By Ricardo Carvajal –

In an unusual “Early Alert,” the Office of Inspector General (OIG) of the Department of Health and Human Services (HHS) publicly took FDA to task for allegedly lacking “an efficient and effective food recall initiation process that helps ensure the safety of the Nation’s food supply.”  The alert describes that finding as preliminary, and as the result of an ongoing audit that is expected to yield a more comprehensive report.  Nonetheless, the alert was somewhat startling, and prompted FDA to issue public statements in response (see here and here).   

In brief, OIG’s preliminary finding was based on a “judgmental sample” of 30 recalls conducted in a two-and-a-half year period.  A footnote in the alert explains OIG’s approach to sampling:  “We selected recalls by considering certain risk factors, including but not limited to the recall classification, length of time for the firm to initiate a recall, and length of time for the FDA to classify a recall.”  In other words, OIG’s sampling was intentionally biased toward selection of the most complex recall situations – precisely those situations that would be most likely to show apparently inordinate delays.  Nowhere does the OIG’s alert acknowledge that underlying complexity, nor does it acknowledge that FDA effectively supervised thousands of recalls during the time frame in question.  Instead, the alert implies that FDA may have unnecessarily placed consumers “at risk of illness or death” as the result of the agency’s lack of “policies and procedures that instruct its recall staff to establish set timeframes for (1) FDA to request that firms voluntarily recall their products and (2) firms to initiate voluntary food recalls.”

For its part, FDA states that the delays identified by OIG are “unacceptable,” and expresses appreciation for OIG’s input.  However, FDA also provides some of the contextual information lacking in OIG’s alert, and concludes that a one-size-fits-all approach to establishing timeframes and deadlines is the wrong remedy.  FDA’s conclusion should be obvious to anyone who has witnessed how a recall decision can hinge on the evaluation of disparate and sometimes conflicting information, which now can include the results product and environmental testing, whole genome sequencing, and epidemiologic investigation.  FDA’s conclusion should also be obvious to anyone with a passing familiarity with instances where an outbreak was attributed to the wrong product.  As FDA notes, “to request a recall without evidence risks recalling the wrong product and leaving consumers vulnerable to contaminated food that is still on the market.”  It also risks wrongly inflicting hefty economic damage that a business might not survive, and for which there may be little chance of recovery from the government.

One can hope that OIG will adopt a more complete and nuanced view of how recalls unfold in the real world before issuing its more comprehensive report, and will understand the need for accuracy as well as speed in evaluating potential recall situations.  Even so, FDA’s statements make clear that the agency is pushing to speed up its response to such situations, and industry should take heed. 

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks a junior to mid-level associate with substantive experience in medical devices and other areas of food and drug law and regulation to assist with a growing practice.  Strong verbal and writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Anne K. Walsh (awalsh@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

By Allyson B. Mullen – 

It is an open secret that at some point in every device company’s life one or more of its devices will likely be out of compliance with the Federal Food, Drug, and Cosmetic Act. That is because the regulatory scheme is complex and subjective, and any problem in the manufacture or use of the device could result in a violation.

Although there are many “technical” violations, FDA does not take enforcement action to remove violative product from the market in most cases. This seeming lack of action is partly because the agency is not aware of every violation.  But even among those that come to the agency’s attention, it simply does not have the resources to take action every time.  More important, doing so would frequently be more detrimental to patients and doctors than leaving violative product on the market. 

Device companies are not always aware of FDA’s enforcement discretion to not take action or how best to advocate for such discretion. FDA’s recent draft guidance, “Factors to Consider Regarding Benefit-Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions” is intended to clarify “the benefit and risk factors FDA may consider in prioritizing resources for compliance and enforcement efforts to maximize medical device quality and patient safety.”  

FDA often formally considers product availability and benefit-risk evaluation when deciding whether to take enforcement action. For example, in consent decrees, it is not uncommon for FDA to permit continued sale of violative devices that FDA determines are “medically necessary.”  To our knowledge, the draft guidance is the first time FDA has comprehensively listed the factors that underlie these enforcement decisions. However, these factors likely have always been used and will continue to be used even prior to finalization of the guidance.

The factors FDA has called out are quite similar to the factors identified in earlier premarket benefit-risk guidances FDA has issued. The factors are:

Benefits

• Type of benefit;
• Magnitude of benefit;
• Likelihood of patients experiencing one or more benefits;
• Duration of effects;
• Patient preference on benefit;
• Benefit factors for healthcare professionals or caregivers; and
• Medical necessity.

Risks

• Risk severity;
• Likelihood or risk;
• Nonconforming product risks;
• Duration of exposure to population;
• False-positive or false-negative results;
• Patient tolerance of risk; and
• Risk factors for healthcare professionals or caregivers.

The draft guidance acknowledges that the benefits and risks associated with a device and its noncompliance may change over time. FDA notes that, “as the medical device is used, patients may experience significantly longer treatment effects than those described in the device labeling.”  While FDA will not typically permit a device company to make device performance claims beyond the cleared/approved labeling, FDA is expressly using such expanded performance data in a benefit-risk assessment. 

The draft guidance does not explain how FDA will weigh or evaluate these factors to make a final decision as to whether or not to take a contemplated enforcement action. It states that FDA will use the outcome of the benefit-risk analysis to “make informed appropriate decisions” and

Specific benefit-risk analyses will again need to be viewed in context, but generally, if FDA’s benefit-risk assessment indicates high benefit to patients with little risk, FDA may decide to work with the manufacturer to address the underlying issue without initiating a formal compliance or enforcement action. If FDA’s benefit-risk assessment indicates low benefit to patients with high risk, FDA would likely take formal compliance or enforcement action to address the problem.

It is highly unlikely that FDA will decline to take enforcement action in every situation where the benefits of a violative device outweigh the potential risks. How far the benefits must outweigh the risks and how certain FDA must be of the benefits and risks in order to avoid enforcement action is not specified in the draft.

The draft guidance indicates that FDA may use the results of the benefit‑risk analysis to inform decisions such as:

• “When should a firm’s recall strategy appropriately include a correction instead of a removal?
• What actions, if any, may FDA take when continued access to a nonconforming device or a device manufactured by a firm with regulatory compliance issues might be needed during a shortage situation?
• When is it in the best interest of the public health to grant a variance from certain [quality system (QS)] regulation requirements for QS issues identified during a PMA pre-approval inspection?
• When might FDA exercise enforcement discretion and not take immediate action against a company for marketing a device with a significant change or modification prior to obtaining clearance, as required by 21 CFR 807.81(a)(3)?
• Is a manufacturer’s proposed correction strategy adequate given the benefit-risk assessments and mitigation activities?
• Upon observing a violation, when might FDA send a Warning Letter or Untitled Letter and when would it be appropriate to take an alternative, more informal approach?”

These questions are not only relevant to situations in which a product shortage could occur if FDA were to take action (e.g., medical necessity). The draft guidance states that the factors in the guidance apply not only “to compliance and enforcement decisions that potentially have a direct effect on product availability, when appropriate, [but] FDA may use the outcome of a benefit-risk assessment to inform other decisions related to compliance and enforcement.”  It states that when making decisions that will not potentially impact product availability, FDA may also consider “whether regulatory non-compliance increases risk of harm to patients, whether taking (or not taking) a contemplated compliance or enforcement action would impact patients, the manufacturer’s regulatory history, and steps taken by the manufacturer to address the situation.”

Because this guidance applies to all potential compliance and enforcement actions, device companies should be aware of the factors FDA will use to analyze these situations and when applicable, use these factors to urge FDA to exercise enforcement discretion and permit important devices to remain on the market while the company comes into compliance.

The draft guidance states that its purpose is to “improve the consistency and transparency of” FDA’s decision making regarding compliance and enforcement actions. Outlining specific factors could certainly help consistency.  To truly increase transparency as to FDA’s decisions, industry needs to know both when FDA has taken action (typically is available through warning letters and other enforcement actions) and also when it has not. The draft guidance helps somewhat with the latter by providing two examples of cases in which enforcement discretion would be exercised.

We commend FDA for attempting to give some insight into its decision making. However, it would be helpful to have many more examples, with as much insight as possible into FDA’s reasoning and weighing of benefit‑risk.  We would hope the final guidance expands the number of examples, especially as to situations in which enforcement discretion applies.

