By Karla L. Palmer –

Following our blogpost describing the four human drug compounding draft guidance documents and draft Memorandum of Understanding (MOU) that FDA released last Friday, FDA formally published the documents in the Federal Register on February 19th.   Interested persons should note the docket numbers in the notices so they can post comments (due 90 days from today for the four draft guidances and 120 days after today’s publication for the draft standard MOU).  FDA also finally withdrew the draft MOU that it issued in January 1999 (to our knowledge no state had signed it).  That 1999 draft, which received over 6,000 public comments, defined “inordinate amounts” as when the number of compounded drugs dispensed or distributed interstate annually is equal to or greater than 20 percent of all drugs dispensed by the facility, and contained other controversial provisions.  Recall that under FDCA Section 503A, states have a choice of either signing an MOU with FDA, or human drug compounders within that state acting pursuant to Section 503A must limit out of state shipments to 5 percent of all prescription orders dispensed or distributed by the pharmacy or physician.  

Concerning the new draft “standard” MOU, FDA consulted with NABP (as statutorily required), and already received 31 public comments on the new MOU after it promulgated draft guidance for Section 503A compounders in December 2013.  FDA reiterated today that it does not intend to enforce the 5 percent limit on interstate distribution of compounded human drug products until after FDA has finalized the MOU and made it available to the states for their consideration and signature.

After considering any comments on the new draft standard MOU, FDA will determine how long it will allow states to “consider whether to sign the [final] MOU before FDA begins to enforce the 5 percent limit in those states that have not signed an MOU.” Nonetheless, the Agency proposes a 180-day period after the final standard MOU is made available for signature.  After that, FDA will enforce the 5 percent limit in States that have not signed the MOU.

The Notice sets forth key provisions of the new draft standard MOU, and compares it to the 1999 version where appropriate.  Some highlights:

Investigation of Complaints — States must investigate complaints related to compounded products distributed out of state, including adverse drug experiences and product quality issues, and take action as necessary to identify public health risks.  States must notify FDA in 72 hours of a “potential public health risk or immediate safety concern,” such as a report of a “serious adverse drug experience” or “serious product quality issue,” and maintain records for three years.  Definitions of these terms, included in the MOU appendix, are taken from relevant sections of FDA’s regulations for manufactured drugs (21 C.F.R.  §§ 310.305 and 314.81).

Unlike the 1999 version, the new MOU is clear that states are only required to investigate complaints for compounds distributed from their state into another state, and are not required to investigate potential FDCA violations.  The new draft MOU also is clear that the types of complaints states should investigate include any adverse drug experience (not just serious adverse drug experiences) and product quality issues that, if left uncorrected, “could lead to potential public health risks or safety concerns.”  FDA states that even “nonserious” adverse drug experiences and product quality issues may be indicative of significant problems at the facility.

Distribution of Inordinate Amounts: “The 30 % Limit” — The new draft MOU requires states to review compounding records during pharmacy inspections to determine whether the physician, pharmacist or pharmacy’s interstate distributions are “inordinate,” and to notify FDA of that determination.  Distributions are “inordinate” if “the number of units of compounded human drug products distributed interstate during any calendar month is equal to or greater than 30 percent of the number of units of compounded and non-compounded drug products distributed or dispensed both intrastate and interstate by such pharmacist, pharmacy, or physician during that calendar month.”  FDA does “not intend to consider” prescriptions dispensed to a patient or patient’s agent where that patient carries the drug across state lines after dispensing at the compounding facility.  Note that the 1999 MOU draft considered a 20 percent total annual interstate limit, and interstate quantities of individual drugs (including different dosage strengths of same active ingredient) could not exceed five percent even if the total distributed interstate was less than the 20 percent.  Unlike the new version, the 1999 draft also excluded from its “inordinate” percentage determination “local” interstate distribution to patients within 50 miles of the compounding pharmacy, and interstate distribution in response to a public health emergency or catastrophic event.  Importantly FDA discussed that a “distribution” now occurs when a compounded drug leaves the facility where it was made, regardless of whether the drug is also deemed to be “dispensed.”

