The American Conference Institute’s (“ACI’s”) 11th annual “Paragraph IV Disputes” conference is right around the corner! The conference will take place from April 24-26, 2017 at the Conrad New York in New York, NY. 

ACI has put together an excellent program for conference attendees that includes presentations from esteemed Judges and key representatives from the FDA, PTO, and the FTC. In addtion, attendees will get to hear from a virtual “who’s who” of Hatch-Waxman litigators and industry decision makers.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, along with Maryll W. Toufanian, Deputy Director of the Office of Generic Drug Policy, FDA, and Margaret J. Sampson, a Partner at Baker Botts L.L.P., will be speaking at a Q&A session on FDA’s October 2016 final rule implementing certain portions of the December 2003 Medicare Modernization Act (see our previous post here).

FDA Law Blog is a conference media partner. As such, we can offer our readers a special discount off the current price tier.  The discount code is: P10-999-FDAB17.  You can access the conference brochure and sign up for the event here.

 We look forward to seeing you at the conference. 

Cue up Neil Sedaka’s 1962 hit “Breaking Up Is Hard to Do,” or, for some of us younger-minded folk, take your pick from one of many Taylor Swift songs (“We Are Never Ever Getting Back Together,” “I Knew You Were Trouble,” and so many more).  What could break-up songs have to do with the Orange Book, you ask?  More than you think!

We try hard not to judge a book by its cover (though that can be difficult given the subject matter here). Instead, we try to look at the substance behind the cover.  And when you do, you realize that there’s a lot of information packed into the 1,400 pages of the current annual print edition of the Orange Book (and just as much information, though organized a bit differently, in the electronic and app versions of the publication).  But, despite all of that information, the Orange Book has her secrets.  During this blogger’s long relationship with the Orange Book, she has revealed (or let us discover) some of her hidden secrets.  Perhaps her biggest secret – and one that has frustrated us at times, sometimes causing a rift in the relationship, and delighted us at other times, bringing us closer together – is that some product listings are more than they appear.  It’s a result of historical baggage.

Beginning with the publication of the 23rd (2003) edition of the Orange Book, FDA clarified that certain injectable drug products should be identified in the publication on a strength-by-strength basis. This clarification (which we’ve noted before in the context of PDUFA user fees) states, in relevant part (in the current 37th [2017] edition of the Orange Book):

Consistent with the definition of strength included in Section 1.2,Therapeutic Equivalence-Related Terms, the strength of parenteral drug products generally is identified by both the total drug content and the concentration of drug substance in a container approved by FDA. In the past, the strength of liquid parenteral drug products in the Orange Book has not been fully displayed.  Rather, the strength of liquid parenteral drug products in the Orange Book has been displayed in terms of concentration, expressed as xmg/mL.  Generally, the amount of dry powder or lyophilized powder in a container is identified as the strength, expressed as xmg/vial.

With the finalization of the Hatch-Waxman Amendments that characterized each strength of a drug product as a listed drug, it became evident that the format of the Orange Book should be changed to reflect each strengthof a parenteral solution. To this end, the Orange Book now displays the strength of all new approvals of parenteral solutions.  Previously, we would have displayed only the concentration of an approved parenteral solution, e.g. 50mg/mL.  If this drug product had a 20 mL and 60 mL container approved, we would now display two product strengths for this product, listing both total drug content and concentration of drug substance in the relevant approved container, e.g. 1Gm / 20mL (50mg/mL) and 3Gm / 60mL (50mg/mL).

But while new products – injectables and other products, like those in metered doses – are broken out and displayed in the Orange Book on a strength-by-strength basis, older products generally are not . . . at least not until there’s a need for FDA to clarify the Orange Book. Let’s use an example:

Drug X was approved under NDA 999999 on January 2, 2000 in multiple strengths and was listed in the Orange Book as follows:

ACTIVE INGREDIENT

INJECTABLE; INJECTION

DRUG X

KK COMPANY

    2.5MG/ML    NDA 999999  001    Jan 2, 2000

    5MG/ML      NDA 999999  002    Jan 2, 2000

    10MG/ML    NDA 999999  003    Jan 2, 2000

    20MG/ML    NDA 999999  004    Jan 2, 2000

The “How Supplied” section of the prescribing information for Drug X describes each product identified above in terms of both concentration and container size (fill volume):

1. 25 mg/10 mL (2.5 mg/mL)
2. 50 mg/20 mL (2.5 mg/mL)
3. 250 mg/100 mL (2.5 mg/mL)
4. 500 mg/200 mL (2.5 mg/mL)
5. 50 mg/10 mL (5 mg/mL)
6. 100 mg/20 mL (5 mg/mL)
7. 500 mg/100 mL (5 mg/mL)
8. 1000 mg/200 mL (5 mg/mL)
9. 100 mg/10 mL (10 mg/mL)
10. 200 mg/20 mL (10 mg/mL)
11. 1000 mg/100 mL (10 mg/mL)
12. 2000 mg/200 mL (10 mg/mL)
13. 200 mg/10 mL (20 mg/mL)
14. 400 mg/20 mL (20 mg/mL)
15. 2000 mg/100 mL (20 mg/mL)
16. 4000 mg/200 mL (20 mg/mL)

Thus, despite the Orange Book showing only 4 separate drug products approved under NDA 999999, there are, in reality, 16 separate drug products approved under NDA 999999 as a result of FDA’s definition of the strength of an injectable drug product as both a function of concentration and container size (fill volume).

Under the scenario above, and depending on the patent estate for Drug X, there might be 16 different opportunities for 180-day exclusivity for an ANDA applicant. . . . or multiple opportunities for a subsequent ANDA applicant to be blocked by a first applicant’s eligibility for 180-day exclusivity. (And that’s why breaking up is hard to do, but sometimes it’s for the best.)  That means generic drug manufacturers need to carefully review not only the Orange Book, but also the “How Supplied” section of the prescribing information for a particular brand-name drug product still identified in the Orange Book with the old concentration-only strength nomenclature.

Time will usually cause the Orange Book to finally reveal the various drug products approved and bundled under a particular NDA. It may start with an entry on FDA’s ANDA Paragraph IV Patent Certifications List that does not appear to comport with an Orange Book drug product listing.  And then FDA may finally update the Orange Book to break-out and identify various sub-drug products when an ANDA for a particular concentration and fill volume is approved (or when a decision on 180-day exclusivity is made).  It’s a bit of a flawed system that probably should be revised so that ANDA applicants have the information necessary to make important drug product submission decisions sooner rather than later.  And FDA might just collect additional PDUFA drug product user fees along the way.

It never ceases to amaze this blogger how a law, like the Hatch-Waxman Amendments, can still generate new fact patterns and controversy after more than 30 years in existence! In today’s post, we look at how one of those new issues arose and how FDA resolved the controversy.

