FDA Issues Guidance Regarding Obtaining Risk Determinations for Investigational IVDs in Oncology Trials

FDA Issues Guidance Regarding Obtaining Risk Determinations for Investigational IVDs in Oncology Trials

By Kurt R. Karst

On April 12, 2018, the three FDA Centers jointly issued the draft guidance, “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination” (draft available here). The draft guidance outlines a process for obtaining FDA’s feedback regarding whether an investigational IVD requires an approved Investigational Device Exemption (IDE) when used in the study of an Oncology therapeutic product. As we discussed in our earlier post (here), FDA’s December draft guidance regarding investigational IVDs includes an expansive definition, indicating that IVDs used in therapeutic product studies must be either investigational or cleared/approved. Thus, this guidance would apply to IVDs that are investigational or those that are currently marketed for non-diagnostic use (e.g., research use only).

The majority of IVD investigations have historically been exempt from the IVD studies pursuant to 21 C.F.R. § 812.2(c)(3). IVD investigations are exempt if the IVD is appropriately labeled as investigational pursuant to 21 C.F.R. Part 809, and it:

(i) Is noninvasive,

(ii) Does not require an invasive sampling procedure that presents significant risk,

(iii) Does not by design or intention introduce energy into a subject, and

(iv) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.

Id. § 812.2(c)(3). FDA issued guidance regarding interpretation of these four criteria in 2010 (available here). The 2010 guidance does not, however, cover all possible IDE exemptions nor does it discuss when/if a companion diagnostic fits within the above criteria. In recent years, investigational IVDs used in therapeutic product clinical studies where the IVD will ultimately be a companion diagnostic have not been exempt from the IDE requirements.

Prior to issuance of the draft streamlined oncology study risk determination guidance, study sponsors could seek a determination from CDRH as to whether an IDE was required for an investigational IVD by submitting a study risk determination pre-submission. The new draft guidance indicates that oncology therapeutic study sponsors can now request this feedback via FDA Form 1571 when it submits an Investigation New Drug (IND) application. CDER or CBER will seek input from CDRH in providing its feedback. The guidance states that sponsors should include the following information on their form when seeking FDA feedback regarding the IDE requirements applicable to IVDs used in the planned study:

  • How the results from the investigational IVD will be applied in the clinical trial;
  • What is known about the prevalence of the biomarker (evaluated by the investigational IVD) in the patient population; and
  • The specimen type that will be collected for investigational IVD testing (including the anatomical site) and whether any biopsy required for investigational IVD testing could present a potential for serious risk to the health, safety, or welfare of the subject.

With regard to the third bullet, FDA notes that this process does not apply “if an invasive biopsy that presents a potential for serious risk to health, safety, or welfare of the subject is required for investigational IVD testing for enrollment.” The guidance appears to suggest that such invasive biopsies automatically require an IDE, a position which would be consistent with § 812.2(c)(3)(ii).

The guidance explains that FDA will provide its feedback regarding whether an investigational IVD requires an IDE in a “May Proceed Letter.” This timing seems appropriate if an IDE is not required. However, if an IDE is required, it would not seem ideal for the drug or device sponsor to need to begin the IDE approval process after the IND has already been approved. Thus, this process seems as though it may be helpful for therapeutic and IVD manufacturers when the sponsor is seeking – and obtains – confirmation that the investigational IVD is exempt from the IDE requirements. In addition, depending on the parties’ (IVD manufacturer and therapeutic manufacturer) relationship, it may be challenging for only the therapeutic sponsor to communicate with FDA via the IND application regarding the proposed diagnostic test.

In our view, this process may be modestly helpful; however, it only addresses part of the IVD-therapeutic product question. The often more important question is whether FDA will view the IVD as a companion diagnostic. The draft guidance doesn’t touch that topic. In order to be truly helpful to study sponsors, we suggest that FDA expand the proposed program to also allow study sponsors to seek a determination as to whether the IVD will be viewed as a companion diagnostic. It is important to note that largely similar information required for the study risk determination also apply when assessing whether an IVD is a companion diagnostic.

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A Busy Week for the Supreme Court in FCA Matters

A Busy Week for the Supreme Court in FCA Matters

By Jennifer M. Thomas

Last week United States ex rel. Campie v. Gilead Sciences Inc. took one step closer to being the first FCA materiality case to be taken up by the Supreme Court since the Court’s seminal decision in Universal Health Services, Inc. v. United States ex rel. Escobar – or one step further away, if you read the tea leaves a different way. On April 16, the Supreme Court invited the U.S. Solicitor general to “file a brief. . . expressing the views of the United States” on Gilead’s petition for writ of certiorari.   It is not unusual for the Court to call for the views of the Solicitor General in a case where the United States is not a party (the United States declined to intervene in Gilead), but the government has a significant interest in the case. When the Supreme Court does call for the Solicitor General’s views on a petition for cert, it often acts in accordance with the Solicitor General’s recommendations (with respect to whether to grant certiorari, not necessarily with respect to the merits of the case).