Although comments on the 1999 draft and the 2013 Section 503A draft guidance objected to defining “inordinate” or placing percentage restrictions on interstate distributions, FDA proposed the following reasons for its 30 percent limit definition of “inordinate”:

• Congress imposed strict restrictions on the distribution of drug products compounded under Section 503A to protect the public health and integrity of the drug approval process.
• Congress did not intend for compounders to become manufacturers operating a substantial portion of its business interstate. 
• Congress recognized that Section 503A compounders are primarily subject to state oversight.  States face challenges if substantial amounts of the compounded products are distributed out of state. 
• The 5 percent limit in Section 503A is a “baseline measure,” leaving FDA (with assistance from NABP) to address whether a limit higher than 5 percent would be appropriate, provided states agree to appropriately investigate compounded products distributed outside of the state. 
• FDA currently believes the 30 percent limit balances access with the need to protect the public health and the drug approval system.
• FDA also considered that patients can now obtain compounded human drug products from outsourcing facilities, which may mitigate access concerns.
• Addressing contiguous states, FDA believes that the 30 percent limit on inordinate amounts is “high enough that special calculations to address interstate distribution between contiguous States or over short distances are not needed.”  FDA added that the draft also excludes from the 30 percent limit those patients that carry the dispensed product across state lines.
• The draft does not exclude from the calculation of “inordinate amounts” interstate distributions in response to a public health emergency or catastrophic event. FDA believes the 30 percent limit affords “adequate opportunity for interstate distributions.”  FDA notes that outsourcing facilities “may be able to compound drugs in an emergency and drugs on FDA’s drug shortage list, further mitigating access concerns.”

A few final points.  It is plain from the notice that FDA does not expect to negotiate with states different provisions of the MOU.  It believes that a standard MOU will prevent a patchwork enforcement approach.  FDA also rejected comments seeking to exempt non sterile drug products and home infusion pharmacies from interstate limits.  FDA stated Congress did not exempt particular drugs or entities from the 5 percent limit; FDA believes that the 5 percent limit and the MOU limit on inordinate amounts “are important to distinguish pharmacy compounding from conventional manufacturing in the guise of compounding, and to protect consumers and the integrity of the drug approval process.”  FDA’s efforts to regulate compounding have proven controversial over the years, and many FDA proposals have triggered significant criticisms. The draft MOU is unlikely to be an exception to this pattern.

By Kurt R. Karst –       

Without even knowing what we’re talking about, it’s probably safe to say that any company would immediately answer “Yes!” to the question posed in the title to this post.  But that’s exactly what FDA is asking some ANDA applicants to do to facilitate the creation of a single, shared Risk Evaluation and Mitigation Strategy (“REMS”). 

FDC Act § 505-1 provides FDA with the authority to require a proposed REMS from an NDA sponsor if the Agency determines that such a strategy “is necessary to ensure that the benefits of the drug outweigh the risks of the drug.”  A REMS may include various elements, such as a Medication Guide, patient package insert, and/or communication plan.  In addition, under FDC Act § 505-1(f), FDA may require that a REMS “include such elements as are necessary to assure safe use of the drug, because of its inherent toxicity or potential harmfulness.”  The Elements To Assure Safe Use (“ETASU”) of such a drug include, among other things, certain restricted distribution, procurement, and dispensing systems. 

ANDAs for generic versions of RLDs with an approved REMS must have the same Medication Guide (if there is one) and the same or a comparable ETASU REMS.  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)].  The Secretary 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 the Secretary 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.

ETASU REMS have been a difficult pill for some ANDA applicants to swallow.  Such REMS have resulted in litigation over the ability of some generic drug companies to obtain product sample to conduct bioequivalence testing (see our previous post here).  And once those studies are conducted, the baseline requirement for a single, shared REMS has further complicated things (see our previous post here).

FDA has apparently taken on the role of facilitator in negotiations for a single shared system.  But before FDA will facilitate such negotiations, the Agency is asking ANDA applicants for permission to disclose certain information to the NDA RLD sponsor, and to hold FDA harmless for any repercussions such disclosure might cause.  That’s a lot to ask of an ANDA sponsor. 

A copy of the disclosure letter FDA has been asking ANDA applicants to sign is provided below.  Although it asks for permission to share only the existence of an ANDA number, it’s the following sentence about which folks might have the greatest concern: “FDA may not be able to withhold information and documents containing such information under 5 U.S.C. 552(b)(4) or FDA’s regulations.”  Of course, almost any document an ANDA applicant sends to FDA contains the application number.  So it seems that the potential exists for almost any ANDA correspondence to become public.