Like so many recent and interesting Hatch-Waxman controversies, the issue arose in the context of an abuse-deterrent drug product – here, Collegium Pharmaceuticals, Inc.’s (“Collegium’s”) NDA 208090 for XTAMPZA ER (oxycodone) Extended-release Capsules. But the controversy surrounding the approval of XTAMPZA ER didn’t concern (at least not initially) the existence of a potentially blocking period of non-patent exclusivity (which is where some new issues have arisen in the context of abuse-deterrent drug products – see our previous post here), but rather the existence of a 30-month patent litigation stay under FDC Act § 505(c)(3)(C). The stay stemmed from a Paragraph IV certification contained in the XTAMPZA ER 505(b)(2) NDA to patents listed in the Orange Book for the listed drug identified in NDA 208090 – i.e., Purdue Pharma L.P.’s (“Purdue’s”) NDA 022272 for OxyContin (oxycodone HCl controlled-release) Tablets.

By way of background, after FDA acknowledged the filing of NDA 208090, Collegium timely provided notice of its Paragraph IV certifications to Purdue and to the owners of certain patents listed in the Orange Book for OxyContin. Purdue and certain patent owners subsequently filed complaints in two district courts alleging patent infringement, and triggering a 30-month stay on the approval of NDA 208090. See Purdue Pharma LP et al. v. Colleaium Pharmaceutical Inc., Case 1:15-cv-00260 (D. Del. Mar. 24, 2015); Purdue Pharma L.P. et al. v. Collegium Pharmaceutical. Inc., Case 1:15-cv-l 1294 (D. Mass. Mar. 26, 2015).  On July 23, 2015, the action filed in Massachusetts was voluntarily dismissed by Purdue, thereby terminating the litigation.  On August 6, 2015, the U.S. District Court for the District of Delaware issued a Memorandum Opinion and Order dismissing the litigation in that jurisdiction for lack of personal jurisdiction.

But then, on October 7, 2015, a funny thing happened . . . . The Delaware District Court issued a Memorandum Order that appears to have vacated the court’s August 6, 2015 Order dismissing for lack of personal jurisdiction patent infringement litigation timely initiated by Purdue.  (We say “appears” because the court’s Order is not expressly characterized as vacating the earlier dismissal order.) The Delaware District Court’s apparent vacatur raised the question of whether or not the previously-terminated 30-month litigation stay was revived. Or, as FDA put it in a Memorandum included in the Approval Package for NDA 208090: “At issue is whether dismissal of a patent infringement action for lack of personal jurisdiction, which is later vacated and transferred to another venue, terminates a 30-month stay of approval of a 505(b)(2) application.”

Collegium (represented by Hyman, Phelps & McNamara, P.C.) argued that the stay was terminated and could not be revived by a subsequent reversal or vacatur. This result, argued Collegium, was dictated by:

(1)       The text of FDC Act § 505(c)(3)(C)(i) (“if before the expiration of [a 30-month stay] the district court decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity), the approval shall be made effective on— (I) the date on which the court enters judgment reflecting the decision.”);

(2)       FDA guidance (“Neither a stay nor reversal of a district court decision finding the patent invalid, unenforceable, or not infringed will have an effect on the approval of the [generic application]. . . .”); and

(3)       FDA and court precedent.  Specifically, a case involving the approval of both an ANDA and a 505(b)(2) NDA for versions of Oxaliplatin Injection (ELOXATIN), which approvals the DC District Court affirmed notwithstanding vacatur of a district court decision of non-nfringement. See Sanofi-Aventis v. FDA, 725 F. Supp. 2d 92 (D.D.C. 2010) (see our previous post here).

FDA, however, disagreed in resolving this case of first impression, and affirmed that the 30-month stay remained in place:

The precise issue here is whether the Delaware district court’s dismissal of the infringement action for lack of personal jurisdiction terminated the 30-month stay, even though the district court later vacated that decision and the patent issues continue to be litigated. We conclude that the stay remains in effect.

As described in the MMA proposed rule, “the statute does not address whether a 30-month stay may be terminated and a 505(b)(2) application or ANDA approved if the court enters an order of dismissal without a finding of patent infringement.” FDA’s general policy has been that a court entry of an order of dismissal, with or without prejudice, of patent infringement litigation that was timely initiated in response to notice of a paragraph IV certification will terminate the 30-month period if the order does not state a finding of patent infringement. In the proposed MMA rule, FDA explained that “[i]t is appropriate that a 30-month stay terminates under these circumstances because the statutory purpose of the stay is to allow time for claims of patent infringement to be litigated prior to approval.”

To our knowledge, FDA has not addressed a case in which the order of dismissal (without a finding of patent infringement) was vacated, and the infringement action giving rise to the 30- month stay remains pending at the time FDA is ready to act on the 505(b)(2) application. Under the unique and specific facts at issue here, we have determined that the 30-month stay remains in effect. The purpose of the above-described general policy is to interpret the statutory ambiguity in section 505(c)(3)(C) in a manner that furthers Congress’ intent — to allow the parties time to litigate claims of patent infringement. As described in the MMA proposed rule, in the common example where the patent owner or exclusive patent licensee dismisses the patent infringement action voluntarily on terms that the court considers proper, and the litigation thereby ends, Congress’ intent is served by terminating the stay. In this case, because the Delaware district court ultimately determined that its dismissal was not proper and the order of dismissal was vacated, and the original infringement action giving rise to the stay remains pending, Congress’ intent is served by considering the stay to be in effect.

As a result of FDA’s decision, the Agency tentatively approved NDA 208090 for XTAMPZA ER, citing the unexpired stay as a basis for the approval action. At that time, there was also a period of unexpired 3-year non-patent exclusivity applicable to OxyContin; however, as FDA noted in the XTAMPZA ER tentative approval letter: “We need not determine at this time whether approval of your 505(b)(2) NDA for XTAMPZA ER would otherwise be blocked by any other drug’s marketing exclusivity expiring before termination of the 30-month stay.”). And that’s a topic we already covered (here).

Litigation between FDA and Ferring Pharmaceuticals Inc. (“Ferring”) over the availability of 5-year New Chemical Entity (“NCE”) exclusivity for Ferring’s colonoscopy preparation, PREPOPIK (sodium picosulfate, magnesium oxide, and citric acid) for Oral Solution (NDA 202535; approved on July 16, 2012), was recently – and quietly – settled by the parties. Although the terms of the settlement have not yet been made public, we think the settlement will have some pretty significant effects on FDA’s consideration of pending ANDAs for multiple drug products.