We previously blogged about the Gilead case here, here, and here. Importantly, the Ninth Circuit’s decision Gilead is an outlier among the Circuits’ various interpretation of Escobar.  In its Gilead decision, the Ninth Circuit arguably seeks to either reverse or ignore Escobar’s emphasis on a rigorous standard for FCA materiality. For readers of this blog, in particular, Gilead is significant; the Ninth Circuit’s reasoning would allow FCA cases to proceed based on FDA regulatory infractions, because the government would have the option not to pay a claim based on the noncompliance—and even if FDA’s response to the infractions indicated that it did not view the regulatory issue as material. Gilead and several amici have urged the Supreme Court to take up the case, in part to avoid undermining FDA’s regulatory authority.

The Supreme Court may be inclined to grant certiorari in Gilead to address the Ninth Circuit’s misreading of Escobar and the FCA materiality standard. Escobar was decided by a unanimous Court in June 2016, and since then the Court’s composition has remained the same except for the addition of Justice Neil Gorsuch. The Court’s request for the Solicitor General’s views also suggests that the Court is willing to take up the Gilead case. But it seems too much to hope that the Solicitor General would recommend a course of action that could make it more difficult for the federal government to recover monies under the FCA, even if the government would welcome a case that revisits Escobar to clarify and/or limit that case’s materiality language. In fact, the government has previously expressed views on FCA materiality under Escobar that are similar to those expressed by the Ninth Circuit in Gilead. See, e.g., Statement of Interest of the United States, United States ex rel. Kolchinsky v. Moody’s Corp., 12-cv-1399 (S.D.N.Y May 8, 2017). The Solicitor General often takes months to file its brief in response a Supreme Court request, so we may have to wait some time to find out exactly what the government has to say.

Separately, on the same day that the Supreme Court made its request in Gilead, it announced the decision to deny certiorari in another significant FCA case, United States ex rel. Nargol v. DePuy Orthopeadics, Inc., relating to the pleading standards for an FCA case under Fed. R. Civ. P. 9(b). Justice Alito did not participate in the decision to deny cert. The Supreme Court’s denial in DePuy leaves in place a First Circuit ruling we blogged about here and here, which applied a relaxed pleading standard to a False Claims Act complaint that alleged indirect submission of false claims. The First Circuit took the position that it was possible for a plaintiff to adequately plead against defendant based on a statistical certainty that false claims were submitted as a result of the defendant’s alleged actions, rather than alleging the specifics of any actual false claims. This decision leaves defendants guessing about the courts’ application of 9(b) to indirect false claim cases, because the Circuits apply divergent pleading standards with respect to the use of statistics to establish the existence of false claims.

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What is Beef? Round Two

What is Beef? Round Two

By Riëtte van Laack

As we previously reported, the United States Cattlemen’s Association (USCA) filed a Petition with the Food Safety and Inspection Service (FSIS), asking that FSIS establish formal definitions of “meat” and “beef” that exclude what petitioners call lab grown meat and products prepared from plant or insect protein. Until April 17, the majority of comments submitted have been in support of the petition.

The National Cattlemen’s Beef Association, (NCBA), however, does not support the Petition. As described in its comment to the Petition, the NCBA does not believe that the action requested by USCA “will adequately provide meaningful protection for beef nomenclature.”  In contrast to the USCA, the NCBA wants FSIS to assert jurisdiction over foods produced from cell or tissue culture that are derived from livestock and poultry animals or their parts, so as to ensure a level playing field. NCBA takes the position that, since cell-cultured or lab-grown meat products are derived from parts of a carcass, in this case stem cells, these products fall squarely within the definition of meat food product.  Even if this were not the case, NCBA believes that “FSIS should assert jurisdiction as a means of ensuring regulatory equity.”

As to the labeling of the product, NCBA seems of two minds. It asserts that the cultured meat should not be permitted to be marketed as beef. Yet, it argues that, if the producers of lab-grown or cultured meat products wish to call these products meat, they must adhere to the same food safety inspection standards and comply with the same labeling standards as traditional meat food products; only in that way can “arbitrary marketing claims,” such as “clean meat,” be avoided.

As far as products that clearly fall outside USDA’s jurisdiction are concerned, such as products made from insects or plants, or other non-animal products, NCBA suggests that FSIS ask FDA to take appropriate and immediate enforcement action against allegedly mislabeled imitation beef products.

In a joint comment, the Good Food Institute, Field Roast Grain Meat Co., Finless Foods, Hungry Planet, Impossible Foods, Lightlife, Sweet Earth Enlightened Foods and the Tofurky Company (collectively GFI) also oppose the USCA Petition. GFI’s comments focus primarily on plant-based products.  GFI argues that FSIS lacks authority over the labeling of such products, and that any restriction to the truthful use of the terms “meat” or “beef” with appropriate qualifiers that accurately disclose the nature of the plant-based product would violate the First Amendment.