FDA Letter to ANDA Applicants     

Instructions to ANDA applicant: Prepare the following disclosure authorization letter on applicants letterhead. Prominently identify the submission containing the disclosure letter with the following wording in bold capital letters at the top of the first page of the submission:

ANDA ###### REMS CORRESPONDENCE

[ANDA NUMBER]
John R. Peters, M.D.
Acting Director, Office of Bioequivalence
Office of Generic Drugs
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

        RE:  FDA Sharing of Non-Public Information concerning [ANDA NUMBER] with [NDA SPONSOR] and ANDA applicants]

Dear Dr. Peters:

On behalf of [ANDA APPLICANT], the applicant of the above-referenced regulated product(s), I authorize the United States Food and Drug Administration (FDA) and its staff to share the information described below with [NDA SPONSOR] and any abbreviated new drug application (ANDA) applicants for [DRUG] for the purpose of facilitating the development of a single shared system REMS for [DRUG].  I understand that the information may contain confidential commercial information within the meaning of 18 U.S.C. § 1905 and 5 U.S.C. § 552(b)(4) that is exempt from public disclosure.  I agree to hold FDA harmless for any injury caused by FDA’s sharing the information with thc parties referenced above.

Information to be shared: The existence of [ANDA NUMBER].  I understand that, after disclosure, FDA may not be able to withhold information and documents containing such information under 5 U.S.C. 552(b)(4) or FDA’s regulations.

Authorization is given to FDA and its staff to disclose the above-mentioned information without deleting confidential commercial information.  As indicated by my signature, I am authorized to provide this consent on behalf of [ANDA APPLICANT] and my full name, title, address, telephone number, and facsimile number is set out below for verification.

Sincerely,
(Signature)
(Printed name)
(Title)
(Telephone & Facsimile Numbers)

By Kurt R. Karst –      

Last year we posted on the possible effect of Inter Partes Review (“IPR”) on the forfeiture of 180-day exclusivity eligibility under the so-called failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) added by the 2003 Medicare Modernization Act.  With no decision yet from the U.S. Court of Appeals for the Federal Circuit on the matter (or from FDA), however, the interplay between IPR and 180-day exclusivity remains an open question.  But in an upcoming law review Note slated for publication this October in the Michigan Law Review, Brian Apel, a law student at Michigan, argues that under the current wording of the statute, IPR – as well as Post-Grant Review (“PGR”) – “will likely prove ineffective for later-filing generics at triggering the failure to market provision.”

By way of background, the Leahy-Smith America Invents Act (“AIA”) created two procedures to replace inter partes reexamination of a patent: IPR and PGR.  Both procedures allow for administrative patent challenge proceedings at the U.S. Patent and Trademark Office (“PTO”) before the Patent Trial and Appeal Board that serve as a parallel or alternative to district court litigation to adjudicate patentability of issued patents.  Whereas PGR is available immediately after patent issuance, IPR becomes available only after the period for PGR has passed. 

The FDC Act’s failure-to-market provisions are one of the six forfeiture provisions added to the statute by the MMA.  Together, the six forfeiture provisions, which borrow heavily from the pre-MMA law, were designed to make the 180-day market exclusivity incentive work more effectively within the Hatch-Waxman framework. 

Under the failure-to-market forfeiture provisions, there must be two events (i.e., “bookends”) to calculate a “later of” event.  The first bookend date (under FDC Act § 505(j)(5)(D)(i)(I)(aa)) is the earlier of the date that is 75 days after ANDA approval or 30 months after ANDA submission.  The other bookend date (under FDC Act § 505(j)(5)(D)(i)(I)(bb)) is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs – two of which are relevant here:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval).”

Another of the six forfeiture provisions – the so-called “collusive agreement” forfeiture provision at FDC Act § 505(j)(5)(D)(i)(V) – addresses the effect on 180-day exclusivity when a first applicant enters into a settlement agreement with the NDA holder and/or owner of the patents listed on the listed drug.  It provides that eligibility for 180-day exclusivity is forfeited if:

The first applicant enters into an agreement with another applicant under this subsection for the drug, the holder of the application for the listed drug, or an owner of the patent that is the subject of the [Paragraph IV certification], the Federal Trade Commission or the Attorney General files a complaint, and there is a final decision of the Federal Trade Commission or the court with regard to the complaint from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the agreement has violated the antitrust laws (as defined in section 12 of Title 15, except that the term includes section 45 of Title 15 to the extent that that section applies to unfair methods of competition).

