Judge Says Lack of State and Federal Plans Means That the Farm Bill’s Interstate Commerce Protections for Hemp Don’t Apply

Judge Says Lack of State and Federal Plans Means That the Farm Bill’s Interstate Commerce Protections for Hemp Don’t Apply

By JP Ellison & Ricardo Carvajal

We previously posted about what the Agricultural Improvement Act of 2018 (commonly referred to as the Farm Bill) did, and did not, do with respect to “hemp” and CBD products derived from hemp.  In that post, we noted that the Farm Bill did not preempt state laws that were more stringent. Our prior post did not discuss the Farm Bill’s interstate commerce provisions, which recently have become the focus of litigation.

Under section 10114, “Interstate Commerce,” there are two provisions–

  • Subsection (a) states as a “RULE OF CONSTRUCTION” that “[n]othing in this title or an amendment made by this title prohibits the interstate commerce of hemp (as defined in section 297A of the Agricultural Marketing Act of1946 (as added by section 10113)) or hemp products.”
  • Subsection (b), titled “TRANSPORTATION OF HEMP AND HEMP PRODUCTS” provides that “[n]o State or Indian Tribe shall prohibit the transportation or shipment of hemp or hemp products produced in accordance with subtitle G of the Agricultural Marketing Act of 1946 (as added by section 10113) through the State or the territory of the Indian Tribe, as applicable.”

The meaning of “in accordance with” played a major role in a recent decision denying a request for emergency relief in connection with what seems to have been “hemp,” under the Farm Bill.  Briefly, in Big Sky Scientific LLC v. Idaho State Police, the Idaho state police seized nearly 13,000 pounds of what appears to be hemp.  They did so because hemp is a controlled substance under Idaho law.  The hemp (or according to Idaho “contraband”) was produced in Oregon and was in route to Colorado.  Idaho took the position that the Farm Bill’s section 10114(b) protection against a state prohibiting transport of hemp did not apply because subtitle G contains provisions setting forth how the Secretary of USDA can “approve” or disapprove” a state or tribal “plan,” or establish his own “plan.”  Idaho argued that until such a plan is approved or established, no hemp can be produced “in accordance with subtitle G.”  At the emergency motion stage, the court agreed finding:

[T]he cargo that was seized on January 24, 2019 was not hemp that has been “produced in accordance with subtitle G.” It could not have been produced in accordance with subtitle G because Oregon does not have a federally approved plan and the Secretary of the United States Department of Agriculture has yet to establish its own plan as Subtitle G requires be done. This is undisputed. It matters not whether the cargo might meet the requirements of subtitle G if such a plan (or something similar) had existed when the crop was grown and harvested, or whether the implementation of the production plan by the Department of Agriculture was delayed somehow because of the recent shutdown of certain operations of the federal government. There simply is no such plan in place and therefore the cargo, whether described as hemp or marijuana, could not have been produced in accordance with subtitle G and therefore could not be subject to the protection of interstate commerce as provided by the 2018 Farm Bill.

The Court made clear that this was not a final determination on the merits and the litigation is proceeding.   We’ll continue to monitor this litigation and other developments.  In the meantime, anyone distributing hemp or CBD products derived from it would do well to check their distribution routes against the varying state laws.

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FDA Doubles Down on Warnings to Stem Cell Clinics

FDA Doubles Down on Warnings to Stem Cell Clinics

By Mark I. Schwartz

In a press release issued on April 3rd, FDA reiterated its warning to stem cell clinics (and implicitly to other HCT/P facilities that are benefiting from enforcement discretion), asserting that the agency has stepped up oversight over such facilities, and will be ramping up even more after the 36 months of enforcement discretion end in November 2020:

Over the past year, we have sent 45 manufacturers and health care providers regulatory correspondence, including warning letters, and we have two court cases pending. We’re committed to taking appropriate steps to address those that jeopardize the health of the people we are sworn to protect.

Today, we’re continuing these efforts. The agency issued a warning letter to Cord for Life, Inc., located in Altamonte Springs, Florida, for manufacturing unapproved umbilical cord blood products in violation of current good manufacturing practice (CGMP) requirements, including failing to validate processes to prevent bacterial contamination, raising potential significant safety concerns that put patients at risk. In addition, we issued 20 letters today to separate manufacturers and health care providers across the country who may be offering unapproved stem cell products, reiterating the FDA’s compliance and enforcement policy.