As far as cultured meat is concerned, GFI’s comments suggest that it believes that these products may be under FSIS jurisdiction. Referring to dictionary definitions for “meat,” GFI argues that meat does not require slaughter.  In a footnote, GFI requests that FSIS work closely with what it calls “clean meat companies” to determine the appropriate labeling for these products.  GFI opposes USCA’s request to limit the definition of beef to meat that comes from cattle “that have been raised and harvested in the traditional manner.”  GFI contends that FSIS does not have the authority to “prop up an industry or favor one production method over another,” and that such narrowing of the definition would inhibit innovation across the industry.  Moreover, GFI points out that what is traditional is subject to interpretation; arguably, current methods of cattle production are not traditional.

On April 13, FSIS announced that it was extending the comment period for the petition (which was set to close on April 17) by another 30 days. Comments submitted after April 13 are posted on regulations.gov.

Meanwhile, in a March 28, 2018 letter to GAO, U.S. Rep. Rosa DeLauro, D-CT requested that GAO “investigate what regulatory framework, if any exists for cell-cultured food products and how this framework compares to other international approaches,” e.g., those in Canada, Japan, and the European Union. According to the request, such information is needed for Congress to address this emerging issue and ensure that it is “properly overseen by the relevant . . . agencies” once these types of products becomes commercially available.

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The FTC Appeals Shire ViroPharma Dismissal

The FTC Appeals Shire ViroPharma Dismissal

By Jennifer M. Thomas

Declaring its intent to stand on the original complaint in FTC v. Shire ViroPharma, the FTC has appealed the District Court for the District of Delaware’s decision to dismiss the Commission’s unfair competition case against Shire without prejudice.  We previously blogged about this case here, and here.

Although District Court dismissals without prejudice are typically not subject to immediate appeal, the FTC seeks appellate jurisdiction by declaring that it will not amend its original Complaint despite the District Court’s grant of leave to do just that.  Rather, the FTC will risk abandoning its case in District Court in favor of seeking a review of the key legal issue by the Third Circuit. This speaks to the significance of the lower court’s ruling that the FTC had failed to meet its statutory burden in bringing the case – the Shire ruling has already been cited against the FTC in at least four other pending cases.

We will continue to follow this case as it develops.

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How Safe is the Safe Harbor?

How Safe is the Safe Harbor?

By Sara W. Koblitz

As the breadth of the “patent safe harbor” continues to expand under the Federal Circuit’s growing body of relevant case law, some patent holders are looking to the Supreme Court to push back. In a Petition for Certiorari filed last week in Classen Immunotherapies v. Elan Pharmaceuticals (and sent to us by Alex MacCormick over at Center Lane, LLC), patent-holders challenge the District Court’s (as affirmed by the Federal Circuit) interpretation of routine and non-routine.

Codified in 35 U.S.C. § 271(e), the safe harbor exempts drug development and approval from patent infringement:

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

Over time, courts have held that the safe harbor applies to both drugs and devices and expanded the use of the patented technology to any activities “reasonably related” to FDA approval,” including data developed in clinical trials for FDA approval. As long as there is a reasonable basis to believe that a patented technology may be used for an FDA submission, the use is protected under the safe harbor.  Merck KGaA v. Integra Lifesciences, 545 U.S. 193 (2005).

In 2015, patent-holders were given a gift from the Federal Circuit when it held that ongoing post-approval commercial manufacturing activities do not fall under the safe harbor. But what the court giveth, it also taketh away.  For in 2016, the District Court held (and the Federal Circuit affirmed without input) in Classen Immunotherapies v. Elan Pharms that the safe-harbor protects data in a supplement to revise labeling.  In this case, Elan used Classen’s patented research tool to study the effect of food on the bioavailability of the already-approved drug Skelaxin.  The clinical data was then submitted to FDA in a citizen petition and an sNDA to revise its labeling.  The District Court concluded that Elan’s use of the research tool was protected by the safe harbor because the post-approval submissions were not routine and were necessary to update the Skelaxin product label regardless of the fact that the use was technically a post-approval commercial activity.

Classen filed this Cert Petition arguing that Elan’s use was outside the scope of the safe harbor because the use of the patented technology for post-marketing safety research was “routine.” Classen also complained that Elan not only used the data for submission to FDA, but also to patent a new use of the drug; protecting Elan under the safe harbor in spite of this additional use, Classen contends, means that the safe harbor will protect any data that is at some point submitted to FDA even if it is not the primary intent.  Classen argues that Elan’s clear commercial post-marketing purposes should play a role in a finding of infringement.

The Supreme Court has not granted cert yet – obvious, since Elan has not even filed its response – but it will be interesting to see if the Court decides to weigh in on the admittedly nebulous distinction between routine and not-routine. It seems that Classen wants to draw the line between pre-market commercial use and post-market commercial use.  But this raises a question of how much commercial use should be considered given that the statute clearly anticipates commercial use.  Is commercial use really the deciding factor, or is it actually routine vs. non-routine?  As recently as 2016, the Supreme Court adopted the routine test, so it’s unlikely that the Court will take the opportunity to further refine the distinction, but it seems like we’ll find out soon.