In his Note, Mr. Apel focuses primarily on the failure-to-market and collusive agreement forfeiture provisions, and argues that as a result of court and FDA decisions, both provisions have failed to live up to their potential as Congress originally intended.

In steps the AIA and the new IPR and PGR post-grant proceedings.  Can these proceedings be used to trigger a forfeiture of exclusivity eligibility?  Mr. Apel confronts the question head-on, looking at the statutory text, legislative history, judicial precedent, and practical application.  Ultimately, he concludes that if the question came to a court or to FDA, neither would be likely to construe the failure-to-market provisions to include IPRs or PGRs.  Why?  Because the failure-to-market provisions use the term “declaratory judgment action” and IPRs and PGRs are simply not a “declaratory judgment action.”  However, writes Mr. Apel, there is decent support for going the other way.  The strong estoppel effect of IPRs and PGRs gives them the effect of a district court action, and Congress intended to trigger the failure-to-market provisions upon resolution of the patent dispute.  Nevertheless, Mr. Apel predicts that those arguments cannot overcome the unambiguous text of the statute, especially in a highly regulated field, and that the statute would need to be amended:

Neither a court nor FDA is likely to adopt a broad enough construction of the failure to market statute to accommodate the new USPTO proceedings.  Thus, amending the failure to market provision to include administrative proceedings would remove the uncertainty in the field and help refocus the Hatch-Waxman Act towards its originally-intended balance.

The Federal Circuit has just started issuing decisions in the first IPRs to ever be filed, but none have concerned pharmaceutical patents that could otherwise be the subject of Hatch-Waxman litigation.  FDA’s recently-published proposed rules (see our previous post here) don’t shed any new light on the matter either, though 180-day exclusivity forfeiture is not the focus of FDA’s proposal.  In any case, practitioners will have to continue to wait as cases move through the system and issues are posed to FDA.

By Karla L. Palmer –  

As it did on the eve of another holiday weekend last July (see our previous posts here and here), on this past Friday (the 13^th), FDA released the long-awaited draft Memorandum of Understanding (MOU) addressing interstate shipment of compounded preparations under FDCA Section 503A and four other compounding draft guidance documents.  See FDA’s Press Release here, which also includes a handy link to all five drafts.

The four draft guidances address: (1) considerations for entities who wish to register under Section 503B; (2) drug repackaging by pharmacies, outsourcing facilities, federal facilities and hospital systems; (3) mixing, diluting, or repackaging biological products; and, (4) Section 503B adverse event reporting.  Neither the guidances nor the draft MOU have been published in the Federal Register (but publication is likely imminent).  Once published, interested parties have 90 days to comment on the draft guidance documents and, according to the FDA press release, 120 days to comment on the draft MOU.  Recall, however, that FDA’s Section 503A final guidance dated July 2, 2014 stated: “FDA does not intend to enforce the 5% limit on interstate distribution until after FDA has finalized an MOU and made it available to the states for their consideration and signature.  The Federal Register notice that will announce the availability of the draft MOU will specify the time period during which the MOU will be made available to the states to sign.  After this time period expires, FDA intends to begin enforcing the 5% limit in states that have not signed the MOU.”  July 2, 2014 Section 503A Guidance at 6 (emphasis added).  Thus, it is still unclear when FDA will begin Section 503A’s 5% limit on interstate shipments of compounded preparations in those states that do not sign an MOU.

A brief summary of each draft guidance document and MOU is below:

(1)        “For Entities Considering Whether to Register As Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act”  

This guidance lists eleven “conditions” for qualifying for the exemptions under Section 503B (i.e., FDCA’s new drug, adequate directions for use, and track and trace requirements).  It also clarifies that a facility can only qualify for the exemptions if all of the facility’s compounded drugs are compounded in accordance with Section 503B.  If a compounder does not intend to compound all drugs at the facility in accordance with Section 503B – including cGMP – then it should not register as an outsourcing facility.  The guidance similarly clarifies the law for those facilities that compound both office use and patient-specific preparations:  Even patient-specific preparations must meet cGMP requirements (no exceptions).

