs are measures of how a patient feels, functions or survives.  The guidance states that a natural history study can help evaluate the ability of a new or existing COA to detect change in a particular disease, including in the pattern of the progression of the disease or its symptoms.  FDA notes that natural history studies can be important vehicles for testing COAs to establish their performance and reproducibility for use in clinical trials.

Meanwhile, biomarkers are objectively measured indicators of biological processes, pathologic processes, or biological responses to therapeutic intervention, such as physiologic measurements, blood tests, and imaging.  The guidance states that a natural history study can help identify or develop biomarkers that can be useful in guiding patient selection and dose selection in drug development programs and can also be predictive of treatment response.  Evidence of a biomarker being predictive of treatment response is important to establishing the potential surrogacy of that biomarker, such as for use as an accelerated approval endpoint.

Use of Natural History Data as an External Control

The Rare Disease Natural History guidance also explores the use of natural history study data to serve as an adequate control group for a clinical trial to support marketing approval.  While FDA previously explicitly recognized the use of historical controls (as described in its guidance on control groups here), and has approved drugs based on studies using historical controls, this guidance provides additional insights into when historical controls are most appropriate in the rare disease context.

Considerations in Selecting or Designing Historical Controls

The Rare Disease Natural History Guidance provides considerations for deciding whether to utilize such a control, given its inherent limitations (e.g., inability to control for certain biases), as well as ways to maximize the utility of these controls when planning for their use.  FDA provides the following considerations:

1. The historical control needs to be very similar to the treated group in all aspects, including disease severity, duration of illness, prior treatments, and other key prognostic factors that affect disease outcomes. FDA notes that patient level data can help support this comparison between treatment groups.  In our experience, patient level data also allows you to appropriately match the historical control to the trial population on these important prognostic variables.
2. Concerns of selection bias can be reduced if natural history studies are similar to the clinical trial in the following ways:
   • Assessment/measurement of critical patient disease characteristics;
   • Aspects of standard of care of the patient population;
   • Data collection intervals and quality consistency; and
   • Well-defined and reliable COAs.

Interpretability of External Controls

The Rare Disease Natural History guidance also sets forth scenarios when natural history controls are most interpretable.  These include when the treatment effect:

• Is large in comparison to potential biases and the known variability in progression;
• Is not affected by patient or investigator motivation or choice of subjects for treatment;
• Can be objectively measured;
• Is measured in a manager that reasonably manages and minimizes bias;
• Has a strong temporal association with administration of the investigational drug; and
• Is consistent with expected pharmacological activity based on the target and perhaps shown in animal models.

While these factors are not unique to the rare disease setting, it underlines the importance of well-defined, carefully documented natural history study protocols that delineate who should be included, the information to be collected, how it is to be collected, the schedule for the data collections (if prospective), and the plan for analysis.

Using Historical Controls to Supplement Concurrent Control Arms

In one noteworthy expansion from previous FDA guidance, the Rare Disease Natural History guidance takes a more wholistic approach (or as the guidance states “a hybrid approach), that endorses the use of external control data to add to a concurrent randomized control arm in a clinical trial.  While not explicitly stated in the guidance, the co-authors of this post view this as an opening to use the historical control to expand an existing placebo control arm to increase its size and, therefore, increase its ability for the trial’s ability to detect a between-group difference when testing its hypotheses.

We propose that sponsors of clinical trials plan their studies to include a small placebo-control arm – one that is minimally sized in order to power the maximum possible treatment effect expected, therefore so that it is still ethical to include such a placebo control.  The sponsor would also collect natural history data in a way that minimizes bias and other weaknesses of historical controls as discussed as FDA lays out in its guidance (and as we outlined above).  Upon completion of the trial, the sponsor would then compare the results of the placebo cohort with that of the natural history cohort and, if sufficiently similar, would use the natural history cohort to “add” to the placebo cohort.

Combining the two cohorts would be permissible if predefined correlations or other assessments of similarity are achieved, providing comfort that that there is less bias in the natural history cohort from known or unknown factors that is not present in the randomized placebo arm.  The average numeric baseline and post-treatment values in the natural history cohort need not be the same as the placebo control cohort, since different patient populations will be expected to be different at baseline, but as long as the magnitude of the change from baseline is similar between the two cohorts, then the two can be deemed similar.  Essentially anchoring the natural history data with the placebo arm data will give regulators an opportunity to assess and, in turn, feel more comfortable with the historical control, which may facilitate greater acceptance of historically-controlled trials.