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Does the Agency Need Statutorily Imposed Incentives for Regulatory Compliance Matters?

Does the Agency Need Statutorily Imposed Incentives for Regulatory Compliance Matters?

By Mark I. Schwartz

Last year, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA) to revise and extend the user fee programs for drugs, medical devices and biosimilar biological products. Section 902 of FDARA requires FDA to publicly report, annually, information related to inspections of facilities necessary for approval of these medical products.

Not later than March 1 of each year, the Secretary of Health and Human Services shall post on the internet website of the Food and Drug Administration information related to inspections of facilities necessary for approval of a drug under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), approval of a device under section 515 of such Act (21 U.S.C. 360e), or clearance of a device under section 510(k) of such Act (21 U.S.C. 360(k)) that were conducted during the previous calendar year. Such information shall include the following:

(1) The median time following a request from staff of the Food and Drug Administration reviewing an application or report to the beginning of the inspection, and the median time from the beginning of an inspection to the issuance of a report pursuant to section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374(b)).

(2) The median time from the issuance of a report pursuant to such section 704(b) to the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting for inspections for which the Secretary concluded that regulatory or enforcement action was indicated.

(3) The median time from the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting to resolution of the regulatory or enforcement action indicated for inspections for which the Secretary concluded that such action was indicated.

(4) The number of times that a facility was issued a report pursuant to such section 704(b) and approval of an application was delayed due to the issuance of a withhold recommendation.

Since this is the first report published under this statutory authority, we have nothing to compare it to. Nevertheless, the information is instructive. For example, in calendar year 2017, the median time between the issuance of a Form 483 for a cGMP inspection and the issuance of a Warning Letter was 191 days (or 6.4 months). For purposes of contrast, the agency’s own Regulatory Procedures Manual says that Warning Letters should be issued within four months of the appropriate reference date, which typically is the issuance of the Form 483:

To ensure the applicability of evidence to the present situation, the agency will strive to issue Warning Letters within four months from the appropriate reference date. Examples of the appropriate reference date are: the last day of the inspection, the date of sample analysis, or the date of evidence collection.

So, to summarize, in 2017, the median issuance time for an agency Warning Letter was 2.4 months longer (or 60% longer) than the goal set out in the agency’s own procedures. It is also well established that, not infrequently, the agency issues Warning Letters up to a year or more from the date of issuance of the Form 483. Clearly, there is room for significant improvement in the speed with which the agency issues Warning Letters.

In calendar year 2017, the median time between the issuance of a Form 483 and the occurrence of a Regulatory Meeting was 169 days (or 5.6 months). A Regulatory Meeting is a meeting requested by FDA management to inform responsible individuals or firms regarding how one or more products, practices, processes, or other activities are considered to be in violation of the law.

The Regulatory Procedures Manual does not provide timelines for the convening of a Regulatory Meeting. Nevertheless, the notion that a firm would need to wait, on average, close to half a year to discuss their Form 483 observations (or their responses to the Form 483) with agency regulators seems unduly limiting, particularly in situations where the Form 483 could be used as a basis to prevent the importation of the firm’s products (i.e., an import alert) or to prevent approval of a pending application (i.e., a compliance check).

In calendar year 2017, there were no resolutions for compliance actions for facilities that were issued a Form 483 in CY 2017, and that had resulted in a Warning Letter, Import Alert, or a Regulatory Meeting, and were named in a pending application.

As the agency states in this report, given the significant remediation efforts and re-inspection by FDA that would be required for resolution, it is unlikely that a site would be inspected, regulatory action taken, and resolution completed within a single calendar year. Perhaps that is part of the problem that Congress was attempting to point out or, more likely, Congress had no idea that it was entirely unrealistic that FDA, as it is currently run, would be able to resolve the compliance action in the same year in which the compliance action was initiated.

In addition, in calendar year 2017, 94 applications were denied approval solely due to a facility-related withhold recommendation because of the lack of compliance at a facility discovered during an inspection that had been completed in that calendar year.  (Biological products reviewed under section 351 of the Public Health Service Act were not included in this report.)  Also, in 2017, the median time between an inspection request from FDA staff to the beginning of an inspection was 102 days, and the median time between the beginning of a prior approval inspection and the issuance of a Form 483 was seven days.

In summary, it will be interesting to track how these timeframes change in the coming years. However, without the introduction of statutorily mandated incentives, such as currently exist under FDARA for review times of NDAs and BLAs, it is doubtful that we will see significant improvements in the issuance time of agency Warning Letters and in the convening of Regulatory Meetings.

This is all to the detriment of industry and the agency alike. After all, the longer it takes FDA to issue a Warning Letter or convene a Regulatory Meeting with non-compliant firms, the longer it will take the firms in question to resolve the issues at hand, bring the facilities back into cGMP compliance and, where relevant, bring the drug products back into distribution.