Procedurally, the draft guidance does not say whether FDA will formally document its benefit-risk analyses and decisions. We wonder if it will because if these analyses are formally documented they may be able to be obtained through a Freedom of Information Act request.  If industry could obtain such analyses, they would likely be heavily redacted, but could provide some additional insight into instances in which FDA chose not to take action. 

One area where this guidance may have a significant affect on current industry practice is off-label promotion. As noted above, FDA indicates it has discretion to perform a benefit‑risk analysis to assess whether or not to issue a warning or untitled letter to a device manufacturer that has made a major change in its device’s intended use without obtaining a new 510(k) clearance (i.e., promoting a device for a new intended use).  Many off-label uses may provide significant benefits to patients and/or doctors while posing low risks. 

It is not clear whether the draft guidance will have an effect on current FDA or industry practice. FDA publishes annual statistics regarding, among other things, the number of warning letters issued and recalls undertaken by industry.  We will certainly be watching to see if there is any significant change in these numbers to assess the potential impact of the guidance.

By Kurt R. Karst –     

It’s been a little more than 4.5 years since we first revealed in a December 11, 2011 FDA Law Blog post the fruits of our hunt for the mythical list of pending proceedings under the Drug Efficacy Study Implementation (“DESI”) program, which started decades ago after enactment of the 1962 Kefauver-Harris Drug Amendments.  The list, dated August 2006, identifies 17 items.  As we explained in our previous post, the list is of interest to some drug manufacturers given the enforcement policy FDA laid out in the Agency’s September 19, 2011 “Compliance Policy Guide: Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs.”

We recently came across an updated version of FDA’s List of Pending DESI Proceedings.  The new list, which updates the August 2006 version (updating the previous 17 items and adding 2 more proceedings), is included in correspondence that FDA sent to the Staff of the House Energy and Commerce Committee in March 2016 in response to some questions the Committee had about the DESI program.  FDA’s response also addresses two questions from the Committee – “For how many DESI drugs have there been successful NDA filings?” and “How many DESI drugs are still on the market?” – which we provide further below. 

In the 10 years since the August 2006 list was put together, FDA seems to have made some headway in completing pending DESI proceedings.  Of the 17 proceedings identified in the August 2006 list, 7 are now identified as closed.  A total of 12 DESI proceedings (including 2 additions) are now identified as pending, including one proceeding that has been the subject of some recent activity.

1. Anticholinergic/Barbituate Combinations (e.g., Donnatal); Docket No. FDA-1975-N-0336 (formerly75N-0184); DESI 597.  This proceeding remains pending with an open hearing request.

2. Donnatal Extentabs; Docket No. FDA-1975-N-0337 (formerly 75N-0223); DESI 597. This proceeding remains pending with an open hearing request.

3. Chloridiazapoxide hydrochloride and clidinium bromide (Librax); Docket No. FDA-1975-N-0336 (formerly 75N-0184); DESI 10837.  This proceeding remains pending with an open hearing request.

4. Xanthine derivatives, ephedrine hydrochloride, phenobarbital, and guaifenesin; Docket Nos. FDA-1976-N-0272 (formerly 76N-0056), FDA-1976-N-0344 (formerly 76N-0057), and FDA-1978-N-0701 (formerly 78N-0070); DESI 1626. This proceeding was closed on January 10, 2014 (79 FR 1877).

5. Theophylline, Ephedrine, and Barbiturate Combinations Docket No. FDA-1976-N-0272 (formerly 76N-0056); DESI 1626. This proceeding was closed on January 10, 2014 (79 FR 1877).

6. Pentaerythritol tetranitrate (PETN) and Secobarbital (Docket No. 75N-0230; DESI 1786. This proceeding remains pending with open hearing requests.  Also, there is an open hearing request under DESI 1786 for Oral Extended-Release Nitroglycerin products; Docket FDA-1977-N-0356 (formerly 77N-0240); DESI 1786.  The portion of DESI 1786 relating to transdermal system nitroglycerin products was closed on November 16, 2015 (80 FR 70822).

7. Isometheptene mucate, dichloralphenazone and acetaminophen (e.g. Midrin); Docket FDA-1975-N-0355 (formerly 75N-0203); DESI 3265. This proceeding was closed on January 10, 2014 (79 FR 1877).

8. Cough/Cold products. All proceedings relating to DESIs 6290, 6514, 11935, and 12152 were closed on January 1, 2011, and March 3, 2011 (76 FR 1175; 76 FR 11790).

9. Benzocaine, Butylamine benzoate, and tetracaine hydrochloride (e.g. Cetacaine); Docket 75N-0203; DESI 8076. This proceeding remains pending with an open hearing request.  (Please note that the DESI and docket numbers for the Cetacaine proceeding are incorrect in the 2006 Attachment to your March 9, 2016 email.)

10. Hydroxyzine hydrochloride intramuscular solution (e.g. Vistaril); Docket No. FDA-1978-N-0441 (formerly 78N-0324); DESI 10392. This proceeding was closed on February 29, 2012 (77 FR 12310).

11. Trimethobenzamide hydrochloride suppository dosage form (e.g. Tigan suppositories); Docket No. FDA-1978-N-0224 (formerly 78N-0224); DESI 11853.  This proceeding was closed on April 9, 2007 (72 FR 17556).  The 2006 Attachment to your March 9, 2016, email contains a reference to “78N-022,” which is not a complete docket number.  Docket 78N-0227, DESI 11853, covered Tigan injection and capsule products and was closed on December 24, 2002 (67 FR 78476).

12. Oxytetracycline, sulfamethizole, and phenazopyridine (e.g. Urobiotic Capsules); Docket FDA-1983-N-0297 (formerly 83N-0030); DESI 50213. This proceeding was closed on January 10, 2014 (79 FR 1877).

13. Potaba (potassium p-aminobenzoate); Docket 77N-0183; DESI 7663. This proceeding remains pending with an open hearing request.

14. Vioform-HC; DESI 10367. Appeal remains pending at the Office of the Commissioner.

15. Vasodilan (Isoxsuprine); DESI 6403. Appeal remains pending at the Office of the Commissioner.

16. Mepergan Fortis (Promethazine and Meperidine); DESI 7337. Appeal remains pending at the Office of the Commissioner.

17. Pentaerythritol tetranitrate (PETN) DESI 1786. Appeal remains pending at the Office of the Commissioner.

18. Fixed-combination estrogen/androgen products; Docket No. FDA-1998-P-0083 (formerly 76N-0377); DESI 7661. This proceeding remains pending with an open hearing request.

19. Amphetamines indicated for the management of exogenous obesity; Docket No. 79N-0190; DESI 5378. This proceeding remains pending with an open hearing request.

As noted above, in addition to updating the August 2006 List of Pending DESI Proceedings, FDA responded to two other DESI-related questions from the Committee:

For how many DESI drugs have there been successful NDA filings?

Approximately 3,400 drug products intended for use in humans were reviewed under the Drug Efficacy Study Implementation (DESI) program.  These prescription drugs had been approved for safety only and collectively had more than 16,000 indications.  The Food and Drug Administration (FDA) requested that firms submit data in support of the efficacy claims for their products. By 1984, of the approximately 3,400 products reviewed, approximately 2,225 had been found to be effective for one or more indications.  FDA estimates that for every product with an approved safety-only new drug application (NDA), there were five identical, related, or similar (IRS) products on the market also subject to the DESI findings (21 CFR 310.6).  In each instance where a product has been found effective under DESI, that product and those IRS to it could submit an application for approval based on the DESI efficacy finding, if they could meet the conditions for marketing for that particular category of product.  Note that the IRS category of applications would also include abbreviated new drug applications (ANDAs) if drugs were identical to the subject of the DESI product.  Drugs related or similar to DESI drugs would likely have been reviewed through the NDA process.  As a result, for every one of the approximately 2,225 DESI closures where a drug has been found effective for one or more indications, it is possible that numerous NDAs and ANDAs have been reviewed and approved.  The FDA does not currently track the number of NDAs or ANDAs approved for DESI drugs.

How many DESI drugs are still on the market?

Fewer than a dozen DESI proceedings remain open or “pending,” covering approximately 20 active ingredients.  FDA is actively working to close these proceedings. It has been FDA’s policy to allow continued marketing of drugs that are subject to a pending DESI proceeding.