As we previously reported, in September 2016, Judge Rudolph Contreras of the U.S. District Court for the District of Columbia issued a Memorandum Opinion granting a Motion for Reconsideration filed by Ferring requesting reconsideration of the DC District Court’s March 2016 ruling that FDA’s pre-October 10, 2014 interpretation of the FDC Act’s NCE exclusivity provisions as applied to a newly approved Fixed-Dose Combination (“FDC”) drug product containing an NCE and a previously approved drug, such as PREPOPIK (see our previous post here), was not arbitrary and capricious. Although Judge Contreras initially backed FDA’s decision to deny NCE exclusivity for PREPOPIK, he reversed course after considering several precedents identified by Ferring in the company’s Motion for Reconsideration, and submitted in response to comments mande by Judge Contreras in his March 2016 ruling that “[i]f there were, in fact, situations in which a drug was eligible for five-year [NCE] exclusivity under the FDA’s prevailing interpretation but failed to receive it because of the order in which it was approved, those circumstances might render the FDA’s policy arbitrary and capricious.”  In addition to PREPOPIK, Ferring identified STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets, NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets, ANORO ELLIPTA (umeclidinium bromide; vilanterol trifenatate), and NUVARING (ethinyl estradiol; etonogestrel) as examples that “demonstrate that a single-entity drug substance’s ability to receive five-year exclusivity can turn arbitrarily on the order in which NDAs including that drug substance are approved.”  With those precedents, Judge Contreras had in hand the ammunition necessary to find FDA’s pre-October 2014 interpretation of NCE exclusivity, as applied to PREPOPIK, to be arbitrary and capricious and in violation of the Administrative Procedure Act.

In November 2016, FDA filed a Notice of Appeal with the U.S. Court of Appeals for the District of Columbia Circuit (Case No. 16-5326), and it seemed as though it would be in the hands of the DC Circuit to resolve the issue of NCE eligibility for PREPOPIK, as well as other drugs affected by the outcome of the case, such as Gilead Sciences, Inc.’s (“Gilead’s”) STRIBILD. (Meanwhile, in October 2016, and again in January 2017, Gilead petitioned FDA – see Docket Nos. FDA-2016-P-3312 and FDA-2017-P-1278 – to recognize NCE exclusivity for STRIBILD “and to apply such exclusivity to all subsequently approved drug products that contain any of the new active moieties (elvitegravir and cobicistat) approved” in STRIBILD.)

But then something unexpected happened. . . . On March 14, 2017, FDA filed with the DC Circuit an Unopposed Motion for Voluntary Dismissal.  The DC Circuit dismissed the case in a March 17, 2017 Order, and also issued its Mandate that same day.

Although we have not yet seen anything to indicate why, or under what terms, the case was voluntarily dismissed, we strongly suspect that FDA agreed to award Ferring 5-year NCE exclusivity for PREPOPIK. That also very likely means that any other similarly situated NDA holder will be awarded NCE exclusivity, such as Gilead for STRIBILD.  We should have confirmation soon, and perhaps in April with an update to the Orange Book.

But resetting the exclusivity periods for PREPOPIK, STRIBILD, and other drugs products is going to cause FDA’s Office of Generic Drugs (“OGD”) and affected ANDA applicants some big headaches. ANDAs under review for generic PREPOPIK have been in-house at OGD since May 2014, and ANDAs for generic versions of Gilead’s TYBOST (cobicistat) Tablets (NDA 203094) were first submitted to FDA in December 2015.  FDA even tentatively approved one ANDA – ANDA 205743 – for generic PREPOPIK on November 21, 2016.

Affected ANDA applicants will likely receive correspondence from OGD providing guidance on the path forward in light of FDA’s decision to recognize NCE exclusivity for affected FDC drug products. Presumably, ANDAs will need to be withdrawn and resubmitted to FDA. But will it be a race to resubmission for ANDA Paragraph IV applicants to secure first applicant status (and thus eligibility for 180-day exclusivity)? Or will FDA backdate ANDA submisions to the so-called NCE-1 dates (e.g., July 16, 2016 for generic PREPOPIK, and August 27, 2016 for generic TYBOST) so that previous first-filers don’t lose their place in line? We’ll see.

Antibiotic-resistant bacteria are claimed to be one of the biggest threats to global health, sickening an estimated 2 million people in the United States each year. There is evidence that some resistance in bacteria is caused by antibiotic use in food animals (cattle, poultry, swine). In the last decade, federal agencies including FDA and APHIS, have taken a number of actions addressing the use of medically important antibiotics in food animals.

Medically important antibiotics are antibiotics that are used in both animals and humans and that are important to treat human infections. Two federal departments are involved in ensuring the safe use of antibiotics in food animals, HHS (primarily FDA) and USDA (primarily APHIS and FSIS). FDA approves and regulates the manufacture and distribution of antibiotics use in food animals and FSIS and APHIS collect information about antibiotic use and resistance in food animals.

In 2011, GAO reported on antibiotic use and identified major gaps in data collection. On March 16, 2017, GAO issued an update. For the update, GAO examined actions by HHS (FDA) and USDA since 2011 to manage the use of antibiotics in food animals and to assess the impact of these actions, actions in other countries, and the extent to which HHS and USDA have conducted on-farm investigations regarding outbreaks from antibiotic-resistant pathogens in animal products.

GAO notes that HHS has made significant progress in veterinary oversight of medically important antibiotics. Actions by FDA include issuance of voluntary guidance to industry and revisions to the veterinary feed directive regulation (here, here, and here). According to FDA, as of January 2017, medically important antibiotics in feed and water of food animals may be used only under the supervision of a veterinarian. (FDA actions did not address oversight of antibiotics administered in injections or through other routes). However, data collection continues to be an issue. FDA has no measures to assess the impact of these actions. Thus, FDA cannot assess whether it is achieving its objective of ensuring judicious use of medically important antibiotics in food animals. Another “gap” identified by GAO is the use of long-term and open-ended use of medically important antibiotics for disease prevention.

In 2016, FDA issued a request for comments regarding the establishment of duration of medically important antimicrobial drugs that currently do not have a duration limitation. The comment period closed March 13, 2017, i.e., just before the GAO report was issued. FDA received a significant number of comments opposing a limit to duration of these drugs.

GAO noted improvements in collecting and reporting data on antibiotics. However, GAO believes that the agencies should have a joint effort to further assess the relationship between the use of antibiotics and antibiotic resistance. Although the agencies have developed a joint data collection plan, lack of funding may hinder the execution of this plan.

GAO reviewed programs to manage the use of antibiotics in food animals in the Netherlands, Canada, Denmark, and the European Union (EU). The programs in those countries and in the EU have resulted in a reduction in the use or sales of antibiotics. However, it is unclear whether the actions taken by those countries would be successful in the US. According to GAO, some U.S. federal officials and stakeholders believe that similar U.S. actions are not feasible because of production differences and other factors.

GAO makes a number of recommendations, including that HHS address oversight gaps, HHS and USDA develop measures to assess success or effectiveness and progress of the actions, and that USDA and HHS develop a framework to decide when to conduct on-farm investigations.