Practical Considerations for Natural History Study Design

The Rare Disease Natural History guidance also includes discussions of different types of natural history studies (e.g., retrospective vs. prospective, cross-sectional vs. longitudinal), as well as an overview of natural history study design elements, which will help orient those not familiar with study design more generally.  Of note, FDA recommends:

• Engage with patients and patient advocates from the early planning stage (to consider data to be collected, need for potential adjustments to an ongoing study, and potential uses of information), and maintain their involvement (for patient identification and recruitment, ongoing community engagement, identifying burdens that may be resulting in dropouts).
• Initiate natural history studies even before an investigational product has been identified to allow for collection of data over a longer duration and with a larger patient population.
• Consider tradeoffs between less convenient, centralized locations that might allow for better standardization of data collection and more convenient, local locations that may be less standardized. Consider also utilizing remote data collection to improve patient convenience.

Ultimately, the Rare Disease Natural History guidance builds incrementally on previous FDA guidance on selection of control groups and on rare disease drug development.  Now patient groups, academic researchers, and drug developers have a single document that can help identify opportunities and considerations when planning a natural history study.  While the majority of the principles in the guidance are not unique to rare diseases, FDA’s issuance of this document within this therapeutic context emphasizes the increased importance these studies play in orphan product development.  This is also accentuated by the guidance’s parting words, calling for interactions with FDA on design and use of natural history studies, whether or not in the context of a particular development program.

By Kurt R. Karst —

Okay, okay . . . .  It’s now a month after Rare Disease Day (on which Hyman, Phelps & McNamara, P.C.’s own Frank J. Sasinowski took part in some of the festivities).  We’re a little late this year in pulling together and posting on the past year in orphan drug designation requests, designations, and approvals; but better late than never, right?  And, in any case, having delayed pulling together this post, we now have the benefit of some rather interesting statistics and information from FDA’s Fiscal Year 2020 Justification of Estimates for Appropriations Committees (i.e., FDA’s FY 2020 Budget Justification), which FDA Commissioner Dr. Scott Gottlieb announced on March 19, 2019 (see pages 102-103 and 113-119 in particular on the Office of Orphan Products Development (“OOPD”)).

In 2018, which marked the 35th anniversary of the passage of the Orphan Drug Act, FDA’s orphan drug program continued to go strong.  Orphan drug designation requests and orphan drug designations dipped compared to 2017 (see our previous post here), but aren’t too shabby.  FDA received 507 orphan drug designation requests and 337 orphan drug designations.  Those numbers are a bit off the previous records of 582 and 526 orphan drug designation requests in 2016 and 2017, respectively, and 477 orphan drug designations in 2017.  The decrease in orphan drug designations may be attributed to FDA’s 2017 Orphan Drug Designation Modernization Plan, which cleared a backlog of pending designation requests, leaving fewer to act on.  Since 1983, FDA has granted nearly 4,800 orphan drug designations, and has received more than 6,800 orphan drug designation requests.

Where FDA really shined in 2018 was with orphan drug approvals.  As one article headline stated: “Orphan drugs dominate FDA’s record-breaking year”.  That’s true: FDA approved 91 orphan drugs in 2018, which is 10 more than the record set in 2017.  It’s important to note, however, that orphan drug approvals 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 (e.g., “repurposed drugs”).  Since 1983, FDA has granted more than 770 orphan drug approvals.  (Though, at the same time we note that about 93% of rare diseases still have no approved therapies.)

Below are three tables—one for each metric we track—showing the year-by-year numbers since 1983, and a fourth table with combined figures.  The numbers are largely based on information from FDA’s Orphan Drug Designations and Approvals Database.

2018 also saw a growing amount of controversy and criticism over orphan drugs (largely unjustified we think) as part of the larger drug pricing debate.  As a result, numerous articles and reports were published last year.  Here’s a list of some of them:

• Orphan Drugs in the United States (Part one): Growth Trends in Rare Disease Treatments
• Orphan Drugs in the United States (Part two): Exclusivity, Pricing and Treated Populations
• Government Accountability Office – Orphan Drugs: FDA Could Improve Designation Review Consistency; Rare Disease Drug Development Challenges Continue
• How Orphan Drugs Became a Highly Profitable Industry
• It’s Time to Reform the Orphan Drug Act
• Orphan Drugs and Their Impact on Pharmaceutical Development
• The Rise of Orphan Drugs for Rare Diseases

These and other concerns about 7-year orphan drug marketing exclusivity perhaps spurred FDA to include the following passage in the Agency’s FY 2020 Budget Justification:

FDA will also conduct assessments of current orphan drug incentives, including market exclusivity, to inform FDA’s policy framework around primary and secondary drug indications.  Included would be a better understanding of how FDA could best incentivize more drug development for ultra-rare diseases.  The requested funding for this initiative will enable FDA to implement advances to support the public health mission of the Agency.