A review of the National Drug Code (NDC) Directory on February 24, 2016, for the active ingredients in each of the open DESI proceedings indicated that there are slightly less than 250 different NDCs listed in the NDC Directory.  These drugs include the products approved as safety-only and those IRS to those safety-only applications, as well as newer applications approved by FDA for both safety and efficacy.  Approximately 50 of these NDCs are associated with FDA-approved products, and the remainder are unapproved while the DESIs remain open.  These currently marketed products include a variety of strengths and dosage forms, different manufacturers, and different combinations of ingredients.

By Karla L. Palmer –

FDA published last week two final “Interim Policies” for compounding using bulk substances under Sections 503A and 503B of the Federal Food, Drug and Cosmetic Act (here and here). FDA first published draft policies back in October 2015 (see our previous post here), and received detailed comments from industry (11 comments addressing the Section 503B draft and 14 comments addressing the Section 503A draft). FDA stated it made several changes to the policies in response to the comments and on its own initiative (but the policies do not seem materially different from their drafts). We address these policies in separate posts.

Section 503B

Like the interim policy for Section 503A bulks, FDA’s final interim policy addressing bulk substances under Section 503B is not all that different from its draft policy published in October 2015. The final guidance describes the conditions that facilities must satisfy to compound preparations in compliance with Section 503B. An outsourcing facility must: (1) compound using bulk substances that appear on a list established by the Secretary for which there is a clinical need, or (2) appear on FDA’s published drug shortage list at the time of compounding, distribution and dispensing. Bulk substances must meet the following additional criteria: (1) if a USP/NF monograph exists, then it must comply with the monograph; (2) it must be manufactured in a FDA-registered facility, and (3) it must be accompanied by a valid certificate of analysis. The final guidance also sets forth the information about clinical need that must be established through the bulks nomination process. (Guidance at 3).

Like the draft policy, the final version includes different “bulks” lists establishing what substances may and may not be used in compounding from the original 2,590 unique nominated substances. Of the nominated substances, 1,740 were allergenic extracts/biological products (which are the subject of a Biologics License Applications (BLAs) and not eligible for the Section 503B the bulks list). The complete three lists are published HERE. As with the Section 503A bulks categories, FDA describes the Section 503B bulks categories as follows:

• List I: Bulk Drug Substances Under Evaluation: These substances may be eligible for the 503B bulks list; they were nominated with sufficient supporting information for FDA to evaluate them and do not appear on any other list.
• List 2: Bulk Drug Substances That Raise Significant Safety Risks: These substances were nominated with sufficient supporting information, but FDA identified “significant safety risks” relating to the use of these substances. If FDA adds to List 2, it will publish that communication on its website, advising the substance is no longer eligible for the policies that apply to substances on List 1. The website is available here. Compounders and outsourcing facilities should also subscribe to FDA’s list serve to receive updates to the list.
• List 3: Bulk Drug Substances Nominated Without Adequate Support: These substances may be eligible for inclusion on the final bulks list, but they were nominated without adequate supporting information for FDA to complete its evaluation. FDA notes these substances maybe renominated through a docket established by FDA, but the substances will not be considered until after FDA makes its way through those substances that were nominated with sufficient support in July 2014.

Unlike Section 503A, there is no obligation FDA to consult the Pharmacy Compounding Advisory Committee (PCAC) before nominating substances, but FDA will consider whether PCAC input on any substances would be helpful to the Agency in its review. It will publish lists identifying substances for which it has determined there is a clinical need, and those substances which it reviewed and determined there is no clinical need for use in compounding.      

FDA also sets forth its “Policy” (at pp. 6- 7) for compounding from bulk substances under section 503B: FDA does not intend to take action against an outsourcing facility for compounding a drug using a bulk substance not on bulks list if the drug (1) appeared on FDA’s shortage list within 60 days of distribution and dispensing and (2) was used to fill and order received when the drug while it was on the shortage list. In addition, FDA does not intend to take action against a facility that compounds using a drug that is not on the 503B bulks list and that is not used to compound a drug on FDA’s shortage list provided the following conditions are met:

1. The bulk substance appears on 503B Category 1 on FDA’s website. Note, however, FDA’s “Summary of Policy” chart at page 10 may create confusion on this point because it states the opposite under the “FDA Policy” Column: “The bulk drug substance is not on the 503B bulks list. However, pending a determination about whether to put the bulk substance on the 503B bulks list , FDA does not intend to take action against an outsourcing facility….” (emphasis added). FDA is likely referring to a substance not appearing on the final bulks list that it will promulgate pursuant to notice-and-comment rulemaking. In addition, the original and subsequent manufacturers of the bulk substance must be registered with FDA, the substance must be accompanied by a valid COA, comply with an applicable USP/NF monograph if one exists, and comply with all other provisions of Section 503B.  
2. Category 2 bulk substances are those that FDA has identified present significant risks in compounding.  
3. Category 3 bulk substances may be eligible for inclusion on the Section 503B bulks list but were nominated with insufficient supporting information for FDA to complete its evaluation. These category 3 substances may only be used to compound a drug that appears on FDA’s drug shortage list. FDA states in a footnote (p. 8) that patients with medical conditions that need to be treated with substances that cannot be used in compounding (i.e., in category 3) “may be able to obtain those drugs through FDA’s expanded access program.” As reflected in comments during PCAC meetings, this can be a burdensome process.

By Kurt R. Karst –    

Earlier this week, Senators Patrick Leahy (D-VT), Chuck Grassley (R-IA), Amy Klobuchar (D-MN), and Mike Lee (R-UT) announced the introduction of bipartisan legislation that they say is intended to “end inappropriate delay tactics that are used by some brand-name drug manufacturers to block competition from more affordable generic drugs.” The bill, S. 3056, is known as the “Creating and Restoring Equal Access to Equivalent Samples Act” (or “CREATES Act”), and addresses both the availability of reference product sample when a product is either subject to a Risk Evaluation and Mitigation Strategies with Elements to Assure Safe Use (“ETASU REMS”) or is under a self-imposed restricted distribution system, and shared REMS negotiations.  The bill was immediately praised by several groups (see here, here, and here).  As we’ve previously noted (see our posts here, here, and here), the availability of product sample for reference products under a restricted distribution system and the issue of shared REMS have been the subject of increasing litigation. Reference product restricted distribution systems and generic drug availability have also piqued the interest of the Federal Trade Commission (see here). 

As noted above, the CREATES Act addresses both ends of the generic drug (and biological product) spectrum: the availability of reference product sample needed to conduct bioequivalence studies (or other testing) in order for a company to submit an ANDA, a 505(b)(2) NDA, or a PHS Act § 351(k) biosimilar application, and the negotiations that surround finalization of a REMS program needed to approve a generic drug application.

With respect to application submission, the CREATES Act would allow the sponsor of an ANDA, a 505(b)(2) NDA, or a biosimilar application (i.e., an “eligible product developer”) to bring an action in federal court to obtain from the brand-name sponsor of a drug or biological product subject to restricted distribution (and that is not in shortage) – either under an ETASU REMS or under a self-imposed restricted distribution system – the sample it needs to conduct testing to seek approval of a generic drug or biosimilar biological product.  Provided certain elements are met, a court may “order the license holder to provide to the eligible product developer without delay sufficient quantities of the covered product on commercially reasonable, market-based terms.”  The bill would also authorize a judge to award monetary damages to an eligible product developer in an amount “sufficient to deter the license holder from failing to provide other eligible product developers with sufficient quantities of a covered product on commercially reasonable, market-based terms. . . .”  The maximum monetary award would not be greater than the revenue that the brand-name license holder earned on the covered product during a period specified in the bill. 

With respect to application approval and shared REMS, we note that under the FDC Act brand-name and generic drug sponsors are generally expected to share a single REMS system. However, the statute allows for a deviation from that single, shared system under certain circumstances.  Specifically, FDC Act § 505-1(i)(1)(B) states:

A drug that is the subject of an [ANDA] and the listed drug shall use a single, shared system under [FDC Act § 505-1(f)]. [FDA] may waive the requirement under the preceding sentence for a drug that is the subject of an [ANDA], and permit the applicant to use a different, comparable aspect of the elements to assure safe use, if [FDA] determines that—

(i) the burden of creating a single, shared system outweighs the benefit of a single, system, taking into consideration the impact on health care providers, patients, the applicant for the [ANDA], and the holder of the [RLD]; or

(ii) an aspect of the [ETASU] for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the [ANDA] certifies that it has sought a license for use of an aspect of the [ETASU] for the applicable listed drug and that it was unable to obtain a license.