USDA agreed with GAO’s recommendations. HHS neither agreed nor disagreed because the incoming HHS transition personnel had insufficient time for review.

In response to the report, U.S. Senators Kirsten Gillibrand (D-N.Y.), Dianne Feinstein (D-Cal.), and Elizabeth Warren (D-Mass.) and U.S. Representatives Rosa DeLauro (D-Conn.) and Louise Slaughter (D-N.Y.) sent a letter to HHS and the USDA urging increased collaboration and oversight to reduce the inappropriate use of medically important antibiotics in food animal production. They ask for prompt answers to issues raised by GAO.

One and a half years since FDA first proposed changes, two months since the final rule was published, one month after objections threatening an Administrative Procedure Act challenge, and one day before the rules would have taken effect, FDA announced on Monday that it would delay its amendments to the regulations regarding “intended use.” Rather than implement the final rule by March 21, 2017, FDA announced it would delay the effective date until March 19, 2018, and even implied there might be a final rule issued “after” the 1-year delay.  82 Fed. Reg. 14319, 14323 (Mar. 20, 2017).

Why so much hubbub about what evidence can be used to discern “intended use”? Because FDA’s authority to regulate a product as a drug or device hinges on whether the product is intended to be used to diagnose, cure, mitigate, treat, or prevent disease.  A famous analogy is water.  If water is intended to quench thirst at mealtimes, it is not considered to be a drug.  If water is intended to cure cancer, then FDA believes it can regulate the claims being made by the water bottler, inspect the manufacturing facilities, take enforcement action, and potentially impose criminal penalties.  So a product’s “intended use” matters, and what evidence can be used to glean intended use can have a significant impact on whether the government can regulate the product and its manufacturer.

In 2015, FDA proposed revising the intended use regulations at 21 C.F.R. §§ 201.128 and 801.4, to remove objectionable language that imputed knowledge to a manufacturer of external uses: “But if a manufacturer knows, or has knowledge of facts that would give him notice, that a [drug or device] introduced into interstate commerce . . . is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug/device which accords with such other uses to which the article is to be put.”  This deletion was favorably received by companies who did not believe it fair to impose requirements on a manufacturer based on the uses of a product over which it did not have control.

Yet as reported here, rather than delete the standard in its final rule, FDA inserted new language that added a different standard to the calculus:  “And if the totality of the evidence establishes that a manufacturer objectively intends that a device [or drug] . . . is to be used for conditions, purposes, or uses other than ones for which it has been approved, . . . he is required . . . to provide for such device [or drug] adequate labeling that accords with such other intended uses.”  Pharmaceutical groups quickly filed a Citizen Petition asking FDA to reconsider the language in the final rule or indefinitely stay the rule.

On March 20, 2017, FDA acquiesced to the request for stay, and agreed to delay the effective date of the rule to invite public comment on the issues raised in the petition and the specific questions FDA posed in its notice.  Interestingly FDA asserted that it is “impracticable, unnecessary, and contrary to the public interest” to solicit public comment on the delay itself, but agreed to “accept public comments for a period of 60 days on whether this rule delaying the effective date should be modified or revoked.”  82 Fed. Reg. at 14321.  It is unknown on what grounds one could object to the delayed effective date of such a controversial rule given the important open issues that FDA admits remain in the final rule.

In addition to the issues raised by the Citizen Petition, FDA specifically solicits comments on the following issues:

1. How should FDA consider situations where companies distribute medical products without explicit promotional claims?
2. What are the potential public health consequences that should be evaluated in determining intended use?
3. How do First Amendment considerations apply to the use of non‑speech evidence in determining intended use, such as the circumstances surrounding the distribution of a product?
4. Is there a distinction between language permitting consideration of “any relevant source of evidence” and “the totality of the evidence”?

With respect to number 4, FDA claimed that the “totality of the evidence” standard is not a change in FDA’s approach regarding evidence of intended use. FDA cited to the preamble to the original proposal in which FDA claimed it set forth the standard that FDA may look to “any relevant source of evidence.”  82 Fed. Reg. at 14320, citing 80 Fed. Reg. 57756, 57757 (Sept. 25, 2015).  This clause, however, appears nowhere in the preamble.  Instead, there are citations to several court opinions that enumerate the types of information from which FDA can determine the objective intent of the person responsible for labeling the product.  All of the examples cited in the preamble already are specified in the intended use regulations (e.g., labeling, promotional claims and advertising, oral or written statements by a manufacturer or its representatives, and circumstances surrounding the distribution or sale of a product).  FDA’s addition of a sentence that includes an “any relevant source of evidence” standard or a “totality of evidence” standard renders the preceding language in the intended use regulations superfluous and unnecessary.

As FDA notes, these issues overlap with the parallel docket in which FDA is considering communications about unapproved uses of approved/cleared medical products, discussed here.  That docket is open until April 19, 2017; this docket will accept both substantive comments as well as comments on the decision to delay the rule until May 19, 2017.  Thus FDA encourages commenters to submit feedback in both dockets.

A final regulation implementing the 340B Drug Discount Program has been caught in the regulatory freeze. In the waning days of the Obama Administration, the Health Resources and Services Administration (“HRSA”) of HHS issued a final regulation describing the methodology for calculating the 340B ceiling price (including so-called penny pricing) and to establish civil monetary penalties for knowing and intentional overcharges of 340B covered entities.  We posted on that regulation here. It originally had a March 6, 2017 effective date, but the preamble stated that enforcement was not to begin until the beginning of the second quarter – i.e., April 1, 2017.

Pursuant to the new administration’s regulatory freeze (see our previous post here), HRSA postponed the effective date until March 21, 2017, but that postponement did not affect the April 1 enforcement date.  However, yesterday, HRSA issued an interim final rule further postponing the effective date until May 22, 2017, and inviting comment on whether the effective date should be even further delayed until October 1, 2017. Comments must be submitted by April 19, 2017.  HRSA explained that the additional delay was necessary to consider questions of fact, law, and policy raised in the rule, consistent with the regulatory freeze memorandum, and to provide regulated entities more time to implement changes necessary to comply with the Final Rule.

On Monday, March 27, FDA and the Society of Toxicology (SOT) will present a colloquium (chaired by Bernadene A. Magnuson, PhD, Health Science Consultants, Inc., and Sabine Francke, DVM, PhD, CFSAN FDA) on Considerations for the Determination of Adversity in Food Chemical Safety Evaluations, the seventh in a series of colloquia titled Emerging Toxicological Science: Challenges in Food and Ingredient Safety.  The colloquia are intended to inform the work of FDA employees, but are open to the public free of charge.  This colloquium begins at 8.30 a.m. featuring the following presentations, and concludes with a panel discussion at around 11:50 a.m. followed by lunch at 1 p.m.