Where we’re still a bit mystified, however, is with respect to OOPD funding.  OOPD’s public health role and importance to FDA’s success cannot be understated.  In fact, here’s how it is described in the FY 2020 Budget Justification:

OOPD administers major provisions of the Orphan Drug Act and other relevant statutes, where Congress sought to provide incentives to promote the development of products for the treatment of rare diseases and for underserved populations.  OOPD incentive program activities facilitate product development innovation and collaboration with private, public and academic entities.  Further, the programs directly support the FDA’s Strategic Policy Roadmap priority area to leverage innovation and competition to improve health care, broaden access, and advance public health goals.

Despite a significant and growing workload and a critical role to play at FDA, OOPD’s funding has for years been (and will likely remain) flat at a little over $29 million.

By Kurt R. Karst & Bob Pollock (Lachman Consultants Blog) —

The “Petitioned ANDA”—It’s a route to ANDA approval that’s been around since even before the enactment of the 1984 Hatch-Waxman Amendments.  For several years after the enactment of Hatch-Waxman, the petitioned ANDA was a mainstay of the generic drug industry’s drug development paradigm.  And although it remains a viable route for many generic drug applicants to obtain approval of a drug product without having to conduct expensive and time-consuming clinical studies, the popularity of the petitioned ANDA has waned in recent years.  The continued success—and reinvigoration—of the petitioned ANDA depends in large part on FDA’s ability to promptly review and act on ANDA suitability petitions within the statutory 90-day period.  But we’re getting a little ahead of ourselves. . . .

In this blog post—posted simultaneously on the FDA Law Blog and the Lachman Consultants Blog—we hope to describe the benefits of the ANDA suitability petition process, look at why it is not working, and suggest some action FDA might consider to get the program back on track.

Codified at FDC Act § 505(j)(2)(C), the ANDA suitability petition is used to request FDA’s permission to submit an ANDA that differs from a brand-name Reference Listed Drug (“RLD”) in strength, dosage form, route of administration, or for the substitution of one active ingredient of the same therapeutic class for another active ingredient in a combination drug (when, and only when, there is a known equipotent dose relationship between the two ingredients).  Over the years, FDA has received somewhere in the neighborhood of 1,500 ANDA suitability petitions.

The ANDA suitability petition provisions of the FDC Act are short and total slightly more than 150 words:

If a person wants to submit an abbreviated application for a new drug which has a different active ingredient or whose route of administration, dosage form, or strength differ from that of a listed drug, such person shall submit a petition to the Secretary seeking permission to file such an application. The Secretary shall approve or disapprove a petition submitted under this subparagraph within ninety days of the date the petition is submitted. The Secretary shall approve such a petition unless the Secretary finds—

(i) that investigations must be conducted to show the safety and effectiveness of the drug or of any of its active ingredients, the route of administration, the dosage form, or strength which differ from the listed drug; or

(ii) that any drug with a different active ingredient may not be adequately evaluated for approval as safe and effective on the basis of the information required to be submitted in an abbreviated application.

It’s the 22 emphasized words above that we focus on here, because prompt FDA action on a suitability petition is critical to a vibrant suitability petition program.  As One of the authors of this post pointed out in a law review article a few years ago, titled “Letting the Devil Ride: Thirty Years of ANDA Suitability Petitions under the Hatch-Waxman Amendments,” FDA’s track record of timely ruling on suitability petitions has been less than stellar.

The Benefits of Suitability Petitions

As noted above, the changes permitted in a suitability petition allow for certain defined changes from that of the RLD if no new safety or efficacy data are necessary to support the proposed change.  Most suitability petitions are approved for changes in strength and dosage form, rather than for changes in route of administration and active ingredient in a combination drug.  (Today this may be largely due to the Pediatric Research Equity Act of 2003, which amended the FDC Act to add Section 505B to give FDA the authority to require sponsors of applications submitted under FDC Act §505 for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to conduct testing in pediatric populations.  An ANDA requiring an approved suitability petition for a change in the RLD in an active ingredient, route of administration, or dosage form triggers PREA because it is a type of application submitted under FDC Act § 505.  The statute requires that the FDA deny a suitability petition if “investigations must be conducted to show the safety and effectiveness of the drug or of any of its active ingredients, the route of administration, the dosage form, or strength which differ from the listed drug.” The requirement to conduct (or even a deferral from conducting) pediatric studies triggers the statutory requirement to deny a suitability petition. Thus, unless the FDA fully waives the PREA pediatric studies requirement, the Agency must deny a suitability petition that requests permission to submit an ANDA for a change in route of administration, dosage form, or active ingredient vis-à-vis the RLD.)