We’ve previously spoken about this issue here and here.

In addition, the agency expressed frustration that some in the stem cell industry continue to assert that autologous stem cell procedures (i.e., procedures that take cells or tissue from a person’s body and re-administer them to the same person, usually after some manipulation, and for a different intended use) are not subject to FDA regulation.

There’s a false premise being asserted by some in the field that a product derived from a person’s own body and then manipulated and reinserted for another use different from the one it played in its original location is not subject to FDA regulation just because it originated from the person it was given back to. But stem cell products can create unique and serious risks depending on how they’re manipulated once they’re taken from the body and how they are used once they’re reinserted in the body.

Interestingly, while the agency had issued a similar press release in December 2018 emphasizing that they were “discouraged” by the overall lack of manufacturers wanting to interact with the agency during the 36 months of enforcement discretion, in the current press release FDA states that the industry has made “modest progress” in coming into compliance, though much more work needs to be done.

Finally, as enforcement discretion comes to an end, in addition to the stick of possible regulatory and enforcement action, the agency also held out the carrot of possible relief for firms that undertake well-designed investigational studies with the intent of collecting information to more clearly identify the safety and benefits of their products.

As we come up on the end of this period during which the FDA intends to exercise enforcement discretion, we may take additional steps to delineate an efficient development path for promising products that pose lower risk to patients and that are being developed by sponsors who’ve engaged the regulatory process in a responsible manner by filing INDs.  These would be cases where the sponsors have undertaken or are in the process of undertaking well-designed investigational studies with the intent of collecting information to more clearly identify the safety and benefits of their products… In addition, during the next year, the agency will explore whether there are additional ways that it can assist legitimate developers of stem cell products to come into compliance with its regulations. [Emphasis added]

What might these additional steps to delineate an efficient development path be?

In what ways might the agency assist legitimate developers to come into compliance?

We have some thoughts.  Stay tuned…

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Medicaid “Right Rebate” Provisions Clear Congress

Medicaid “Right Rebate” Provisions Clear Congress

By Alan M. Kirschenbaum

The Senate on Tuesday passed H.R. 1839, a bill of Medicaid amendments that included new penalties for mis-categorizing a drug under the Medicaid Drug Rebate Program (MDRP).  The bill already cleared the House on March 25, and is now headed to Donald Trump for signature.  The bill grew out of an investigation conducted by Senate Judiciary Committee Chairman Chuck Grassley into Mylan’s Epi-Pen.  In August 2017 Mylan settled qui tam allegations brought under the Federal False Claims Act by Sanofi-Aventis that Mylan had reduced its rebates under the MDRP by mis-classifying Epi-Pen as a non-innovator drug.  Mylan did not admit the allegations and there was no determination of liability.  Although the Mylan case made headlines, in part because of the Congressional investigation, other drug manufacturers have settled similar allegations in the past.

Under the MDRP, a manufacturer pays greater per-unit rebates for innovator drugs (i.e., those approved under NDAs) than for non-innovator drugs (i.e., those approved under ANDAs and certain unapproved drugs).  The drug category ─ innovator or non-innovator ─ is reported to CMS by the manufacturer.  The Medicaid Rebate statute already contains civil penalties for providing false drug information, and Federal False Claims Act penalties may also apply as discussed above, but Section 6 of H.R. 1839 imposes several additional penalties on manufacturers who misclassify their drugs.  First, a manufacturer that knowingly misclassifies a drug must pay a penalty of twice the difference between the rebates that the manufacturer paid and the amount it would have paid had the drug category been correctly reported.  Second, if CMS determines that a manufacturer misclassified a drug – whether or not the manufacturer knew or should have known that the drug was misclassified – CMS must notify the manufacturer about the error and require a timely category correction, and the manufacturer must pay the underpaid rebates.  If a manufacturer is so notified but fails to timely correct the misclassification, CMS may either correct the misclassification on its own initiative, suspend the drug from the MDRP and exclude it from Medicaid coverage, impose a civil penalty of 23.1% of the drug’s average manufacturer price multiplied by the number of units dispensed during the period of the misclassification, or any combination of the above.  Finally, an exclusion penalty may be imposed on a manufacturer who knowingly misclassifies a drug, fails to correct a misclassification, or provides false information.  These provisions become effective upon enactment.