• Adversity into Regulatory Science: Historical Perspective and Future Challenges – Nigel Walker, PhD, DABT, National Institute of Environmental Health Sciences, Research Triangle Park, NC
• When Is Adversity Legally Cognizable? – Ricardo Carvajal, JD, MS, Hyman, Phelps & McNamara PC, Washington, DC
• No Observed Adverse Effect Level: Sucralose As a Case Study – Bernadene A. Magnuson, PhD, Health Science Consultants, Inc., Mississauga, ON, Canada
• New Approaches to Adversity Assessment in Food Safety Evaluation – Daniel Krewski, PhD, MHA, University of Ottawa, Ottawa, ON, Canada

Although registration to attend the colloquium in person is now closed, registration for the webcast is still available here.

On March 15-17, 2017, the American Society for Experimental Neurotherapeutics (ASENT) held its 19th Annual Meeting in Rockville, MD. The meeting brought together clinical investigators, pharmaceutical industry sponsors, officials from drug regulatory agencies, and patient advocacy organizations to address and advance the science of neurotherapeutics.

On Wednesday, March 15th, Hyman Phelps, & McNamara’s (HP&M’s) Frank J. Sasinowski presented on regulatory innovations in neurological disorder therapies, including discussing the recent approvals of Spinraza for SMA and Exondys 51 for DMD. His presentation highlighted issues and opportunities related to:

• Role of patient advocates in the drug approval process;
• Reliance on historically-controlled trials in rare diseases;
• Cumulative distribution as a means to establish clinical meaningfulness; and
• Use of Accelerated Approval in neurological diseases.

Slides from Frank Sasinowski’s presentation are available here.

On Friday, March 17th, HP&M’s Kurt R. Karst presented on repurposing drugs, including providing an overview of the regulatory pathways for repurposed drugs, legislative attempts o address repurposing (e.g., the OPEN Act), and the current environment surrounding orphan drugs and drug repurposing. Late breaking topics discussed included the proposed OPEN Act and the recent Congressional inquiry into potential abuses of the Orphan Drug Act (see our previous post here).  Slides from Kurt Karst’s presentation are available here.

Oh Canada! Congress has decided that it’s once again time to start looking to our neighbors to the north for some help increasing accessibility and decreasing cost of prescription drugs.  With two new bills introduced in the last month, one in each chamber of Congress, it seems that congressional Democrats are hoping to import more than just hockey and Tim Horton’s from Canada.

On February 28, 2017, Senators Bernie Sanders, Cory Booker, and Bob Casey introduced S. 469, the “Affordable and Safe Prescription Drug Importation Act.” (A companion bill was introduced in the House of Representatives – H.R. 1245 – by Representative Elijah Cummings.) Designed to help lower the cost of prescription drugs by allowing Americans to import medicine from Canada, S. 469 would amend FDC Act § 804 to direct FDA to promulgate regulations facilitating the importation of “qualifying prescription drugs” from “certified foreign sellers” in Canada and other permitted countries into the U.S.  The bill has lengthy definitions of “qualifying prescription drugs” and “certified foreign sellers,” but in short, the bill allows importation of drugs approved in Canada that comply with FDA GMPs (other than controlled substances, inhaled drugs for surgery, and compounded drugs) to be imported foreign wholesale distributors or licensed pharmacy operators certified by FDA to meet certain conditions. Eventually, FDA may open up importation of drugs from OECD countries with comparable legal standards for approval.

H.R. 1480, introduced in the House of Representatives by Chellie Pingree of Maine as the “Safe and Affordable Drugs from Canada Act of 2017,” introduces similar, but much less detailed legislation. H.R. 1480 amends the FDC Act to permit for importation a 90 day or less supply of prescription drugs from Canada for personal use only.  The drugs must be purchased from an approved and certified Canadian pharmacy with a valid prescription from a health care provider licensed in the U.S.  More products are excluded under H.R. 1480 than S. 469, as H.R. 1480 explicitly excludes controlled substances, biologics, infused drugs, intravenously injected drugs, inhaled drugs for surgery, parenteral drugs, biotechnology-processed products (i.e. therapeutic DNA plasmid products, monoclonal antibody products, therapeutic synthide peptic products with fewer than 40 amino acids, and recombinant DNA-derived products), and refrigerated products from importation.  Senator John McCain’s S. 92, an almost identical bill, was introduced in the Senate in January 2017.

While both bills introduce some questions about supply chain accountability, they both reflect a fairly simple way to reduce drug prices while the rest of Congress fights it out over coverage. Similar efforts have failed in the past (see Sen. McCain’s version introduced in 2015 that went nowhere), but with the Congressional Budget Office projecting that millions of Americans may become uninsured with the repeal of the Affordable Care Act, this bill might see some action this year. Like we’ve had to say a lot this year: we’ll just have to wait and see what happens. . . . Eh?

There are many things that are unique to the 505(b)(2) NDA approval pathway. Some are good and some are . . . well, let’s just say that they have proven to be frustrating for  some 505(b)(2) applicants.   Perhaps one of the most nettlesome aspects of the 505(b)(2) NDA pathway arises by operation (or should we say by lack of operation?) of FDC Act § 505A(o), which is part of the Best Pharmaceuticals for Children Act (“BPCA”).

FDC Act § 505A(o), titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage Provision” (or Section 11 of the BPCA), allows an ANDA applicant to omit from its labeling certain patent- and/or exclusivity-protected information concerning the pediatric use of a drug, and to include a disclaimer with respect to the omitted information. (Such a disclaimer might state: “Pediatric use information is approved for [COMPANY’S BRAND-NAME DRUG]. However, due to [COMPANY’S] marketing exclusivity rights, this drug product is not labeled with that pediatric information.”)  Specifically, FDC Act § 505A(o) states:

(1) GENERAL RULE.— A drug for which an application has been submitted or approved under section 505(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 502 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 505(j)(5)(F) of this title.

(2) LABELING.— Notwithstanding clauses (iii) and (iv) of section 505(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 505(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.

(3) PRESERVATION OF PEDIATRIC EXCLUSIVITY AND OTHER PROVISIONS.— This subsection does not affect—

(A) the availability or scope of exclusivity under this section;

(B) the availability or scope of exclusivity under section 505 for pediatric formulations;

(C) the question of the eligibility for approval of any application under section 505(j) that omits any other conditions of approval entitled to exclusivity under clause (iii) or (iv) of section 505(j)(5)(F); or

(D) except as expressly provided in paragraphs (1) and (2), the operation of section 505.

We’ve seen FDC Act § 505A(o) come into play before, and sometimes in court. The provision was at issue in litigation over generic CRESTOR (rosuvastatin calcium) (here and here) and generic ABILIFY (aripiprazole) (see our previous post here).