Changes proposed in a suitability petition may significantly improve patient compliance.  For instance, if a drug is available in 25 mg and 50 mg tablet strengths and the labeling of the RLD states that that single doses of up to 150 mg may be required for certain patients, then a change to include a 100 mg scored or 150 mg tablet may help a patient take fewer dosage units to achieve the required dose.  In other instances, approval of intermediate dosage strengths may help patients who otherwise have to break tablets at scoring marks to reach those doses.  This may be even more important for the elderly, infirmed or visually impaired patients.  Other changes, such as from a tablet to a capsule (and vice versa) may help patients who have difficulty swallowing either tablets or capsules.  In addition, approval of oral solutions could aid in the delivery of drugs to patients that have dysphagia or other maladies, or those patient who just cannot seem to swallow solid dosage forms.

The suitability petition process also permits drug companies to expand available generic products (thus creating greater competition while potentially addressing a current unmet need), while at the same time avoiding the use of the more resources intensive (and expensive) 505(b)(2) NDA process for the same types of changes permitted under a suitability petition.

Why the Suitability Petition Process is Not Working at the FDA?

Input for reviewing suitability petitions and their proposed changes is required from various FDA components in the Center for Drug Evaluation and Research (“CDER”).  While the number of CDER components that chimed in on suitability petitions was small at first, that number has grown significantly over the years, resulting in an unwieldy process.

At the time of the passage of the Hatch-Waxman Amendments there was a small committee comprised of two people from the Office of Generic Drugs (“OGD”), Dr. Jim Bilstad and Dr. Bob Temple (the only two Office Directors at that time), and a member of the Office of Chief Counsel (“OCC”).  Staff work with recommendations was prepared by OGD and forwarded to the respective CDER Division Directors who were responsible for the RLD, and decisions were made at a monthly suitability petition committee meeting.  If the CDER Division Directors did not object and the committee’s recommendation was to approve the petition, then the final decision rested with the committee.  If the CDER Division Directors or if the committee recommendation was to deny the petition, then a draft denial letter was prepared and run through the OCC representative and an action letter was prepared.

Today there are too many cooks in the kitchen!  There are many more CDER Office and Division Directors who need to have a “say” in a suitability petition decision.  Moreover, the institutional knowledge regarding suitability petition precedent has, with a very few exceptions, been lost.  This further slows down the process.  And then there’s the post-PDUFA and GDUFA environment at FDA where a significant amount of CDER’s attention is directed towards meeting user fee goals.  Despite the fact that the FDC Act directs FDA to rule on a suitability petition within 90 days of submission, it’s not a user fee goal.  As such, FDA has essentially let the suitability petition process go adrift in favor of addressing “higher” user fee priorities.

The Association for Accessible Medicine (“AAM”) estimates that hundreds of ANDA suitability petitions are currently pending at FDA.  Some of those petitions have been pending at FDA for over 8 years!   According to data compiled from the FDA Law Blog Citizen Petition Tracker, FDA received 135 ANDA suitability petitions between 2013 and 2019.  Of those 135 petitions, an astounding 113 (or 84%) remain pending (see table below).  Of the 22 petitions that have been resolved, 2 (1.5%) were denied, 5 (4%) were granted and 15 (11%) were withdrawn (with half of those petitions later resubmitted and that remain pending).

Delving deeper into the numbers, we see that two of the pending petitions are for drugs that are in shortage, and for which the brand-name RLD is not marketed: (1) sodium chloride, 23.4%, which is regularly used as a diluent for intravenous infusions; and (2) cysteine hydrochloride injection, 5%, which provides amino acid therapy to newborn infants.  In each case, the changes requested are merely to the volume of product provided (i.e., strength) and raise no new safety or effectiveness questions.  While these petitions remain pending, patients are without an option for these products. Twenty of the pending suitability petitions concern drugs that have no generic competition.  And six of these are on FDA’s List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic.  These drugs are for indications including Type 2 Diabetes, cancer, heart disease, and broad-spectrum antibiotic uses.

FDA’s efforts to address the ANDA suitability petition backlog have thus far been unsuccessful.  For example, in August 2013, FDA published a Manual of Policies and Procedures (“MAPP”) establishing the policies and procedures for responding to suitability petitions and reiterating that “the Agency will approve or deny the petition no later than 90 days after the petition is submitted.”  That MAPP—MAPP 5240.5, revised in August 2018 to remove any reference to the 90-day period—has not resulted in any noticeable change in the speed with which FDA responds to suitability petition.  Heck, FDA has not even updated the Agency’s ANDA Suitability Petition Tracking Reports since August 2015!