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Fourth Circuit Finds Maryland Price Gouging Law Unconstitutional

Fourth Circuit Finds Maryland Price Gouging Law Unconstitutional

By Serra J. Schlanger & Alan M. Kirschenbaum

On Friday, April 13, 2018, the U.S. Court of Appeals for the Fourth Circuit ruled that Maryland’s law prohibiting “price gouging” by generic pharmaceutical manufacturers (HB 631) is unconstitutional because it violates the dormant commerce clause by directly regulating transactions that occur outside of Maryland. Circuit Judge Agee joined the majority opinion written by Circuit Judge Thacker; Circuit Judge Wynn wrote a dissenting opinion that HB 631 does not violate the commerce clause (both opinions are available here).

As discussed in our previous post on HB 631 (see here), this law sought to limit generic drug pricing by prohibiting a generic drug manufacturer or wholesale distributor from making unconscionable increases in the price of an “essential off-patent or generic drug.” To assist the Maryland Attorney General (AG) in identifying violations, the law authorized the Maryland Medical Assistance Program (“MMAP”) to notify the AG of a price increase when (1) the Wholesale Acquisition Cost (“WAC”) of a prescription drug increased by at least 50% within the preceding one-year period or when the price paid by MMAP would increase by at least 50% within the preceding one-year period, and (2) the WAC for either a 30-day supply or a full course of treatment exceeded $80. The law also provided the AG with civil remedies, including injunctive relief, monetary relief, and civil penalties, for violations of the law.

As we also previously reported, in July 2017 the Association for Accessible Medicines (“AAM”) filed suit seeking declaratory and injunctive relief against the implementation and enforcement of HB 631. AAM challenged HB 631 on two constitutional grounds: (1) that HB 631 violates the dormant Commerce Clause of the Federal Constitution because it regulates commerce wholly outside of Maryland; and (2) that HB 631 is impermissibly vague and therefore violates the Fourteenth Amendment Due Process Clause.

This case reached the Fourth Circuit after AAM appealed a decision by the U.S. District Court for the District of Maryland that granted the State of Maryland’s motion to dismiss AAM’s challenge based on the dormant commerce clause, but allowed the vagueness claim to proceed. The District Court also denied AAM’s motion for injunctive relief.

The Fourth Circuit relied on three determinations to find HB 631 unconstitutional:

  1. The law focuses, not on the price that a Maryland consumer pays for a drug, but instead on the price initially charged by the manufacturer or wholesaler. Therefore, a violative price gouging transaction may occur outside of Maryland even the transaction “did not result in a single pill being shipped into Maryland.”
  2. Even if the Act did require a nexus to an actual sale in Maryland, a violation is triggered by the manufacturer’s or wholesaler’s initial sale. These “upstream” sales occur almost exclusively outside of Maryland.
  3. If other states enacted similar laws, this would impose a significant burden on interstate commerce involving prescription drugs.

Because the Fourth Circuit found HB 631 unconstitutional based on AAM’s dormant commerce clause argument, the Court did not address whether the statute was also void for vagueness. However, the majority did acknowledge that the law’s “relatively subjective definition of what constitutes an unlawful price increase only exacerbates the problem[s]” that would occur if other states imposed similar laws. The majority stressed that, although Maryland could not constitutionally control prescription drug pricing in the manner utilized by HB 631, Maryland and other states could enact other legislation to secure lower prescription drug prices for their citizens.

Another commerce clause challenge has been brought by the Pharmaceutical Research and Manufacturers of America against a price increase transparency law in California (see our previous post here). We will continue to watch developments in the growing number of states that are seeking to limit drug costs through legislation, as well as legal challenges to those laws.

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Last Minute Dissolution Testing Requirement Avoids Forfeiture of 180-Day Exclusivity for Generic COREG CR Staggered Strengths

Last Minute Dissolution Testing Requirement Avoids Forfeiture of 180-Day Exclusivity for Generic COREG CR Staggered Strengths

By Kurt R. Karst

As folks know by now, each month we pore over the latest Orange Book Cumulative Supplement in an effort to keep our popular 180-Day Exclusivity Tracker as current as possible, and to look for interesting precedents. One recent entry in particular caught our attention.  It was for ANDA 090132 for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, a generic version of SmithKline’s COREG CR Extended-Release Capsules (NDA 022012).  The Orange Book Cumulative Supplement showed the addition of periods of “PC” exclusivity (i.e., 180-day patent challenge exclusivity) expiring on May 7, 2018 for all four strengths covered under the ANDA now owned by Sun Pharmaceutical Industries Inc. (“Sun”) (formerly owned by Mutual Pharmaceutical Company, Inc. (“Mutual”)).  What made the entry of 180-day exclusivity interesting is that FDA’s October 25, 2017 letter approving the ANDA included the Agency’s all-too-familiar 180-day exclusivity “punt” language:

With respect to 180-day generic drug exclusivity, we note that Sun was the first ANDA applicant for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, to submit a substantially complete ANDA with a paragraph IV certification. Therefore, with this approval, Sun may be eligible for 180 days of generic drug exclusivity for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg. The Agency notes that Sun failed to obtain tentative approval of its ANDA within 30 months after the date on which the ANDA was filed. See section 505(j)(5)(D)(i)(IV) of the FD&C Act (forfeiture of exclusivity for failure to obtain tentative approval). The Agency is not, however, making a formal determination at this time of Sun’s eligibility for 180-day generic drug exclusivity. It will do so only if a subsequent paragraph IV applicant becomes eligible for full approval (a) within 180 days after Sun begins commercial marketing of Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, or (b) at any time prior to the expiration of the ‘156 patent if Sun has not begun commercial marketing.

FDA’s Orange Book entry showing the addition of 180-day exclusivity could mean only one thing: that the Agency was forced into a position of determining whether or not eligibility for 180-day exclusivity was forfeited, and FDA determined that it was not. (We’ve referred to this type of decision as a “punt return,” as opposed to a “fumble return” – see our previous posts here, here, and here.)

FDA’s “punt return” determination was confirmed by FDA’s December 6, 2017 tentative approval of Impax Laboratories, Inc.’s (“Impax’s”) ANDA 204717 for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg. FDA stated in that tentative approval letter:

[W]e are unable to grant final approval to your ANDA at this time. Prior to the submission of your ANDA, another applicant or applicants submitted a substantially complete ANDA providing for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg, and containing a paragraph IV certification. Your ANDA will be eligible for final approval on May 7, 2018, which is the date that is 180 days after the commercial marketing date identified in section 505(j)(5)(B)(iv) of the FD&C Act.

While these facts are nice to have, we wanted to know more! What was the basis of FDA’s “punt return” determination?  So we obtained a copy of FDA’s exclusivity determination to satisfy our curiosity.    It shows that FDA ruled on November 3, 2017 – about a month before tentatively approving Impax ANDA 204717 – that Mutual (now Sun) maintained eligibility for exclusivity for all four strengths because of a change in the requirements for approval with respect to showing bioequivalence.

Under the statutory failure to obtain-timely tentative (or final) approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV), eligibility for 180-day exclusivity is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).

According to FDA’s ANDA Paragraph IV Certifications List, the first ANDA containing a Paragraph IV certification for Carvedilol Phosphate Extended-Release Capsules was submitted to FDA on November 19, 2007 (80 mg), on December 21, 2007 (40 mg), and on March 18, 2008 (10 mg and 20 mg). In fact, it was Mutual that qualified as the sole “first applicant” for all four strengths based on its original ANDA submission and subsequent strength amendments.  Thus, as FDA states in the Agency’s exclusivity determination, “Mutual had 30 months to obtain tentative approval or approval for the purposes of section 505(j)(5)(D)(i)(IV) of the Act.  Thirty months from the submission of the original ANDA containing the 80 mg strength is May 19, 2010.  Thirty months from the submission of the new strength amendment for the 40 mg strength is June 21, 2010. Thirty months from the submission of the new strength amendment for the 10 and 20 mg strengths is September 18, 2010.”

FDA never tentatively approved Mutual ANDA 090132, and did not approve the ANDA until nearly ten years after it was submitted to the Agency. Nevertheless, FDA determined that eligibility for 180-day exclusivity was not forfeited.  And although there was a Citizen Petition (Docket No. FDA-2010-P-2016) that FDA considered during the pendency of ANDA 090132 (and that the Agency responded to in October 2010), the Agency says that “[t]here is no evidence that FDA’s consideration of this petition, itself, caused a delay in approval or tentative approval of Mutual’s ANDA.”  Thus, FDC Act § 505(q)(1)(G) did not come into play.

So this is a case of pure consideration of what was going on at the 30-month periods under FDC Act § 505(j)(5)(D)(i)(IV). To that end, FDA identified new dissolution testing requirements imposed after the submission of Mutual ANDA 090132 – and, in fact, just a few to several months before the 30-month forfeiture dates – that provide a basis for review changes and approval requirements:

At the time ANDA 090132 was submitted, FDA did not require that applicants conduct dissolution testing using ethanol for ANDAs for modified-release drug products. In February 2010, after the submission of ANDA 090132 but several months prior to the 30-month forfeiture dates for this ANDA, the Agency published a draft product-specific guidance for Carvedilol Phosphate Extended Release Capsules (referencing NDA 022012, Coreg CR (Carvedilol Phosphate) Extended Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg).’ Due to concerns of dose dumping from this drug product when taken with alcohol, the draft product-specific guidance stated that applicants should also conduct dissolution testing using various concentrations of ethanol in the dissolution medium.” On May 14, 2010, approximately three months after the publication of the draft product-specific guidance and prior to the 30-month forfeiture dates for this ANDA, Mutual submitted an amendment which purported to address the new dissolution testing described in the Agency’s draft product-specific guidance for Carvediol Phosphate Extended Release Capsules. At the 30-month forfeiture dates for this ANDA, the dissolution data for ANDA 090132 was still under review.  The Agency found the dissolution testing adequate on March 16, 2011.