FDA has allowed very few deviations from a single, shared REMS system (see here and here).

The CREATES Act would allow an eligible product developer to bring an action in federal court seeking an order that a brand-name company whose product is covered by an ETASU REMS: (1) “enter into a single, shared system of elements to assure safe use with the eligible product developer on commercially reasonable terms;” (2) “allow the eligible product developer to join a previously approved system of elements to assure safe use with respect to the covered product on commercially reasonable terms;” or (3) “demonstrate that [FDA] has waived the requirement for the covered product to be part of a single, shared system of elements to assure safe use.” The bill would also authorize a judge to award an eligible product developer reasonable attorney fees, costs of the civil action, and “a monetary amount sufficient to deter the license holder from failing to reach agreements that would allow other eligible product developers to participate in a single, shared system of elements to assure safe use on commercially reasonable terms.”  The maximum monetary award would not be greater than the revenue that the brand-name license holder earned on the covered product during a period specified in the bill (and that is different than the period identified for product sample purposes). 

Finally, the CREATES Act would create a limitation of liability on brand-name sponsors who provide product sample to eligible product developers. “A license holder shall not be liable for any claim arising out of the failure of an eligible product developer to follow adequate safe-guards to assure safe use of the covered product during development or testing activities described in this section, including transportation, handling, use, or disposal of the covered product by the eligible product developer,” states a provision in the bill. 

The CREATES Act is the latest effort by Congress to address restricted distribution product availability and shared REMS. Some aspects of the CREATES Act are clearly inspired by legislation introduced in 2014 and 2015 – specifically, the Fair Access for Safe and Timely Generics Act (“FAST Generics Act”) (H.R. 5657 and H.R. 2841) – but the CREATES Act goes further than previous legislation, allowing  eligible product developers to obtain a court order (see our previous post here).  The FAST Generics Act did not get much traction on Capitol Hill, but the CREATES Act might with heightened concerns over drug pricing. 

By Allyson B. Mullen –

Symbols have been an accepted part of device labeling outside of the U.S. for many years. In the U.S., however, symbols alone have not been permitted on medical device labeling, with the exception of guidance allowing use of “Rx Only.”  To have a single global label, device manufacturers have had to cram explanatory text next to symbols on labels and include lengthy lists of symbols in instructions for use manuals defining each symbol.  To add to the challenges, the explanatory text next to each symbol must be translated into numerous different languages to meet the legal and regulatory requirements of countries outside the U.S.  Obviously, all of this additional text defeats the purpose of using symbols, but is necessary for marketing in other countries, if companies want to have a single global product (i.e., a product with labeling that meets U.S. and OUS requirements).

Three years ago, FDA proposed a rule that would permit device manufacturers to use stand‑alone symbols on device labeling. In the meantime, this issue has continued to fester.  So it is good news that FDA finalized the rule on June 15, 2016. 

Under the final rule, device manufacturers may use symbols on device labeling in one of the following ways:

1. Continue using a symbol(s) with adjacent explanatory text.
2. Use a symbol alone without adjacent explanatory text, so long as any one of the following conditions are met:
1. (i) the symbol is taken from an FDA-recognized standard, (ii) it is used in accordance with the standard, and (iii) the symbol and its definition are included in a Symbol Glossary that is included with the device’s labeling.
2. (i) the symbol is taken from a standard developed by a standards development organization (SDO), but it is not FDA-recognized, (ii) it is used in accordance with the standard, (iii) the manufacturer makes a determination that “the symbol is likely to be read and understood by the ordinary individual under customary conditions of purchase and use,” and (iv) the symbol and its definition are included in a Symbol Glossary that is included with the device’s labeling.
3. (i) the symbol is taken from an FDA-recognized standard, (ii) it is NOT used in accordance with the standard, (iii) the manufacturer makes a determination that “the symbol is likely to be read and understood by the ordinary individual under customary conditions of purchase and use,” and (iv) the symbol and its definition are included in a Symbol Glossary that is included with the device’s labeling.

In scenarios 2.b and 2.c, the burden is on the manufacturer to determine that “the symbol is likely to be read and understood by the ordinary individual under customary conditions of purchase and use.” Validation of a device’s labeling may provide some evidence that the symbol is likely to be read and understood.  The final rule also now formally allows device manufacturers to use the Rx Only symbol in lieu of the longer prescription use only statement. 

The final rule is relatively unchanged from the proposed rule, which we previously blogged on here. The most significant changes from the proposed to the final rule are:

• Manufacturers may use symbols from non-FDA recognized standards without explanatory text, as long the requirements described above are met.
• The symbols glossary must be “included in the labeling” meaning either including a fully copy of the glossary in the paper labeling or a statement identifying the location of the glossary (e.g., a website link).
• FDA clarified what organizations qualify as SDOs.
• FDA clarified the required elements of a symbols glossary.

Permitting use of standalone symbols is an important step towards global harmonization of device labeling. We commend FDA for finalizing this important rule.  FDA also made the final rule more meaningful by, on the same day, updating its list of recognized standards to include several medical device symbols standards including, among others, ISO 15223 – Medical devices—symbols to be used with medical device labels, labelling, and information to be supplied—Part 1: General requirements. We expect this final rule to be embraced by industry.

  In recent years, the level of scrutiny on foreign pharmaceutical manufacturing facilities in countries like China and India has skyrocketed—along with the demand and dependence of western countries on the supply of goods coming from those facilities. With the international pharmaceutical supply chain imperiled like never before, what can drug manufacturers do to protect themselves?

This free webinar, presented by Dechert LLP and Hyman, Phelps & McNamara P.C., will discuss recent pharmaceutical supply chain developments and what steps companies need to take to prevent and remediate compliance issues in the context of:

• The uptick in investigations in China and India.
• The potential impact of adverse regulatory actions against nonconforming facilities.
• Threats Posed by Bribery and Corruption.
• Anti-corruption compliance issues from U.S. and Asian perspectives.
• “War stories” from recent investigations.

When

Wednesday, June 22, 2016
12:00 p.m. – 1:00 p.m. ET

Where

This presentation will be simulcast via Webex as a webinar.  Please click here to register. 

Speakers

Douglas B. Farquhar
Director
Hyman, Phelps & McNamara PC
Washington, D.C.

Mark I. Schwartz
Of Counsel
Hyman, Phelps & McNamara PC
Washington, D.C.

Jeremy B. Zucker
Partner
Dechert LLP
Washington, D.C.

Lewis Ho
Partner
Dechert LLP
Hong Kong

Kareena Teh
Partner
Dechert LLP
Hong Kong

Application for accreditation of this program for Continuing Legal Education (CLE) in California, Massachusetts, New Jersey, and New York is currently pending.

For questions, please contact Reiko Tate (reiko.tate@dechert.com).

By Allyson B. Mullen –

On June 10, FDA issued the draft guidance, “Dissemination of Patient-Specific Information from Devices by Device Manufacturers.”  At a mere six pages long, this guidance is not tipping the scales by any means, but its few short pages contain some important information for device manufacturers interested in providing patient-specific information from devices.

The draft guidance notes that patients are becoming more involved in their health. Accordingly, patients are seeking to obtain information “recorded, stored, processed, retrieved, and/or derived from a medical device.”  The draft guidance defines such patient-specific information as:

any information unique to an individual patient or unique to that patient’s treatment or diagnosis that, consistent with the intended use of a medical device, may be recorded, stored, processed, retrieved, and/or derived from that medical device. This information may include, but is not limited to, recorded patient data, device usage/output statistics, healthcare provider inputs, incidence of alarms, and/or records of device malfunctions or failures. This information does not include any interpretations of data aside from those interpretations of data normally reported by the device to the patient or the patient’s healthcare provider. Generally, categories for patient-specific information may include, but are not limited to: (1) data a healthcare provider inputs to record the status and ongoing treatment of an individual patient or (2) information stored by the device to record usage, alarms, or outputs (e.g., pulse oximetry data, heart electrical activity, and rhythms as monitored by a pacemaker). Patient specific case logs entered into a medical device by a healthcare provider may be included under this definition.

The draft guidance indicates that FDA will consider reports of patient-specific information as labeling, which must comply with the FDC Act. If a device manufacturer intends to begin providing reports of patient-specific information, according to the draft guidance, it may do so “without obtaining additional premarket review.”  We find this point interesting for various reasons, including that it is made without any distinction for the device’s classification.  According to the draft guidance, no additional premarket review is required even if the device recording, storing, processing, retrieving, and/or deriving the patient-specific information is a class III device.