Perhaps as a result of FDA’s failure to timely address suitability petitions, Congress expressed its expectation that FDA meet this 90-day target in Section 805 of the 2017 Food and Drug Administration Reauthorization Act (“FDARA”).  In addition to a “sense of Congress” provision stating that FDA “shall meet the requirement under [FDC Act § 5050)(2)(C)] and [21 C.F.R. § 314.93(e)] of responding to suitability petitions within 90 days of submission,” Congress hoped to encourage FDA to expedite responses to such petitions by requiring a report of the number of outstanding suitability petitions and a report of the number of suitability petitions that remained outstanding 180 days after submission. FDARA § 805. In addition, the GDUFA II Performance Goals Letter states that “FDA aspires to respond to Suitability Petitions in a more timely and predictable manner.” GDUFA II Performance Goals Letter at 23.  FDA has thus far not complied with this congressional mandate and GDUFA II Performance Goal.

As a result of the current disfunction of the ANDA suitability petition process, firms have instead been using the 505(b)(2) NDA route, as it covers the same type of changes permitted by an ANDA suitability petition.  But the submission of a 505(b)(2) NDA not only means the payment of a hefty application user fee, but also annual program fees (in some cases).

How to Fix the ANDA Suitability Petition Process?   

There are two paths that we believe FDA could take to address the suitability petition backlog, and to lay the groundwork for future success.

First, FDA could contract out the staff work to develop a recommendation based on the statutory and regulatory requirements and past precedent that the Agency could use as a basis for its final decision-making process.  This approach may raise some eyebrows as there could be hints of conflict of interest from private contractors relative to their potential affiliations.

Second—and perhaps the best approach—would be for FDA to detail a select few individuals to spend a good portion of their day managing the suitability petition process with the goal of cleaning up the backlog of petitions and establishing a foundation upon which future petitions could be handled within the Agency.  The use of those with historical perspective should be of greatest benefit for FDA and their wisdom could then also be transferred to others within the Agency.  This “suitability petition hit squad” may be able to revive the vibrancy of the petition process while providing FDA, patients, and industry with the service it deserves and a long-term solution for continuing the process going forward.

Absent FDA being able to address the issue internally, Congress might have to step in and make some changes to the statute.  For example, Congress might consider extending—perhaps as part of the next iteration of GDUFA––the 90-day response deadline to reflect deadlines that are more familiar to and attainable by FDA, such as the 150-day, 180-day, or 270-day petition response deadlines imposed by Congress in recent years.

An attainable deadline will give greater certainty to the ANDA suitability petition process, will reassure the generic drug industry that it is a viable and practical route to ANDA approval, and may lead to a renewed interest in submitting ANDA suitability petitions.

Spring is here!  How do we know?  Is it the cherry blossoms starting to bloom in Washington, DC?  Is it the daffodils emerging from hibernation?  No – we know it’s Spring because the annual American Conference Institute (“ACI”) “Paragraph IV Disputes” conference is right around the corner.

That’s right, ACI will be holding its 13th annual “Paragraph IV Disputes” conference from April 29-30, 2019 at the Conrad New York in New York City.  The 2019 conference is a special one with the 35th Anniversary of the Hatch-Waxman Amendments later this year (September 24, 2019).  Attendees will get to hear from a virtual “who’s who” of Hatch-Waxman litigators and industry decision makers.

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be moderating a panel titled “Latest FDA Initiatives Affecting Generic Drug Access and Pricing.”  The panel speakers are FDA’s Grail Sipes, Deputy Center Director, Regulatory Policy, CDER, and Maryll Toufanian, Director Office of Generic Drug Policy, CDER.  We’ll be delving into the latest and greatest FDA policy and legal initiatives, including the Drug Competition Action Plan and Competitive Generic Therapies.

FDA Law Blog is a conference media partner.  As such, we can offer our readers a special discount off the current price tier.  The discount code is: D10-896-896AX01.  You can access the conference brochure and sign up here.

By Karla L. Palmer —

We posted last year about the dispute over FDA’s determination to include certain nominated substances on its Bulk Substances List 1 for Section 503B outsourcing facilities.  Recall that in 2017, after FDA approved Endo/Par’s Vasostrict® finished drug product, several entities nominated active pharmaceutical ingredient vasopressin for inclusion on FDA’s Section 503B Bulk Substances List 1.  After review of the nominations, FDA added vasopressin to Bulks List 1 in mid-2017.  Next, FDA’s nomination and listing process (already the subject of two Agency revisions and “redos” since 2014, blogged about here) ground to a halt.  The nominations process and the list itself was (and remains) the subject of contentious litigation involving FDA, Endo Pharmaceuticals and its subsidiary Par Sterile Products, and outsourcing facility Athenex Pharma Solutions.