The bill also contains a long overdue “clarifying definition.”  Since enactment in 1990, the Medicaid rebate statute’s definitions of single source and innovator multiple source drugs – i.e., the drugs subject to higher rebates – refer to drugs approved under an “original new drug application,” a term that is not defined.  Over the years, many manufacturers, and even CMS in a regulation proposed in 1995 (never finalized), have construed that term to exclude NDAs that rely on literature studies or data previously submitted in other applications – for example section 505(b)(2) applications or applications submitted under FDA’s pre-1984 “paper NDA” policy – since those NDAs arguably are not “original”.  In a 2016 final rule, CMS read the term “original” out of the statute and construed “original NDA” to simply mean “NDA”, unless CMS grants a narrow exception.  Congress has now codified that approach by deleting the confusing term “original”, and adding that a drug approved under an NDA is an innovator unless CMS determines that a “narrow exception” applies.  Thus, Congress has finally eliminated a word that has been a source of confusion, controversy, misclassifications and disputed classifications, and an enormous sum of penalties during the 29 years since enactment.

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FDA Starts A Discussion About How To Regulate Artificial Intelligence / Machine Learning Software As A Medical Device

FDA Starts A Discussion About How To Regulate Artificial Intelligence / Machine Learning Software As A Medical Device

By Jeffrey K. Shapiro

A cutting-edge aspect of digital health is software as a medical device (SaMD) that uses artificial intelligence and machine learning to improve its performance based on real world use and experience.  Until earlier this week, FDA has said very little about how to handle the challenge of regulating software for diagnosing or treating patient that learns and adapts in the field.  That changed when the FDA Commissioner announced the release of a 20-page discussion paper outlining a potential framework for regulation.

The press release itself is relatively long and detailed, but the key elements of the framework are in the discussion paper.  It is intended to elicit comments and feedback from interested parties.  FDA even includes 18 focus questions, similar to what industry typically uses in presubmission packages for FDA.

Section I of the discussion paper provides discusses traditional medical device regulation and the challenged posed by Artificial Intelligence / Machine Learning‑based software (AI/ML‑based Software).  Section II provides additional background about regulation of SaMD generally.  Section III provides a typology of the kinds of modifications in the field that can occur with AI/ML‑based Software.  Section IV is key, outlining a Total Product Life Cycle (TPLC) regulatory approach that grapples with the question of how postmarket evolution of AI/ML‑based Software that would ordinary require new premarket submissions can be effectively authorized by FDA in advance during the initial premarket review.  In a nutshell, it appears that FDA aims to incorporate an envelope of permissible modifications in the field, provided there is sufficient characterization of how they will occur, how they will be controlled, and how patient risks will be monitored and managed.

That is something of an over‑simplification, but not to worry — we will provide a deeper dive into the discussion paper in the very near future!

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In a Parallel Universe: FDA Authorizes First REMS “Parallel System”

In a Parallel Universe: FDA Authorizes First REMS “Parallel System”

By Sara W. Koblitz

As we discussed last summer, FDA has recognized that negotiations surrounding the development of a Single, Shared System REMS may fail, and, to that end, issued a guidance detailing the Agency’s waivers process.  Now, the market has borne the fruits of that labor in the form of a “Parallel System (PS)” REMS.  Just last week, FDA approved the first Parallel System REMS when it approved several generic versions of Letairis (ambrisentan) for the treatment of pulmonary arterial hypertension with two separate REMS programs.

For the unfamiliar, section 505-1 of the Food, Drug, and Cosmetic Act provides FDA the authority to require a Risk Evaluation and Mitigation Strategy, known as a REMS, when necessary to ensure that the benefits of a drug outweigh its risks.  Section 505-1 also requires that an ANDA referencing a drug with a REMS with Elements to Assure Safe Use implement a “single, shared system” with the RLD for any such REMS.   FDA may waive the requirement if FDA determines that the burden of creating a single shared system outweighs the benefit of the single shared system or the RLD’s system is covered by a patent or other trade secret protection.