At this point you may be asking: “Why are you discussing 505(b)(2) NDAs in the context of a provision that concerns only ANDAs?” After all, FDC Act § 505A(o) is titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling” (emphasis added), and there’s no indication that FDA raised any concerns with the provision in a report submitted to Congress in July 2016.  But that’s precisely the point!  FDC Act § 505A(o) does not address 505(b)(2) NDAs.  The BPCA neither addresses the carve-out or retention of protected pediatric information from 505(b)(2) product labeling, nor does the BPCA address the use of disclaimers for protected pediatric use information that is carved-out of 505(b)(2) product labeling.

If FDA determines that the protected pediatric information is important safety information, and therefore, must be retained in 505(b)(2) product labeling for reasons of safe use, then a full approval for the affected 505(b)(2) product cannot be issued until pediatric exclusivity has expired. Instead, FDA could issue only a tentative approval, with final approval dependent on the expiration of exclusivity applicable to pediatric labeling information.  This is true regardless of how close a 505(b)(2) NDA product may be to an ANDA drug product (and which ANDA could be approved by operation of FDC Act § 505A(o)).  For example, a drug product that is essentially a generic version of a brand-name listed drug, but that is submitted under a 505(b)(2) NDA simply by virtue of the sponsor’s use of a so-called “non-exception excipient,” thus precluding ANDA submission (see our previous post here), may be blocked from obtaining final approval because FDC Act § 505A(o) does not accommodate 505(b)(2) NDAs.

With the growing popularity of 505(b)(2) NDAs, which the Tufts Center for the Study of Drug Development recently assessed, the inability of a 505(b)(2) NDA applicant to obtain final approval because of protected pediatric information is on the rise. We sifted through several 505(b)(2) NDA approval packages and found quite a few FDA assessments concerning the ability (or inability) of a 505(b)(2) applicant to omit protected pediatric information.  Sometimes FDA concluded that the 505(b)(2) NDA could be approved with a labeling carve-out, and sometimes FDA determined that only tentative approval could be granted because FDC Act § 505A(o) does not apply to 505(b)(2) NDAs.  Here’s a rundown of the FDA assessments we found:

• NDA 022312 – Docetaxel Injection (Approved on January 11, 2012)
• NDA 201811 – Argatroban Injection (Approved on March 23, 2015)
• NDA 207963 – Palonosetron HCl Injection (Approved on August 22, 2016)
• NDA 203049 – Argatroban Injection (Approved on January 5, 2012)
• NDA 201743 – Argatroban Injection (Approved on May 9, 2011)
• NDA 022485 – Argatroban Injection (Approved on May 9, 2011)
• NDA 022434 – Argatroban Injection (Approved on June 29, 2011)
• NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Approved on June 25, 2012)
• NDA 200795 – Gemcitabine Injection (Approved on August 4, 2011)

We also came across some 505(b)(2) NDA tentative approval letters containing the standard language regarding exclusivity (i.e., “The listed reference drug product upon which you based your application is subject to a period of exclusivity protection and therefore final approval of your application under section 505(c)(3) of the Act (21 U.S.C. 355(c)(3)) may not be made effective until the period has expired.”) that we suspect is related to a period of pediatric exclusivity and where FDA has determined that a carve-out is not permissible:

• NDA 022359 – Argatroban Injection (Tentatively Approved on July 28, 2010)
• NDA 205122 – QUDEXY XR (topiramate) Extended-release Capsules (Tentatively Approved on April 15, 2016)
• NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Tentatively Approved on August 18, 2016)
• NDA 208645 – Bortezomib Injection (Tentatively Approved on October 20, 2016)

Congress is currently debating reauthorization of the Prescription Drug User Fee Act. As part of that process, Congress will likely also consider other changes to the law, including changes to provisions applicable to pediatric drug development (see, e.g., S. 456/H.R. 1231, the Research to Accelerate Cures and Equity for Children Act). Should another one of those issues for consideration be whether or not FDC Act § 505A(o) should be amended to accommodate 505(b)(2) NDAs.

On March 14, in the Federal Register, FDA published a list of Class II devices that the agency proposes exempting from the 510(k) requirements. A copy of the Federal Register notice can be found here. As you may recall from our earlier post, Section 3054 of the 21^st Century Cures Act required FDA to publish such a list for public comment. Under this new law, FDA is required to publish such a list once every five years beginning this year.

The proposed list is quite extensive. However, many of the devices on the list are already informally exempt.  In 2015, FDA published a final guidance, “Intent to Exempt Certain Unclassified, Class II, and Class I Reserved Medical Devices from Premarket Notification Requirements,” listing numerous unclassified, Class I, and Class II devices that FDA believed qualified for 510(k) exemption.  The Class II devices from this final guidance now appear on FDA’s proposed list for public comment.  Thus, much of this proposed list is unenlightening.

There are, however, a number of new devices on the list including a large list of in vitro diagnostic (IVD) devices, such as gene expression profiling reagents and DNA genetic analyzers.  FDA has also proposed exempting high-throughput genomic sequence analyzer for clinical use.  All of these examples are relatively new devices.

Perhaps the most notable proposed exemption, however, relates to drugs of abuse tests. FDA has proposed exempting virtually all drugs-of-abuse testing including those performed by traditional screening methods such as enzyme immunoassay and radioimmunoassay, and newer confirmatory methods such as mass spectrometry and gas chromatography.  The proposed exemption includes not just professional use tests, but also some over-the-counter tests.

The proposed exemption for drugs-of-abuse test systems is limited to “test systems intended for employment and insurance testing and does not include test systems intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military.)”

By regulation, FDA regulates drugs-of-abuse testing devices are intended for use “in the diagnosis and treatment of [drug] use or overdose” (see, e.g., 21 C.F.R. § 862.3250(a) (cocaine and cocaine metabolite test system)) and in some instances “in monitoring levels of [drug] to ensure appropriate therapy” (see, e.g., 21 C.F.R. §§ 862.3150(a) (barbiturate test system), 862.3170(a) (benzodiazepine test system)).

FDA has carved out a narrow exception to regulatory oversight of drugs-of-abuse test systems, in which FDA exercises enforcement discretion over tests used solely for forensic (law enforcement) purposes, “because there are protections to ensure sample integrity and test accuracy that are not generally available in the home, workplace, insurance and sports settings” including the rules of evidence in judicial proceedings.”  See 65 Fed. Reg. 18,230, 18,230 (Apr. 7, 2000) (here).

The regulatory scheme for drugs-of-abuse test systems have been a bit of a regulatory mystery for some over the years. Warning letters have asserted that test systems intended for workplace drug testing does not qualify as exempt forensic testing.  See, e.g., FDA, Warning Letter to American Bio Medica Corp. (July 30, 2009) (this warning letter also led to a 2013 Consent Decree relating to drugs-of-abuse tests for workplace testing requiring 510(k) clearance); and FDA, Warning Letter to Branan Medical Corp., Inc. (Dec. 28, 2009).  FDA’s proposal suggests that the Agency now considers employment and insurance testing to be of sufficiently low risk that they may warrant 510(k) exemption.