The draft guidance provides some broad considerations for device manufacturers planning to report patient-specific information:

• Provide adequate content to ensure the information presented is interpretable and useful to the patient;
• Consider providing supplementary instructions, materials or references to aid patient understanding of the data;
• Provide comprehensive and contemporary information, including all reasonably available patient-specific information;
• Provide relevant context, including for example, how a parameter was measured and recorded; and
• Indicate whom to contact with questions regarding the data (e.g., the patient’s healthcare provider for questions about the data and/or the device manufacturer for questions about the device).

These considerations appear relatively straight forward and based on common sense to us, but FDA felt they were worth putting in a draft guidance. If FDA were to regulate laboratory developed tests, then this new guidance, if adopted, could affect the way in which labs generate reports to patients.

By Riëtte van Laack –

On May 31, 2016, the Food Safety Coalition submitted a Petition to the Food Safety Inspection Service (FSIS) to amend regulations requiring safe food handling instructions (SHI) on certain meat and poultry products.

The Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA) authorize FSIS to mandate that meat and poultry products bear label information “to assure that . . . the public will be informed of the manner of handling required to maintain the article in a wholesome condition.” Pursuant to this authority, the FSIS has issued regulations, 9 C.F.R. §§ 381.125; 317.2(l), specifying a safe handling statement or instruction that alerts consumers that raw and partially cooked meat may contain pathogens, and detailing what are considered safe food handling practices – at least as of 1994. These regulations mandate that the label for raw and partially cooked meat and poultry include the following statements:

“This product was prepared from inspected and passed meat and/or poultry. Some food products may contain bacteria that could cause illness if the product is mishandled or cooked improperly. For your protection, follow these safe handling instructions.”

“Keep refrigerated or frozen. Thaw in refrigerator or microwave.” (Any portion of this statement that is in conflict with the product's specific handling instructions may be omitted, and a graphic illustration of a refrigerator must be displayed next to the statement.);

“Keep raw meat and poultry separate from other foods. Wash working surfaces (including cutting boards), utensils, and hands after touching raw meat or poultry.” (A graphic illustration of soapy hands under a faucet must be displayed next to the statement.);

“Cook thoroughly.” (A graphic illustration of a skillet must be displayed next to the statement.); and

“Keep hot foods hot. Refrigerate leftovers immediately or discard.” (A graphic illustration of a thermometer must be displayed next to the statement.)

For example:

According to Petitioners, there is much evidence that these safe handling instructions are no longer sufficient.

Petitioners ask that FSIS revise the regulations to include:

• An end-point temperature for raw and partially cooked product categories as well as any “rest time” requirement;
• Instructions to use a thermometer to verify that the product has reached the recommended internal temperature;
• Information on safe handling practices to minimize risks associated with improper sanitation, handling, storage, and temperature control for meat, poultry and catfish products;
• Include the four “check your steps” (clean, cook, separate and chill) safe food handling graphics instead of the graphics currently displayed; and
• A web address for additional information on cooking recommendations.

In addition to revising the contents of the SHI, Petitioners ask that FSIS revise the regulation to mandate the use of “easily legible type located away from curved or seamed areas of packages” and use of “Use bold or large font for end-point temperatures and ‘rest time’ instructions.”

Petitioners contend that FSIS is aware of the need to revise the SHI and in fact has performed consumer studies as to consumers’ understanding of certain label statements. FSIS has recently initiated a second round of consumer perception studies. However, the Petitioners do not want FSIS to further delay revisions and ask that FSIS proceed with rulemaking now.

In addition to revising the SHI for meat and poultry, Petitioners request that FSIS issue a new regulation mandating a SHI statement for catfish. The latter request presumes that catfish will remain under FSIS inspection instead of reverting back to FDA inspection.

By Riëtte van Laack

As we reported previously, in 2013, Health Science Funding, LLC (HSF) filed what might be the first medical food lawsuit against FDA.  Plaintiff markets a medical food for women with lupus, Prastera® DHEA.  Medical foods may be marketed without pre-market approval by FDA.  In fact, as HSF learned, FDA will not approve or review the label for a medical food or any other food before marketing, even if the company requests that FDA do so.

In 2013, seemingly unwilling to live with the uncertainty as to whether FDA would disagree with HSF’s determination that Prastera qualifies as medical food under the Orphan Drug Act Amendments of 1988, 21 U.S.C. §360ee(b)(3), HSF filed a complaint asking that the Court declare that Prastera is a medical food and enjoin FDA from taking action against Prastera in the future.  The Court did not seize the “opportunity to create a legacy” provided by HSF’s lawsuit and, in November 2013, after various communications with the parties dismissed the case without prejudice.

HSF apparently concluded that the Court closed the case because FDA had agreed to let the company market its medical food and to refrain from any enforcement action in exchange for HSF’s stay of its request for Declaratory Judgment.  FDA inspected the firm 1.5 years later, and, apparently, threatened seizure.  HSF believed that was inconsistent with this “agreement.” 

After several failed attempts to get FDA to commit to refrain from taking enforcement action, HSF again went to Court.  HSF filed a new complaint, again requesting that the Court issue a declaratory judgment and enjoin FDA from taking enforcement action. 

The Court granted FDA’s motion to dismiss. This time, the Court issued an opinion which clarifies that the case was premature.  As FDA had not taken any final agency action, HSF’s claims were not ripe.  The court found that FDA had only informally advised HSF that Prastera does not appear to meet the requirements for a medical food.  FDA had “not enforced, nor made any attempt to enforce [the Federal Food, Drug, and Cosmetic Act] against Plaintiff or its product[].”  Thus, there was no agency action, let alone final agency action, for the Court to review.  For similar reasons, the Court determined that HSF had no standing to bring a claim for injunctive relief. 

Because the Court concluded that it has no jurisdiction, it did not need to address the other issues FDA raised in its motion to dismiss, such as what constitutes a medical food and whether FDA’s interpretation of the medical food definition is valid.  Like any other company, HSF has to live with the uncertainty as to whether FDA will determine that its product does qualify as a medical food and, if not, whether and when the Agency will decide to take an enforcement action against the product. 

FDA is no friend to the medical food category, and this case further illustrates the marketing uncertainty surrounding virtually all medical foods.  FDA’s issuance of recent final guidance, that is in conflict with the broad statutory definition of medical foods has negatively impacted the future of this market category.  Nevertheless, regulatory risk for most medical foods, while unavoidable, can be effectively managed.  However, asking FDA for approval or suing the Agency is not part of such strategy.

by Jennifer Newberger - 

Since September 1995, FDA and CMS have operated under an interagency agreement (IA) regarding Medicare coverage for investigational devices.  That same month, CMS also published a rule that permitted Medicare coverage of certain devices with an approved investigational device exemption (IDE) in place.  The rule established the process by which FDA would assist CMS in determining which investigational devices should be covered under Medicare.  The process was based on placing devices into one of two categories:  Category A, for “Experimental/ Investigational” devices, or Category B, “Non-experimental/Investigational” devices.  Categorization depends upon the level of risk associated with the device.  Category B devices present a lower level of risk, based on information available at the time of the categorization demonstrating that an initial level of safety and effectiveness has already been established.  See   42 C.F.R. § 405.201 et seq.

Under the regulation and the IA, CMS uses FDA’s categorization to determine whether an investigational device may receive coverage under Medicare.  For Category B devices, Medicare may cover both the device and “routine care items and services.”  For Category A devices, however, CMS only reimburses the routine care items and services, but not the device itself. 

In 2013, CMS revised the definitions for Category A and B devices as follows:

• A Category A device is “a device for which ‘absolute risk’ of the device type has not been established (that is, initial questions of safety and effectiveness have not been resolved) and the FDA is unsure whether the device type can be safe and effective.”

• A Category B device is “a device for which the incremental risk is the primary risk in question (that is, initial questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA premarket approval or clearance for that device type.”

Over time, it became apparent that not all devices necessarily fit into either Category A or Category B.  This was especially true for the following types of devices:

• Devices that had been studied in early feasibility studies, but had undergone modifications that raised significant new safety questions.

• Devices for which additional data became available since the original categorization of the device indicating that certain safety issues had been resolved.