After proposing to change the nomination process in March 2018 (here), which continued a stay in the litigation against FDA brought by Endo/Par, FDA received approximately 60 industry comments.  It published its final guidance for the section 503B nomination process on March 4, 2019 (here).  In response to those 60 comments “or on its own,” FDA stated it made certain changes in the final guidance document; however, those changes do not change the process in which FDA intends to engage to review a nominated substance.  Instead, FDA’s final guidance on the nomination process explains in more detail

how Congress’ limitation on bulk drug substances that can be used in compounding under section 530B helps preserve the integrity of the new drug approval process, and identifie[s] the process to request that FDA identify or remove a bulk drug substance from that list after the Agency has made a final determination with respect to that substance….

At the same time FDA published final guidance on the nomination process, FDA issued another final guidance document, this time removing two bulk substances from FDA’s interim Bulks List 1: vasopressin and nicardipine hydrochloride (here).

Addressing the more controversial subject of compounding using vasopressin, FDA stated among other reasons that nominations and comments it received did not identify an attribute of commercially available Vasostrict® that makes it “medically unsuitable for patients,” and that the compounded products “are intended to address” that attribute.  FDA also stated that the proposal for compounders to compound a “ready-to-use” formulation versus the commercially available Vasostrict® product for improved efficiency for prescribers or healthcare providers, or to address the possibility that the approved drug may be mishandled by a medical professional, is not a “clinical need to compound a drug product” using a bulk substance.

Not surprisingly, outsourcing facility Athenex Pharmacy Solutions LLC filed a lawsuit pursuant to the Administrative Procedures Act against FDA and others challenging FDA’s bulks determination (on the same day as FDA’s Federal Register notice announcing its vasopressin decision).  Although Athenex originally sought immediate injunctive relief from the D.C. District Court barring FDA from enforcing its vasopressin determination, FDA has agreed not to engage in an enforcement action against Athenex based solely on use of vasopressin until after the district court issues a decision on the merits concerning whether FDA’s actions removing vasopressin from its Bulks List 1 were appropriate.

In its Memorandum in Support of its Motion for Summary Judgment on the merits of the lawsuit, filed on March 18, 2019, Athenex notes that vasopressin has been used in medical care for almost a century to treat life threatening and emergency conditions.  Athenex argues that FDA made the decision to exclude the ingredient from its Bulks List because “a pharmaceutical company is using it to make a branded drug product … that FDA thinks that doctors should choose to use instead of Athenex’s compounded vasopressin drug product.”

Athenex argues that FDA has misinterpreted Congress’ “plain language” instruction concerning whether there is a “clinical need” for substances as “directing FDA to decide whether doctors should always choose an existing branded product over any compounded product made with that substance.”  Among other problems, FDA’s vasopressin determination wrongfully invades the practice of medicine.  In addition, because vasopressin is indeed a component of an approved drug product, FDA has “officially acknowledged” vasopressin is an active pharmaceutical ingredient that meets patients’ “clinical needs.”  Athenex also argues that the plain language of the statutory definition of “bulk drug substance” confirms the subject of the clinical need inquiry required under section 503B is for the active pharmaceutical ingredient and not the finished drug product.      

Athenex next argues that its vasopressin compounded formulation is different from Vasostrict® in clinically significant ways that FDA wrongfully and arbitrarily ignores.  First, unlike the commercially available drug, Athenex’s vasopressin formulation is provided in a ready-to-use formulation and thus avoids Vasostrict’s® 16-step administration process.  Furthermore, Vasostrict®, as stated on its own label, is contraindicated in patients with a known allergy to chlorobutanol and Athenex’s vasopressin is not.  Athenex argues that FDA arbitrarily disregarded these clinically significant differences when it determined to remove vasopressin from section 503B’s Bulks List 1.

We look forward to reviewing FDA’s opposition to Athenex’s Memorandum, and watching what happens next in this long-running “David versus Goliath” saga.

By James E. Valentine —

On March 16, 2019, Advances in Therapy published a commentary authored by HP&M Attorney James E. Valentine along with co-authors Marielle Contesse, Tracy Wall, and Mindy Leffler.  The paper sets forth the case, and provides a methodologic overview, for incorporating qualitative patient and caregiver video interviews into clinical trials as one method for rigorously capturing patient experiences and caregiver observations (referred to as PPC and CPC Assessments).  This paper comes on the heels of a recent National Academies of Sciences workshop report on the Science of Patient Input that cited James Valentine’s recommendation for this type of methodology as a novel way to solicit patient experiences in clinical trials (see previous coverage here).

James Valentine and his co-authors propose the novel PPC and CPC Assessments to help overcome the many methodological challenges to measuring treatment effect in rare diseases.  Because of the small number of patients and the nature of rare diseases, study design often involves a tension between properly powering a study and minimizing heterogeneity of the study population.   Broadening the inclusion criteria to power the study can result in increased heterogeneity, which then makes it difficult to select outcome measures with sensitivity across the study population.  This diversity, combined with the novelty of the drug being assessed, may mean that it is not always possible to predict the different ways treatment benefit might manifest across patients, further complicating the selection of outcome measures.  Lastly, there is often a lack of validated, disease-specific outcome measures, which leads to borrowing outcome measures that were used in other diseases, which lack sensitivity.  These methodological challenges in rare disease clinical trials can lead to uncertainty about whether some trials fail as a result of failed measurement of the drug effect rather than failed treatment.