The proposed exemption for insurance and employment testing is separate from the forensic testing carve out. One notable difference is that forensic drugs-of-abuse tests are not subject to any FDA regulatory oversight under FDA’s enforcement discretion whereas the new proposal would only exempt workplace and insurance tests from the 510(k) requirements.  Workplace and insurance drugs-of-abuse tests (along with manufacturers of other devices on the proposed exemption list) will still be required to comply with all other applicable FDA regulatory requirements, including the design controls, to the extent applicable, MDR reporting, and reporting corrections and removals.  Manufacturers of such devices will also continue to be subject to FDA inspections.

If finalized, the exemptions, including the drugs-of-abuse tests would still be subject to the .9 limitations, which requires a manufacturer to obtain 510(k) clearance for an exempt device type, if (i) the device is intended for a use different from the intended use of a legally marketed device in that generic type of device, (ii) the device operates using a different fundamental scientific technology than a legally marketed device in that generic type of device, or (iii) if it falls within a certain category of IVDs. FDA will be accepting comments on the proposed list of devices for 510(k) exemption for the next 60 days.

On Friday, Amgen submitted its Opening and Response Brief at the Supreme Court in the matter of Sandoz v. Amgen, Nos. 15-1039, 15-1195.  The brief addressed two major questions with respect to the BPCIA: when an applicant can provide 180-day notice of biosimilar marketing and whether the applicant is required to participate in BPCIA’s version of the patent dance.  Amgen vehemently argues that notice is appropriate only after licensure and that participation in the patent dance is mandatory.  Should the Court not agree with Amgen’s interpretation of the BPCIA, Amgen envisions “chaos” in the biosimilar world.

None of Amgen’s arguments here are new, as this matter was extensively litigated in the lower courts (see our previous coverage here, here, here, and here).   Amgen argues that parties must participate in the patent dance for the statute to have its intended effect and that notice can come only after licensure to ensure time to efficiently enforce its patents.  Amgen emphatically reasons that the proper result is obvious, as it both reflects the statute’s text and structure and it better promotes the statutes purpose.

Based on the text and structure of § 262(l)(8)(A), Amgen contends that the Federal Circuit correctly held that applicants provide post-licensure notice at least 180 days before marketing.  Referring to a product that has already been “licensed” by FDA, Amgen argues that the statute’s text is clear that notice can be submitted only after licensure.  But more important to Amgen’s “chaos” theory put forth in the brief, the structure of § 262(l)(8)(A) confirms that notice must be post-licensure.  Section § 262(l) creates two phases of patent litigation: an immediate action for those patents appropriate for early litigation and a secondary action for all remaining patents and patents later acquired or licensed by the sponsor.  According to Amgen, the marketing notice triggers the start of the second phase of litigation by lifting the bar on declaratory-judgment and preliminary injunction actions.

In the Response portion of the brief, Amgen argues that the patent dance is mandatory because there is no reason to deviate from the typical meaning of the word “shall.” Just because the statute explicitly contemplates an applicant’s noncompliance by permitting the sponsor to bring legal action for failure to comply does not indicate that the compliance with the statute is optional.  This interpretation is consistent with the statutory purpose and legislative history of the BPCIA.  Congress rejected a permissive statute in an earlier proposal of the BPCIA, but elected the mandatory language in the final version of the bill.

We raised questions in a previous post about the practicality of the patent dance under the BPCIA if it is indeed voluntary, and Amgen’s brief certainly emphasizes these concerns. Amgen argues that Sandoz’s interpretation of the BPCIA would require reference product sponsors to sue on every conceivable relevant patent in order to protect its patent rights. Without exchange of product information, the reference product sponsor has no way of knowing which patents are implicated.  And if an applicant could choose not to provide required disclosures and refuse to provide 180 days’ notice of commercial marketing, the sponsor could only enforce its patent rights through emergency injunctive relief after licensure.  Couched in its chaos theory, Amgen argues that Sandoz’s interpretation would negate the “process” that the BPCIA was intended to introduce. Instead, Amgen believes that reference product sponsors will just have to close their eyes and sue without any knowledge of actual infringement.

The U.S. Government Accountability Office (GAO) recently issued a January 2017 report to the Senate Committee on Health, Education, Labor, and Pensions.  The GAO report examines:

• The steps FDA has taken to encourage the development of antibiotics to treat serious or life-threatening infections since the enactment of title VIII of the Food and Drug Safety and Innovation Act, which is commonly referred to as the Generating Antibiotic Incentives Now (GAIN) provisions; and
• Drug sponsors’ perspectives on FDA’s efforts to encourage the development of antibiotics to treat serious or life-threatening infections since the enactment of GAIN.

GAO analyzed FDA data on requests for QIDP designation since the enactment of the GAIN provisions as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) on July 9, 2012 through December 31, 2015. GAO also interviewed ten industry sponsors on FDA’s efforts to encourage the development of antibiotics to treat serious or life-threatening infections since July 9, 2012.

GAO’s report provides a helpful overview of the QIDP program, an accounting of the drugs that have been granted QIDP designation, and findings related to FDA’s antibiotic development guidance documents. GAO also issued two recommendations, discussed below.

GAO Recommendations/FDA Response

Key Findings

• Since 2012, FDA has granted 101 of 109 (93%) requests for QIDP designation.
• Despite their eligibility, many drug sponsors with QIDP designation have not applied for fast track designation. Of the 101 QIDP-designated products, sponsors submitted only 61 (60%) requests for fast track designation. FDA granted all 61 (100%) of these requests.
• Six drugs with QIDP designation have been approved (see table below).

Drugs Approved with QIDP Designation

* ABSSSI = acute bacterial skin and skin structure infections; IAI = intra-abdominal infections; UTI = urinary tract infections

Additional Findings

• QIDP designation typically increased communication between FDA and sponsors and expedited the review of QIDP-designated drug applications.
• Sponsors noted FDA’s receptivity to considering new approaches to the design of clinical trials for antibiotic products.
• As of August 2016, FDA had coordinated the release of 14 updated or new guidance documents on antibiotic development; however, half of these guidance documents are in draft form.
• Sponsors expressed concerned regarding how much they could rely on FDA’s draft guidance documents and the lack of guidance describing the QIDP designation and its requirements.

Periodically, legislators and others become concerned about reports citing the high price of some orphan drugs, including drugs that achieve blockbuster status (earning more than $1 billion a year). Several proposals have been introduced in response to such concerns.  In 1990, Congress passed legislation that would have limited market exclusivity in some circumstances, but the President vetoed it.

***

Critics in Congress and in the pharmaceutical industry and patient groups say that while the [Orphan Drug Act] has generally worked, it has proved to be a bonanza for the makers of some very big drugs, allowing them to charge higher prices than there would have been with competition.