Accordingly, FDA concluded that Mutual (Sun) did not forfeit eligibility for 180-day exclusivity because of the change and because Mutual remained in hot pursuit of ANDA approval by addressing the FDA changes:

We conclude that there was a change in the requirements for approval with respect to bioequivalence, as outlined above, and that this change was a cause of Mutual’s failure to obtain tentative approval by the forfeiture dates. After the submission of Mutual’s ANDA, in the February 2010 draft product-specific guidance, the Agency advised applicants to conduct additional dissolution testing using various concentrations of ethanol in the dissolution medium for Carvedilol Phosphate Extended Release Capsules. Mutual actively addressed this change in the requirements for approval before the 30-month forfeiture dates for this ANDA when it submitted its May 14, 2010 amendment containing information to address the new dissolution testing described in the February 2010 draft product-specific guidance. As of the 30-month forfeiture dates for this ANDA, the Agency was still reviewing Mutual’s dissolution information.  Based on these facts (including, among other things, that Mutual had been actively addressing the change in approval requirements and that FDA was reviewing Mutual’s efforts at the 30-month forfeiture dates), we conclude that the requirement to comply with the new dissolution testing using various concentrations of ethanol in the dissolution medium was a cause of Mutual’s failure to obtain tentative approval by the forfeiture date.

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The Food Labeling Modernization Act Is Back Again…

The Food Labeling Modernization Act Is Back Again…

By Riëtte van Laack

On April 2, Rep. Frank Pallone, Jr. introduced the Food Labeling Modernization Act (FLMA) of 2018, an updated version of the FLMA of 2015. As we previously reported, the FLMA of 2015 was an updated version of the FLMA of 2013.

The FLMA of 2018 differs from the FLMA of 2015 in a few respects. Some provisions in the 2015 bill have been removed because they are no longer relevant, e.g., since FDA amended the nutrition labeling regulations in 2016, there no longer is a need for a bill requiring that FDA modernize the nutrition facts panel.  Some other provisions have been amended to be more specific.  Notably, the 2018 FLMA provision requiring front of package labeling is more prescriptive, in that it specifies that  “there shall be a single, simple, standard symbol system that displays calorie information related to the serving size . . . and information related to the content of saturated and trans fats, sodium, added sugars, and any other nutrients that the Secretary determines are strongly associated with public health concerns,” whereas the 2015 version provided that “[t]here should be a single simple, standard symbol system that displays calorie information related to a common serving size, and information related to nutrients strongly associated with public health concerns.”

The 2018 bill contains only two truly new provisions, namely a provision related to the compliance date of FDA’s 2016 nutrition labeling regulation and a provision related to labeling of phosphorus.

Specifically, the bill would prohibit any further extensions of the compliance date for FDA’s final regulations updating the Nutrition Facts label. Last year, FDA proposed to extend the compliance date for those regulations until January 1, 2020, for manufacturers with $10 million or more in annual food sales, and to January 1, 2021 for manufacturers with less than $10 million in annual food sales in the United States.

For foods containing phosphorus, the 2018 FLMA requires the disclosure of phosphorus immediately after or next to the ingredient statement, along with the quantity reported in milligrams per serving or, alternatively, declaration of the amount of phosphorus (in mg) in the  Nutrition Facts panel.  In response to its proposal to amend the nutrition labeling regulation, FDA had received numerous requests to make phosphorus declaration mandatory. However, FDA denied those requests because, while “a mandatory phosphorous declaration may aid patients with chronic kidney disease and dialysis patients,” FDA concluded that phosphorus is not a nutrient of public health concern for the general healthy U.S. population.

Much of what is included in the 2018 FLMA is already on FDA’s agenda as outlined FDA’s Nutrition Innovation Strategy, e.g., defining natural and redefining healthy. The bill limits FDA’s freedom in doing so by setting specific guardrails, such as a limit to the amount of added sugars for foods that would qualify for the healthy claim.  The 2018 FLMA appears to still focus on nutrients.  As FDA has recognized, modern nutrition science no longer focuses on nutrients, such as total fat, cholesterol, and added sugars, but focuses on certain foods and dietary patterns.

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FDA Commissioner Gottlieb Emerges as a Champion for Patient Engagement in 2018; Patient-Centric Guidance Development, Rare Disease Listening Sessions, and the Benefit-Risk Framework

FDA Commissioner Gottlieb Emerges as a Champion for Patient Engagement in 2018; Patient-Centric Guidance Development, Rare Disease Listening Sessions, and the Benefit-Risk Framework

By James E. Valentine

While FDA’s medical product centers have been advancing programs and policies that support incorporating the voice of the patient into their regulatory decision-making for several years (see previous coverage of CDRH here and CDER/CBER here), in the first quarter of 2018 this work has been elevated as a central theme in Commissioner Scott Gottlieb’s public statements – it appears that the Commissioner of Food and Drugs made it a New Year’s resolution to be a champion for patient engagement.