In an effort to:

(1) create a bulwark against type 2 errors as a result of these challenges to assessing treatment effect in rare diseases,

(2) maximize the contribution to the scientific data by each and every rare disease patient volunteering to participate in studies, and

(3) embrace the principle of “patient-focused drug development” to ensure that the breadth and depth of patient insight into their experience is considered in FDA approval decisions,

the PPC and CPC Assessments can be employed to capture patients’ and caregivers’ perceptions of change using semi-structured video interviews that can be implemented before, during, and after a clinical trial.  Furthermore, these qualitative interviews can be done in the clinic, over the phone (via a mobile application), or with a web conferencing system.  The paper provides an in-depth discussion of how to design and implement the PPC and CPC Assessment methodology based on the experiences of each of the authors who come to this as regulatory experts, patient advocates, clinical researchers, and/or drug developers.

The paper concludes that seeing the patients and caregivers on video and hearing directly from them about their experiences can be important information for regulators, payers, and prescribers.  Among other things, this kind of patient experience report may provide context to the meaningfulness of clinical trial endpoints, where patients and their caregivers voice how changes experienced during a trial impacted how they felt or functioned in daily life.  Or it may encourage regulators and payers to consider an impact on patient quality of life that may not have been documented in the study’s more conventional outcome measures.  Finally, the 21st Century Cures Act requests FDA to include a description of how patient experience data was obtained and reviewed by FDA, and this new methodology would provide a means tailor-made to this purpose.

By Sara W. Koblitz —

About 6 weeks after Vanda filed its complaint, the company’s lawsuit has joined its clinical trial: on hold.  Last week, the District Court of D.C. granted FDA’s motion for a voluntary remand of the case challenging FDA’s requirement to perform 9-month large animal studies prior to commencing studies in humans staying the case for 45 days from the Court’s Order while FDA reevaluates its position.  While Vanda supported a voluntary remand, it strongly advocated that the Court stay the case while vacating the clinical hold on its 52-week human study.

FDA requested a voluntary remand to “address certain procedural issues Vanda noted in its Complaint, including the allegations about the agency’s response to scientific arguments submitted by Vanda and the treatment of a guidance document as a binding rule.”  Notwithstanding all the usual pre-litigation negotiations about the issue that were discussed in Vanda’s Complaint, only now will FDA “provide a full written explanation of the agency’s analysis and ultimate position.”  FDA does not, however, seem willing to reexamine its fidelity to guidance – stating that it intends to address on remand “the legal import of the guidance document and fully setting out the scientific basis for its actions here.”   From this statement, it is unclear whether FDA is actually planning to re-review the scientific merits of Vanda’s arguments or merely provide more explanation upon remand.  Importantly, FDA also requested that the Court remand without vacatur of the original agency decision if the court agrees to FDA’s remand request, meaning that the the Partial Clinical Hold should remain in place until FDA provides its new analysis.

Because Vanda agreed to the voluntary remand, the only issues remaining for the Court decide with respect to this motion are the questions of remand without vacatur and length of a stay.  Vanda argued that the Clinical Hold has no valid legal basis because FDA was required to analyze these issues before issuing the Clinical Hold.  Vanda hypothesized that FDA is “merely stalling in an attempt to make superficial changes to a legally deficient hold—in effect ‘putting lipstick on a pig’” and shouldn’t be given additional time to make procedural corrections while further delaying Vanda’s clinical trial program.  Because “unsupported agency action normally warrants vacatur” and because remand without vacatur is fundamentally inconsistent with the APA, Vanda argued that only remand with vacatur is appropriate.  Vanda also argued against the 75 day stay that FDA requested, arguing that a 30 day stay – the amount of time that FDA would normally have to consider an entirely new IND – is more appropriate.

The Court agreed to the voluntary remand to give FDA the opportunity to “cure its mistakes,” but declined to vacate the Clinical Hold.  The Court actually questioned whether it has authority to vacate an agency action in the absence of a request for emergency relief.  This is especially true because FDA’s filing did not concede that the Clinical Hold order is invalid.  But the Court emphasized that even if it could, it would not vacate the Clinical Hold because it has not been determined deficient and the procedural defects are likely to be corrected on remand.  Questions of patient safety risks further supported the Court’s decision.  In an act of compromise, the Court decided to stay the case for 45 days (75 days from FDA’s motion) – until April 28, 2019 – rather than the 75 days (from the Court’s decision) FDA requested.