Due to changes made to the original iteration of the device, it may have been appropriate to change the initial categorization of the device.  Unfortunately, neither the rule nor the IA provided FDA with the authority to change the categorization of a device once made. 

To address these issues regarding categorization, FDA and CMS entered into a Memorandum of Understanding (MOU) dated December 2, 2015.  On June 1, 2016, one day before the MOU was to go into effect, FDA issued a draft guidance document to implement the MOU.  Upon finalization, the “policies and framework in this guidance will represent the Agency’s current thinking on categorization.”

The draft guidance states that FDA will place a device in Category A if one or more of the following criteria are met:

• No PMA approval, 510(k) clearance or de novo request has been granted for the proposed device or similar devices, and non-clinical and/or clinical data on the proposed device do not resolve initial questions of safety and effectiveness.

• The proposed device has different characteristics compared to a legally marketed device; and information related to the marketed devices does not resolve initial questions of safety and effectiveness for the proposed device. Available non-clinical and/or clinical data on the proposed device also do not resolve these questions.

• The proposed device is being studied for a new indication or new intended use for which information from the proposed or similar device related to the previous indication does not resolve initial questions of safety and effectiveness. Available non-clinical and/or clinical data on the proposed device relative to the new indication or intended use also do not resolve these questions.

Category B devices are those for which one or more of the following criteria are met:

• No PMA approval, 510(k) clearance or de novo request has been granted for the proposed device or similar devices; however, available clinical data (e.g., feasibility study data) and/or non-clinical data for the proposed device or a similar device resolve the initial questions of safety and effectiveness.

• The proposed device has similar characteristics compared to a legally marketed device, and information related to the marketed device resolves the initial questions of safety and effectiveness for the proposed device. Additional non-clinical and/or clinical data on the proposed device may have been used in conjunction with the leveraged information to resolve these questions.

• The proposed device is being studied for a new indication or new intended use; however, information from the proposed or similar device related to the previously indication resolves the initial questions of safety and effectiveness. Additional non-clinical and/or clinical data on the proposed device may have been used in conjunction with the leveraged information to resolve these questions. 

The descriptions of the category A and B devices will allow FDA to take into consideration developments regarding the device that occurred subsequent to the initial categorization, and to change categories if needed.  The sponsor of a device should include a request to change the category as an IDE supplement.  FDA will include a categorization decision in either the IDE approval letter to the sponsor or a letter to the sponsor in response to a request for category change.  

By Kurt R. Karst – 

It was just last week when one orphan drug exclusivity labeling carve-out case (presumptively) came to an end when the U.S. Court of Appeals for the District of Columbia Circuit ruled for FDA in the context of a generic version of  FUSILEV (levoleucovorin) for Injection (see our previous post here).  Little did we know, however, that just a few days prior to that June 3, 2016 D.C. Circuit decision AstraZeneca Pharmaceuticals LP (“AstraZeneca”) submitted a Citizen Petition (Docket No. FDA-2016-P-1485) to FDA (dated May 31, 2016) raising yet another orphan drug exclusivity labeling carve-out issue.  The petition immediately reminded us of that famous quote from Don Michael Corleone in The Godfather: Part 3 – “Just when I thought I was out, they pull me back in" – where the “I” is “FDA” and the “they” is “AstraZeneca.”

AstraZeneca’s petition was posted on regulations.gov earlier this week and concerns FDA approval of ANDAs and 505(b)(2) applications for generic and “follow-on” versions of the company’s blockbuster drug CRESTOR (rosuvastatin calcium) Tablets, 5 mg, 10 mg, 20 mg, and 40 mg, which FDA approved on August 12, 2003 under NDA 021366.  The petition stems from FDA’s May 27, 2016 approval of Supplement 033 to CRESTOR NDA 021366 adding a new indication: “for treatment of pediatric patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total C, nonHDL-C and ApoB as an adjunct to diet, either alone or with other lipid-lowering treatments.”  AstraZeneca will presumably be granted a period of orphan drug exclusivity for this use until May 2023 based on an earlier orphan drug designation for the drug for pediatric HoFH. 

According to AstraZeneca:

First, carving out AstraZeneca’s protected pediatric HoFH labeling from the labeling of a product marketed under an ANDA or section 505(b)(2) NDA would present substantial safety and efficacy risks.  Although FDA may in some instances approve ANDAs that omit protected pediatric labeling, FDA has made clear that a carve out is inappropriate when, as here, the protected pediatric labeling is “necessary for the safe use of the drug.”  Crestor® is labeled for treatment of HoFH in adult and pediatric patients, and for treatment of heterozygous familial hypercholesterolemia (“HeFH”), a related but far less severe condition.  In many instances, the recommended dosage and course of treatment differ between adult HoFH and pediatric HoFH patients, and likewise between HeFH and HoFH patients.  Given these differences, there are substantial risks that doctors would over- or under-treat pediatric HoFH patients if generic or other rosuvastatin calcium omitted AstraZeneca’s protected pediatric HoFH labeling.

Second, irrespective of whether a carve out would present a safety risk, FDA lacks legal authority to carve out pediatric labeling protected by orphan drug exclusivity.  Together, the Hatch-Waxman Act’s same-labeling requirement and FDA’s pediatric-labeling regulations impose a categorical rule: pediatric labeling information subject to orphan drug exclusivity may not be omitted from generic-drug labeling.  The Best Pharmaceuticals for Children Act, 21 U.S.C. § 505A(o), permits the carve out of labeling protected only by patent and Hatch-Waxman exclusivity—and therefore provides no basis for carving out labeling protected by orphan drug exclusivity.  FDA also possesses several other “general” carve-out authorities, see 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7), but those authorities are inapposite in light of FDA’s subsequently adopted pediatric-labeling rules and Congress’s enactment of section 505A(o).  Indeed, prior to the passage of section 505A(o), FDA concluded that it lacked authority to carve out protected pediatric labeling in circumstances nearly identical to those presented here.  FDA and the United States District Court for the District of Maryland concluded in the Otsuka litigation that FDA has authority to carve out pediatric labeling protected by orphan drug exclusivity.  However, that conclusion is incorrect for the reasons given above and in Part II.B of this Citizen Petition.

As noted above, AstraZeneca’s petition once again raises our old friend FDC Act § 505A(o).  That provision, titled “Prompt approval of drugs under section 355(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage  Provision” (or Section 11 of the Best Pharmaceuticals for Children Act) states:

(1) General rule – A drug for which an application has been submitted or approved under section 355(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 352 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 355(j)(5)(F) of this title.

(2) Labeling – Notwithstanding clauses (iii) and (iv) of section 355(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)], the Secretary may require that the labeling of a drug approved under section 355(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—

(A) a statement that, because of marketing exclusivity for a manufacturer—

(i) the drug is not labeled for pediatric use; or

(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and

(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.

FDC Act § 505A(o) was front and center in an April 2015 FDA Letter Decision concerning approval of ANDAs for generic versions Otsuka Pharmaceutical Co.’s (“Otsuka’s”) ABILIFY (aripiprazole) with labeling that omitted information concerning pediatric patients and protected by orphan drug exclusivity.  And, as noted above, that FDA Letter Decision led to litigation and a May 2015 decision in favor of FDA (which supported a labeling carve-out by generics) by the U.S. District Court for the District of Maryland (see our previous posts here and here).

In the petition, AstraZeneca first asserts that the carve-out situation presented as a result of the recent approval of Supplement 033 for pediatric HoFH meets a three-part policy FDA laid out in the Agency’s April 2015 ABILIFY Letter Decision:

FDA has adopted a safety and efficacy policy (the “Policy”) that squarely applies to AstraZeneca’s protected pediatric HoFH labeling.  Under the Policy, a generic drug is “misbranded” and “will not [be] approve[d]” where

1. the reference-listed drug “is approved in adults and pediatric patients for the same indication”;
2. “the pediatric information is protected by exclusivity and is significantly different from the information regarding use in adults for the same indication”; and
3. “a carve-out of [the] pediatric information while the adult information is retained in the ANDA labeling may result in a potential safety risk to pediatric patients.”

Astra Zeneca argues that each criterion above is met in the case of CRESTOR.  “Unlike Abilify, Crestor® meets all three of the Policy’s criteria and is therefore entitled to de facto exclusivity for the duration of AstraZeneca’s seven-year period of orphan drug exclusivity,” says AstraZeneca.