This is said a bit tongue-in-cheek, as these are not Dr. Gottlieb’s first signals of being an advocate for patient-centricity. His administration previously established an FDA-wide Patient Affairs Staff to foster inter- and intra-Agency collaboration on issues of patient engagement, as well as the Patient Engagement Collaborative, an advisory group of patient advocacy organizations. However, as someone that has spent nearly a decade developing patient engagement policies and aiding patient communities engaging in medical product development and regulatory decision-making, it is refreshing to see the Nation’s top drug official further elevate progress in this area, as evidenced by his recent public statements.  (See our new “Patient Advocacy Organizations” industry page on our firm’s website.)

Advancing the Patient-Centric Development of Drug Development Guidance

On February 15th, Commissioner Gottlieb announced the development of five guidance documents on complex, serious neurological conditions – areas where he acknowledges FDA must “become more nimble, collaborative and patient-focused” to address these urgent unmet needs.  What is novel about these disease-specific drug development guidances is that three of them were developed in consultation with the respective patient communities.  In fact, two of FDA’s guidance documents were initially developed and proposed as draft guidance by a patient advocacy organization (The ALS Association’s & Parent Project Muscular Dystrophy’s), providing insights into those diseases that helped FDA advance their own draft guidances.  Then, according to Commissioner Gottleib, the draft guidance on early Alzheimer’s disease drug development was a result of “working closely with patients” informing the innovative approaches to studying very early disease before onset of dementia.

Patient-centric guidance development brings the voice of the patient more central to informing FDA’s current thinking on clinical trial design and determinations of clinical meaningfulness, among other things. This type of activity was advanced at a March 19th public workshop, which was held to inform development of guidance, as required by the 21st Century Cures Act, on considerations for patient advocacy organizations to develop and submit proposed draft guidance, like was done for ALS and Duchenne.

Embracing the Role of Patients in Treating Rare Diseases

On February 26th, in observation of Rare Disease Day, Commissioner Gottlieb announced that FDA was entering into a Memorandum of Understanding with the National Organization for Rare Diseases “to conduct outreach with [the] new Patient Affairs Staff on ways to enhance the incorporation of patient experience into regulatory discussions.”  The MOU will do this, in part, through the planning of a series of listening sessions with rare disease patient communities to foster “early and iterative engagement” to establish an understanding of certain rare diseases and their unmet needs to inform medical product development programs.  This was reiterated by Gottlieb’s Acting Director of the Patient Affairs Staff, Andrea Furia-Helms, who previously led FDA’s Patient Representative Program for 10 years (her statement is available here).

Partnering with Patients to Incorporate Their Experience into FDA’s Benefit-Risk Decisions

Under PDUFA V, FDA held 20+ disease-specific meetings under the Patient-Focused Drug Development (PFDD) initiative, which generated the therapeutic, or clinical, context for those diseases directly from the experiences and perspectives of those patients who live with them. This input was intended to inform FDA’s benefit-risk decisions for investigational products intended to treat those diseases, and were to be articulated by Agency review staff in the “benefit-risk assessment framework”.   On March 30th, Commissioner Gottlieb announced an updated implementation plan for “Benefit-Risk Assessment in Drug Regulatory Decision-Making.”  A key tenant of this plan for fiscal years 2018-2022 is to continue to incorporate the patient voice into benefit-risk assessments under PDUFA VI and 21st Century Cures.  The plan highlights a number of efforts to enable more systematically gather and incorporate patient experience data, such as that which was collected during PFDD meetings:

  • Developing PFDD guidance on the collection of, submission to, and use of “patient experience data” by the Agency (see our firm’s comment with suggestions for the first PFDD guidance on this topic here);
  • Continuing to host PFDD meetings;
  • Encouraging patients stakeholders to conduct their own externally-led PFDD meetings (this has become a very productive venue for patent engagement; by our count, the 12th and 13th such meetings were held jointly on April 6th for two rare, severe dermatologic conditions);
  • Providing patient stakeholders more channels to provide input, such as by hosting Patient Engagement Advisory Committee meetings; and
  • Facilitating access to externally-submitted reports of patient experience data, such as Voice of the Patient reports from externally-led PFDD meetings.

Together, this plan and the activities discussed in Commissioner Gottlieb’s previous statements earlier this year will continue the shift to a more patient-centric and patient engaged regulatory framework. In the words of Commissioner Gottlieb:

Tools for capturing the patient experience…are transforming nearly every aspect of medical product development. Patients are teaching us about the benefits that matter most to them and the risks that they are most concerned about. Patients are, rightly so, becoming the driving force of the medical research enterprise.

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