Given that Vanda has been fighting its battle with FDA on this issue since May 2018, it’s interesting that it took litigation to compel FDA to address Vanda’s procedural and scientific complaints with any sort of gravity.  The government notes that Vanda did not “invoke the appeal procedures,” but Vanda explained in its Complaint that its attempt to do so through the Formal Dispute Resolution process was met with additional procedural roadblocks.  FDA’s remand request is especially considering in that FDA essentially admits that it did not fully comply with the procedural requirements for imposing a Clinical Hold.  Many small companies are before FDA every day and may encounter similar issues but don’t have the resources to fight FDA in court.  The Agency fully admits that it did not comply with its own requirements, and it is now asking for the opportunity to do so only after Vanda filed a lawsuit.  Even if FDA is just going to “put lipstick on a pig” here and redraft its Clinical Hold Letter to include a reasoned explanation, all interested parties should agree that it shouldn’t take litigation to pry such an explanation from FDA.

By Rachael E. Hunt —

FDA recently issued a draft guidance document, Nonbinding Feedback After Certain FDA Inspections of Device Establishments, which outlines the process for obtaining FDA feedback on proposed remedial actions in response to observations issued on a Form 483, the Agency’s Inspectional Observations Form, following an inspection.

Background

Section 702 of the FDA Reauthorization Act of 2017 (FDARA) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to require FDA to provide nonbinding feedback in certain circumstances after an FDA inspection of a device establishment.  Specifically, FDCA section 704(h)(2) states:

(A) The Secretary shall, with respect to a request described in subparagraph (B), provide nonbinding feedback with respect to such request not later than 45 days after the Secretary receives such request.

(B) A request described in this subparagraph is a request for feedback—

(i) that is made by the owner, operator, or agent in charge of such establishment in a timely manner; and

(ii) with respect to actions proposed to be taken by a device establishment in a response to a report received by such establishment pursuant to subsection (b) that involve a public health priority, that implicate systemic or major actions, or relate to emerging safety issues (as determined by the Secretary).

Statutory Eligibility and Justification

In the draft guidance, FDA reiterates the statutory criteria for nonbinding feedback: the request must describe how one or more observations “involve a public health priority,” “implicate systemic or major actions,” or “relate to emerging safety issues (as determined by [FDA]).”  The request must, therefore, include a justification as to why one of the eligibility criteria is met.  FDA provides the following examples of observations that would likely meet the statutory criteria for nonbinding feedback:

• An observation regarding conditions that, if unaddressed, are likely to result in the release of a violative product that may cause death or serious injury.
• An observation regarding quality system or subsystem deficiencies which have or are likely to result in a nonconforming, violative and/or defective device.
• An observation relating to an emerging safety issue that, if unresolved, is likely to result in the release of devices likely to cause death or serious injury.

Request for Feedback

Eligible requests should be submitted no later than 15 business days after a Form 483 is issued and should be addressed to the same FDA contact responsible for receiving any response to the Form FDA 483.  Any response to a Form 483 should be distinct from a request for nonbinding feedback, although the two submissions can be sent together.

The request should state the inspectional observation for which feedback is being requested as well as the proposed remedial actions, including a proposed timeline.

FDA’s Response

Upon receiving a request, FDA will first determine whether the eligibility criteria are met.  If not, FDA will notify the requestor within 45 days that the request is ineligible. If the request does meet one of the criteria, FDA is required to provide nonbinding feedback within 45 calendar days.  This feedback will indicate whether the proposed actions appear adequate, partially adequate, or inadequate.  Where FDA’s feedback is that a proposed action is partially adequate or inadequate, FDA will provide an explanation and a recommendation as to what may be needed for FDA to consider the proposed actions adequate.

Limitations of Feedback

The draft guidance articulates the limitations of the feedback provided by FDA, watering down most of the utility of this program.  Specifically, the guidance notes that FDA’s feedback “may not adequately address the cause of the problems that led to the inspectional observations, and additional action may be warranted.”  The guidance also notes that FDA’s feedback does not prevent additional observations or regulatory action.  Any response from FDA would, therefore, provide little comfort to a sponsor who had already admitted that a Form 483 observation “involve[s] a public health priority,” “implicate[s] systemic or major actions,” or “relate[s] to emerging safety issues (as determined by [FDA]).”  The process, therefore, puts sponsors in a lose-lose situation.  While the admissions could be used in an enforcement action or a products liability lawsuit to demonstrate knowledge of a problem, a failure to request available feedback could be used to show negligence or willful ignorance of the same.

We encourage stakeholders to review the draft guidance and provide comments under docket number FDA-2018-D-4711.  The comment period closes on April 22, 2019.