And regardless of whether or not the “Policy” applies here, says AstraZeneca, FDA may not carve out orphan drug exclusivity-protected pediatric HoFH information from ANDA and 505(b)(2) labeling because the Agency lacks the authority to do so, despite what the District of Maryland ruled in Otsuka, which is “incorrect and should be overturned.”

[N]one of FDA’s carve-out authorities applies to pediatric labeling protected by orphan drug exclusivity, regardless of a factual inquiry into whether the omitted labeling raises a safety issue. . . .

[First, ] FDA’s pediatric-labeling regulations mandate that dosing, specific indications, and safety data pertaining to pediatric uses “must appear in all prescription drug labeling.”  21 C.F.R. §§ 201.57(a), (a)(6)–(7), (a)(13), (c)(2)(i)(B), (c)(3)(i)(H) . . . .   These FDA pediatric-labeling regulations create a barrier to approval of a generic drug when (i) the reference-listed drug is approved for one or more pediatric indications and (ii) at least one of those pediatric indications is protected by patent, Hatch-Waxman, or some other form of exclusivity. . . .

[Second,] [b]ecause section 505A(o) does not address other forms of exclusivity—including exclusivity afforded by the Orphan Drug Act, 21 U.S.C. § 360cc(a)—the barrier to generic-drug approvals presented in the Glucophage precedent remains with respect to orphan drug exclusivity.

[Third,] [FDA’s] general carve-out regulations [(i.e., 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7))]  do not fill the void left by section 505A(o) for at least five reasons [detailed later in the petition].

AstraZeneca, which pushed FDA to quickly approve Supplement 033, wants FDA to act promptly on the company’s petition.  Why?  July 8, 2016 is the date that pediatric exclusivity applicable to U.S. Patent No. RE 37,314 listed in the Orange Book for CRESTOR expires, and when FDA is expected to approve multiple and currently tentatively approved ANDAs for generic CRESTOR.  FDA already approved one ANDA – Watson Laboratories, Inc.’s (“Watson’s”) ANDA 079167; approved on April 29, 2016 (see here and here) – for generic CRESTOR.  According to AstraZeneca, however, that ANDA approval was authorized because the company “granted Watson a patent license and a selective waiver of all periods of exclusivity applicable to FDA’s May 27, 2016, approval of the pediatric HoFH indication and labeling with respect to Watson’s marketing of its generic rosuvastatin product.” 

Watson is apparently one of several “first applicants” eligible for 180-day exclusivity, which would have been triggered on May 2, 2016 when the company commercially marketed its generic CRESTOR.  FDA notes in the approval letter for ANDA 079167 that Watson may have forfeited eligibility for 180-day exclusivity for failure to obtain timely tentative approval, but that “[a]t least one first applicant remains eligible for 180-day generic drug exclusivity for Rosuvastatin Calcium Tablets, 5 mg, 10 mg, 20 mg, and 40 mg,” thus setting up a Nateglinide-like situation (see our previous post here).

If FDA does approve ANDAs for generic CRESTOR on July 8, 2016, then it seems likely that litigation will ensue – probably not in the U.S. District Court for the District of Maryland given that court’s Otsuka decision – and FDA’s carve-out authority under FDC Act § 505A(o) will once again be tested.

By Jenifer R. Stach & Ricardo Carvajal –

Carrying through on what had been designated as a high priority item, FDA rolled out its sodium reduction initiative with several actions, all on the same day.  On June 1, 2016, FDA published a Federal Register notice to announce the availability of draft guidance, held a same-day webinar (see slides here), issued a response letter denying a 2005 citizen petition submitted by the Center for Science in the Public Interest (CSPI), and updated the FDA Voice blog with a post by CFSAN Director Susan Mayne, Ph.D.

The draft guidance, “Voluntary Sodium Reduction Goals: Target Mean and Upper Bound Concentrations for Sodium in Commercially Processed, Packaged, and Prepared Foods” provides recommendations to reduce the estimated average U.S. sodium intake of 3,400 mg/day to 2,300 mg/day over the next ten years.  FDA expects that the goal to reduce average sodium intake will benefit the U.S. population in reducing hypertension, a major risk factor in cardiovascular disease and stroke.  However, questions have been raised about what the optimal level of sodium intake might be, and whether low sodium intake exposes most people to increased risk of death and cardiovascular events while only benefiting the small minority of the population with hypertension and a high sodium intake.     

The draft guidance acknowledges that sodium reduction is a complicated endeavor, given the many functions of sodium-containing ingredients in food.  To achieve the short-term and long-term sodium intake goals of 3,000 mg/day and 2,300 mg/day, FDA proposes to set short-term 2-year targets and long-term 10-year targets for sodium content in sixteen major categories of commercially processed, packaged, and prepared foods (see page 4 of the guidance and page 2 of the slides).  These sixteen major categories include:  1) Dairy-Cheese, 2) Fats, Oils, and Dressings, 3) Fruits, Vegetables, and Legumes, 4) Nuts and Seeds, 5) Soups, 6) Sauces, Gravies, Dips, Condiments, and Seasonings, 7) Cereals, 8) Bakery Products, 9) Meat and Poultry, 10) Fish and Other Seafood, 11) Snacks, 12) Sandwiches, 13) Mixed Ingredient Dishes, 14) Salads, 15) Other Combination Foods, and 16) Baby/Toddler Foods.  Within these sixteen categories, FDA has further provided 150 sub-categories (see Appendix 1 to the draft guidance).  In the webinar, Dr. Mayne stated that FDA created the categories to avoid a “one size fits all approach.”  Categories are weighted according to the leading selling products in each category.

In a nod to concerns that sodium reduction could lead to increased levels of other nutrients, the overview section of the draft guidance states that “[c]hange should not negatively affect the nutritional quality of the foods by modifying other nutrient levels (e.g., added sugars or saturated fat) to less-healthy levels (e.g., taking into account all Dietary Guidelines recommendations and FDA policies).”  FDA intends to monitor these levels as part of an ongoing effort to monitor sodium intake levels.

While FDA acknowledged that consumer education is important, the agency has concluded that education is not enough to reduce sodium consumption.  FDA is operating under the premise that “[a]pproximately 75 percent of total sodium intake comes from processed and commercially prepared (e.g., restaurant) foods,” so FDA is relying on industry to take voluntary action with respect to reduced sodium levels in those foods.  The guidance specifically encourages large food manufacturers (whose products make up a significant proportion of national sales in one or more categories) and national and regional restaurant chains to pay particular attention to the recommendations. 

FDA also acknowledges ongoing efforts to reduce sodium in foods by the New York City Department of Health and Mental Hygiene in partnership with 70 local and state health departments, initiatives by the United Kingdom’s Food Safety Authority, and the joint FDA and FSIS request for comment on sodium reduction in 2011 (see our blog post here). 

As announced in the draft guidance, the Federal Register notice, and webinar slides, FDA is seeking comment on:

• FDA’s proposed food categories
• Methods for determining sodium content and developing recommended targets
• Challenges of implementation for short-term and long-term goals

FDA is providing separate comment periods for the short-term and long-term sodium content targets.  With respect to the short-term 2-year targets, FDA is providing a 90-day comment period, with comments due on August 31, 2016.  For the long-term 10-year target, FDA is providing a 150-day comment period with comments due on October 31, 2016.  FDA intends to hold a series of discussions with stakeholders, with the first discussion to be held as a webinar at the end of June. 

In its letter denying CSPI’s citizen petition, FDA described its approach to sodium reduction as “the most effective and appropriate approach at this time based on the scientific and technical information currently available to us about the feasibility sodium reducction across the entire breadth of the complex and heterogeneous U.S. food supply.”  FDA explicitly declined CSPI’s request to revoke the GRAS status of salt, and thereby subject salt to regulation as a food additive.  As we noted in a prior posting, CSPI sued FDA to compel action on its citizen petition.  The denial of the petition and the rollout of FDA’s sodium reduction initiative effectively bring that litigation to a close.  Two days after the rollout, CSPI filed a notice of dismissal.