In this instance, FDA explained that one generic manufacturer of ambrisentan would not join with other manufacturers to enter into a shared REMS system because doing so would prevent the use of retail pharmacies for product distribution.  Three other generic manufacturers of ambrisentan formed a single, shared system with Gilead, the RLD sponsor, adopting the same methods of distribution under the Letairis REMS, which dispenses to female patients only through specialty pharmacies.  The announcement of the two separate REMS systems occurred in conjunction with FDA’s announcement of the four generic approvals.  FDA has emphasized that the separate REMS program “achieves the same level of safety as the REMS for the brand-name ambrisentan.”

FDA has exercised its authority to waive a shared system before.  For example, for sodium oxybate oral solution, FDA found that both the burden of creating a shared system outweighed the benefit and that aspects of the Elements to Assure Safe Use in the RLD REMS, Xyrem, were protected by patent to which the ANDA applicants were not able to obtain a license.  FDA issued this waiver determination days before approval of the relevant ANDAs.  Similarly, FDA made a similar determination in April 2015 to waive the single shared system requirement for alosetron hydrochloride products referencing Lotronex.  There, FDA determined that the burden of creating a share system outweighs the benefits after several failed rounds of negotiations (and a refusal to participate in any further negotiations by the RLD sponsor given an ongoing FTC inquiry into its conduct during REMS negotiations).  Again, the waiver decision was released days before the relevant ANDA approval.

The ambrisentan single shared REMS waiver is the first since the June 2018 publication of the waiver guidance.  It’s still too early to tell what impact the guidance has had on waiver requests, particularly because no waiver decision has been issued yet – and it’s not even clear that a formal decision will be issued.  But it is exemplary of FDA’s ongoing commitment to working with ANDA holders on expediting generic entry, particularly when hurdles arise in the negotiation of a shared REMS, which may suggest anticompetitive motives.  While unrelated, it’s also interesting that the necessity of the separate waiver arises from a difference in the preferred distribution chain, indicating that the use of a specialty pharmacy may be more restrictive than necessary; however, given that three other generic manufacturers have signed on to the Letairis version of the REMS, it stands to reason that FDA has not viewed the restrictive distribution as implemented for anticompetitive reasons.

The tinkering with the REMS system isn’t quite done yet even with this exercise of the June 2018 guidance.  Congress is still looking at the single shared REMS system too with a new version of the CREATES Act, last discussed here in 2016.  The Act, re-introduced in the Senate in February 2019 and in the house in March 2019, aims to address the use of REMS and related to distribution restrictions as “reasons to not sell quantities of a covered product to generic product developers, causing barriers and delays in getting generic products on the market.”  CREATES Act of 2019 § 2(6).  It permits a product developer to bring civil action against an RLD or reference product (biologic) sponsor alleging that the sponsor has declined to provide sufficient quantities of the covered product on commercially reasonable, market-based terms.  The Creates Act will also amend section 505-1 of the FDC Act to allow an ANDA holder to use “a different comparable aspect of the elements to assure safe use,” which by definition is a “Separate REMS” under the Act.  The Act has bipartisan support, but a similar bill made no progress last year in Congress.

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Don’t Test Me! FDA Applies “Deemed Triggered” Regulation to 180-Day Generic Drug Exclusivity

Don’t Test Me! FDA Applies “Deemed Triggered” Regulation to 180-Day Generic Drug Exclusivity

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.

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Upcoming Conference on Digital Health Regulatory Issues

Upcoming Conference on Digital Health Regulatory Issues

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.)

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Breaking Down FDA’s New Rare Disease Natural History Studies Guidance: Practical Considerations

Breaking Down FDA’s New Rare Disease Natural History Studies Guidance: Practical Considerations

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.

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Orphan Drug Designation Requests and Designations Dipped in 2018, But Orphan Approvals Are Up Again!

Orphan Drug Designation Requests and Designations Dipped in 2018, But Orphan Approvals Are Up Again!

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:

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.

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ANDA Suitability Petitions: The Way Back to Normalcy (and Some Sanity)

ANDA Suitability Petitions: The Way Back to Normalcy (and Some Sanity)

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.

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