With all of the recent hubbub around orphan drugs and pricing, you might think the two quotes above were ripped from recent stories. In fact, the first quote is taken from a 2010 Institute of Medicine report, titled “Rare Diseases and Orphan Products: Accelerating Research and Development” (see our previous post here).  The second quote is from an April 1990 article in the New York Times, titled “Orphan Drug Law Spurs Debate.”  The fact that you likely could not identify the age of the quotes above means that we’re in the midst of another one of those “periods” referred to in the IOM report, where legislators take a look at the Orphan Drug Act to decide whether or not changes need to me made to the law.

The latest round of interest started perhaps within the past two years, as legislators began consideration of legislation – the “Orphan Product Extensions Now Act,” or “OPEN Act” – to amend the FDC Act to provide a 6-month extension of exclusivity periods for companies that obtain approval of a previously approved drug for a new, rare condition. (By the by, the OPEN Act was reintroduced in February as H.R. 1223, the “Orphan Product Extensions Now Accelerating Cures and Treatments Act.”)  Then there was an article in the American Journal of Clinical Oncology, titled “The Orphan Drug Act: Restoring the Mission to Rare Diseases,” alleging that companies are “gaming” the orphan drug system established by the Orphan Drug Act “to use the law for mainstream drugs.”  A report from Public Citizen on the OPEN Act, titled “House Orphan Drug Proposal: A Windfall for Pharma, False ‘Cure’ for Patients” (see our previous post here), followed.  Then things calmed down a bit . . . .  until recently.

In January 2017, Kaiser Health News published a report, titled “The Orphan Drug Machine: Drugmakers Manipulate Orphan Drug Rules To Create Prized Monopolies.”  That report caught the attention of Senator Chuck Grassley (R-IA), who stated  that he would explore possible misuses of the orphan drug program.  Then last week, Sen. Grassley (along with Senators Orrin Hatch (R-UT) and Tom Cotton (R-AR)) sent a letter to the Government Accountability Office (“GAO”) requesting certain information (much of which is already publicly available) and an investigation into “whether the [Orphan Drug Act] is still incentivizing product development for diseases with fewer than 200,000 affected individuals, as intended, and provide any regulatory or legislative changes that may be needed in order to preserve the intent of this vital law.”  The letter to GAO states the Senators’ general concern: so-called “evergreening” of orphan drug exclusivity.

While few will argue against the importance of the development of [orphan] drugs, several recent press reports suggest that some pharmaceutical manufacturers might be taking advantage of the multiple designation allowance in the orphan drug approval process.

A review of FDA’s Orphan Drug Designations and Approvals Database shows that there are many, many drugs and biological products with multiple orphan drug designations and/or approvals.  In some cases, there are just a couple of entries on the list for the same drug.  In other cases, such as with Imatinib and Ibrutinib, there are quite a few entries.

In most cases, a single period of 7-year orphan drug exclusivity extends from a single orphan drug designation granted by FDA’s Office of Orphan Products Development. Each designation covers a different orphan disease or condition.  And once the first period of orphan drug exclusivity expires, FDA may be able to approve an ANDA for a generic version of the drug product with labeling that omits information on a subsequent use protected by orphan drug exclusivity.  This carve-out option has been affirmed by FDA in various Letter Decisions and Citizen Petition response, and by the courts – see, e.g., Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F.3d 141 (4th Cir. 2002) (here).

If the reference in the letter to the GAO to “multiple designation allowance” that “some pharmaceutical manufacturers might be taking advantage of” is merely a concern with multiple orphan drug designations that lead to separate grants of orphan drug exclusivity for separate diseases or conditions, then this blogger does not see a particular need for concern. It’s not an evergreening issue at all!  The Orphan Drug Act is working exactly as intended, and generic competition is generally not thwarted because of the ability of an ANDA applicant to carve-out of its labeling (and thus avoid) a period of unexpired orphan drug exclusivity on the brand-name Reference Listed Drug.

But there may be a real evergreening issue that’s probably been overlooked by most folks. In some cases, a single orphan drug designation can result in multiple periods of orphan drug exclusivity.  (A table of examples is provided at the end of this post.)  FDA explained this concept in the preamble to the Agency’s October 2011 proposed orphan drug regulations:

The scope of orphan exclusive approval for a designated drug is limited to the approved indication or use, even if the underlying orphan designation is broader. If the sponsor who originally obtained orphan exclusive approval of the drug for only a subset of the orphan disease or condition for which the drug was designated subsequently obtains approval of the drug for one or more additional subsets of that orphan disease or condition, FDA will recognize orphan-drug exclusive approval, as appropriate, for those additional subsets from the date of such additional marketing approval(s).  Before obtaining such additional marketing approval(s), the sponsor in this instance would not need to have obtained additional orphan designation for the additional subset(s) of the orphan disease or condition. [(Emphasis added)]

In most instances, multiple and staggered periods of orphan drug exclusivity stemming from the same designation do not stymie generic competition. For example, if FDA grants an orphan drug designation for Drug X for Disease Y and the sponsor first obtains approval of the drug for use in adults with Disease Y and then later for the same drug for use in children with Disease Y, FDA would grant two separate periods of orphan drug exclusivity – one for each approval.  An ANDA applicant may obtain approval of the drug for the adult population indication once the initial period of orphan drug exclusivity expires, and then later for the pediatric population indication once that second period of orphan drug exclusivity expires.

But not all cases are as easy as the one above. You see, indications, like Pokémon, can evolve into something new.  There appear to be a growing number of cases where FDA has granted multiple periods of orphan drug exclusivity based on the same original orphan drug designation, and where the drug’s indication evolves into something new, shedding and subsuming the previous indication statement.  This could occur, for example, as different disease stages or different lines of therapy are approved.  (Some possible examples of this might be in the cases of Ibrutinib, Cinacalcet, Bortezomib, and Bevacizumab.)  As the old labeling is shed, the new labeling may not allow for an ANDA (or biosimilar) applicant to easily (if at all) omit information protected by a new 7-year period of orphan drug exclusivity.

But is the solution to what may be a real evergreening problem opening up the Orphan Drug Act? This blogger thinks that there could be a better solution.  If the issue preventing a carve-out is the text of the brand-name drug labeling, then one remedy is to have better communication between the Office of New Drugs (“OND”) and the Office of Generic Drugs (“OGD”) during the course of brand-name drug labeling reviews and drafting.  OGD’s experience with labeling reviews and carve-outs should not be overlooked, and can lead to labeling that does not cause carve-out controversies years down the road.  Another possible remedy is for OGD to take a broader view of permissible labeling changes.  That is, considering so-called labeling “carve-ins” that clarify the omission of other labeling information (and effectively return an indication to its previous state).  It’s a topic FDA raised a few years back (see our previous post here), but that the Agency ultimately decided not to address.

Multiple Orphan Drug Exclusivity Periods Based on a Single Orphan Drug Designation