By Kurt R. Karst & Douglas B. Farquhar –

On June 3, 2016, a three-judge panel (Judges Thomas B. Griffith, Brett M. Kavanaugh, and  Robert L. Wilkins) of the U.S. Court of Appeals for the District of Columbia Circuit ruled for FDA and Intervenor-Appellee Sandoz, Inc. (“Sandoz”) (represented by Hyman, Phelps & McNamara, P.C.) and upheld FDA’s approval of Sandoz’s generic levoleucovorin drug product. The Court issued an Opinion and Order affirming a May 27, 2015 summary judgment Decision from Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia. The rulings came in a lawsuit lodged by Spectrum Pharmaceuticals, Inc. (“Spectrum”) challenging FDA’s February 24, 2015 denial of a related Citizen Petition (Docket No. FDA-2014-P-1649) and March 9, 2015 approval of Sandoz’s ANDA 203563 for a generic version of Spectrum’s FUSILEV (levoleucovorin) for Injection with a labeling “carve-out” (Sandoz’s label omits certain information about an indication protected by orphan drug exclusivity).  The win for FDA (and Sandoz) further extends the Agency’s winning streak on generic drug labeling carve-out challenges.

As we previously reported (here and here), Spectrum initially filed a Complaint and a Motion for Temporary Restraining Order and/or Preliminary Injunction alleging that FDA’s approval of ANDA 203563 in certain vial sizes was unlawful. Spectrum claimed that Sandoz’s approval for the unprotected methotrexate use and with labeling omitting the orphan drug exclusivity-protected colorectal cancer use violated the company’s orphan drug exclusivity.  Spectrum’s Motion for Temporary Restraining Order was denied in an April 29, 2015 Minute Order, and a Hearing on Spectrum’s Motion for Preliminary Injunction was set for May 18, 2015.  The parties subsequently filed Cross-Motions for Summary Judgment. 

In his May 27, 2015 Memorandum Opinion, Judge Lamberth granted FDA’s and Sandoz’s Motions for Summary Judgment and denied Spectrum’s Motions for Preliminary Injunction and Summary Judgment, holding that FDA’s approval of Sandoz ANDA 203563 was valid.  In doing so, Judge Lamberth held that: (1) FDA’s Approval of Sandoz ANDA 203563 did not violate the Orphan Drug Act or Spectrum’s orphan drug exclusivity because physicians may prescribe Sandoz’s generic version of FUSILEV for the protected colorectal cancer use; (2) FDA’s approval of ANDA 203563 in a large vial size for the methotrexate indication was not arbitrary and capricious even though Spectrum argued it was inconsistent with an earlier FDA position on the permissible uses of larger vial sizes; and (3) FDA’s approval of Sandoz ANDA 203563 with labeling omitting information on FUSILEV’s protected colorectal cancer use was a permissible labeling carve-out, despite Spectrum’s argument that it resulted in a generic drug that is less safe than FUSILEV for the remaining conditions of use.  Judge Lamberth ruled that FDA, under the FDC Act and FDA regulations, should not have granted expedited review to Sandoz’s ANDA without notifying Spectrum in advance, but held that the lack of notice had no effect because Spectrum’s arguments had already been fully considered by the Agency.

On appeal, and reviewing the case de novo, the D.C. Circuit panel affirmed Judge Lamberth’s decision.  With respect to Spectrum’s primary argument – i.e., that FDA violated Spectrum’s orphan drug exclusivity for colorectal cancer when the Agency approved Sandoz ANDA 203563 in a large vial size for FUSILEV’s methotrexate indication, because Sandoz’s product could nevertheless be used in colorectal cancer patients – the Court found permissible FDA’s interpretation of the statute – i.e., that orphan drug exclusivity protects only a labeled use and that a generic drug that is not labeled with that use cannot violate another company’s orphan drug exclusivity.  According to the panel:

First, FDA’s reading of the statute closely hews to the text.  As the Fourth Circuit reasoned in Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F.3d 141 (4th Cir. 2002), the words “for such disease or condition” suggest Congress intended to make section 360cc “disease-specific, not drug-specific,” and the rest of the statutory language focuses on protecting approved indications, not intended off-label uses.  The statute creates limits on the approval of an “application,” which by implication directs FDA to evaluate what is written on the application.  An application will necessarily include only stated indications, not intended off-label uses. 

Second, FDA’s interpretation conforms to the statutory purposes of the Orphan Drug Act. Spectrum raises a number of policy arguments, urging primarily that the agency’s approach would undermine the Orphan Drug Act’s incentives for drug innovation.  But . . . innovation was not Congress’s only concern when it created the drug approval process.  Congress also sought to promote affordable drugs.  FDA’s interpretation accommodates both interests by allowing generic producers to enter the market for certain purposes while, at the same time, protecting a company’s right to market its pioneer drugs for exclusive uses. . . . 

To the extent FDA has discretion in choosing how best to implement the Orphan Drug Act, it is up to the agency to strike the balance between the congressional policy goals of drug affordability and innovation.  We will not impose a choice on FDA that Congress did not require.   Spectrum’s policy concerns cannot supplant FDA’s reasonable resolution of these issues, especially because we already rejected similar arguments that allowing labeling carve-outs at all under the Food, Drug, and Cosmetic Act undermines the exclusivity rights of producers of pioneer drugs.  See Bristol-Myers, 91 F.3d at 1499-1501.  There is nothing in the Orphan Drug Act that changes our view.  [(Some internal citations omitted; emphasis in original.)]

Spectrum further argued that even if the Orphan Drug Act doesn’t require FDA to take into account the intended off-label use of a generic drug, FDA’s orphan drug regulations do.  For example, FDA’s regulation at 21 C.F.R. § 314.3(b)(14) defines the term “same drug” to mean, in part, “a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug” (emphasis added).  This argument also missed the mark, found the Court:

We agree with FDA and conclude that during the approval process, the agency can look solely to Sandoz’s labeling claims to determine the intended use of its drug.  FDA’s approach here is consistent with how the agency has interpreted “intended use” outside of the ANDA approval context to mean “the objective intent of the persons legally responsible for the labeling of drugs.”  21 C.F.R. § 201.128.  Under that regulation, intent “is determined by such persons’ expressions” or “may be shown by the circumstances surrounding the distribution” of the drugs. Id. (emphasis added).  For example, intent may be shown by “labeling claims” or other statements by drug manufacturers.  Id.  To be sure, FDA recognizes that there may be situations in which it will look beyond just the manufacturer’s statements, but nothing in its regulations requires FDA to do so.  FDA’s decision to look to Sandoz’s labeling claims as an objective measure of Sandoz’s intent is reasonable and consistent with FDA’s regulations.

The Court was also unpersuaded by Spectrum’s remaining two arguments. 

With respect to Spectrum’s argument that FDA’s approval of Sandoz ANDA 203563 in a large vial size entailed an unjustified policy change in light of an earlier general draft guidance document on allowable excess volume and labeled vial size in injectable drug products, the Court found that “there was no departure that would demand explanation here.”  “The guidance document at issue,” said the Court, “offers a general approach for pharmaceutical drugs, and such broad guidance must give way to more specific risk analysis by the agency.” 

Finally, Spectrum’s argument that FDA was required to give the company notice and an opportunity to be heard before expediting review of Sandoz ANDA 203563 in response to a drug shortage also fell flat with the Court, disagreeing with Judge Lamberth on this issue.  The Orphan Drug Act (FDC Act § 527(b)(1)) provides that FDA can approve another application for a drug protected by orphan drug exclusivity if FDA finds, “after providing the holder notice an opportunity for the submission of views,” that the company with orphan drug exclusivity “cannot assure the availability of sufficient quantities of the drug to meet the needs [of patients] with the disease or condition for which the drug was designated.”  FDA’s regulation at 21 C.F.R. § 316.36 implements this provision and largely tracks the statute.  But as the Court correctly states, these provisions don’t apply in the case where an ANDA is to be approved for a use not protected by orphan drug exclusivity:

The Orphan Drug Act creates a notice obligation only when FDA abrogates a pioneer drug’s period of market exclusivity. . . .  The clear purpose of the notice obligation is to protect the rights of producers of pioneer drugs in the event FDA decides a drug shortage requires it to eliminate those rights.  In contrast, the statute says nothing at all about notice requirements when FDA expedites its review of an ANDA or simply evaluates a drug shortage without more. . . .  Because FDA did not cut short Spectrum’s period of market exclusivity, Spectrum was not entitled to notice and an opportunity to be heard before the agency approved Sandoz’s ANDA.

Hopefully the Circuit Court’s panel decision marks the end of the matter, though we’ll be waiting intently to see if a petition for rehearing/rehearing en banc is filed in the coming weeks.