An outsourcing facility should also consider the following:

• To meet the “outsourcing facility” definition, it must be engaged in sterile drug compounding.  
• The definition of compounding under Section 503B(d)(1) does not include repackaging (but repackaging is addressed in another draft guidance, below).
• For purposes of 503B, a drug including a sterile drug does not include a biological product under Public Health Service Act (PHS) Section 351 or an animal drug under FDCA Section 512 (but biological products are also addressed in another draft guidance).
• A facility should not register as an outsourcing facility if the only activities conducted at the facility are repackaging, compounding non-sterile or animal drugs, or mixing, diluting, or repackaging biological products subject to licensure under Section 351 of the PHS Act, because none of the products would qualify for the exemptions under Section 503B.  It seems such activities could only be conducted by pharmacies pursuant to patient specific prescriptions.  .  
• Facilities that only compound non-sterile drugs are not eligible for the exemptions from the federal laws’ requirements that any new drug be distributed only after FDA approval, adequate directions for use, and track and track requirements; nevertheless, if the facility compounds sterile and non-sterile drugs, then those non-sterile products are eligible for exemptions in Sections 505, 502(f)(1), and 582 if the drugs are otherwise compounded in accordance with Section 503B.  

(2)        “Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities”

This guidance defines “repackaging” compounders: The act of “taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug.”  Repackaging also includes placing contents of multiple finished drug containers (e.g., vials) into one container, “as long as the container does not include other ingredients.”  FDA notes that, “if the drug is manipulated in any other way, including if the drug is reconstituted, diluted, mixed, or combined with another ingredient,” then it is not considered repackaging.  FDA’s draft guidance describes the conditions under which FDA does not intend to take action for violations of the law when pharmacies, federal facilities or outsourcing facilities repackage certain drug products.  In other words, in these situations, FDA will exercise what it has traditionally called its “enforcement discretion” not to sanction or punish these facilities for engaging in what FDA describes as illegal acts.

The draft guidance explicitly does not address repackaging of animal drugs, repackaging by entities that are not state-licensed pharmacies, drugs administered at the point of care, and dispensing solid dosage forms directly to individual patients in amounts less than in the original container.   FDA notes that drug packaging is a part of the drug review and approval process; repackaging may affect the sterility of the product and other characteristics that could adversely affect the safety and efficacy of the drug.

The guidance addresses FDCA Section 506F, dealing with hospitals within health systems repackaging drugs in the event of drug shortages to extend supply when certain statutory conditions are met (page 4).  Section 506F will terminate when the guidance becomes final.   

FDA describes conditions under which it will exercise enforcement discretion in the context of drug repackaging.  Some of the highlights:

• The repackaged drug must be an approved drug unless that drug is on FDA’s shortage list.
• The drug must be repackaged by a pharmacy, federal facility or outsourcing facility, and under the direct supervision of a pharmacist.
• If repackaged by a pharmacy or federal facility (but not an outsourcing facility), the drug must be pursuant to a prescription or order for an individually identified patient.  It may be repackaged in advance of a prescription or order (but not dispensed) if that amount does not exceed the amount repackaged in the previous, consecutive  14-day period, and based on a history of receipt of prescriptions or orders over a consecutive 14-day period for such repackaged drug products.
• Except for single-dose vials, the drug must be repackaged in a way that does not conflict with approved labeling.
• The repackaged product must be assigned a beyond use date (BUD) (which is the date included on the label within which the repackaged drug must be used)  as detailed in the draft guidance, considering the drug’s stated in-use time, USP guidelines, or cGMP depending on whether the drug product is an approved drug product, the type of facility and drug product (pages 6-8).  
• The drug may not be sold or transferred by an entity other than the entity that repackaged the drug.  In other words, repackaged drugs may not be distributed by wholesalers or middlemen.
• Repackaged drugs may only be distributed in states in which the facility meets all applicable state requirements.
• Drugs repackaged by outsourcing facilities must include required information on their labels and meet other requirements of 503B (pages 8-9).
• FDA will not take action against repackagers of approved or unapproved drug products on FDA’s shortage list, provided the facility meets all conditions of the draft guidance, during the period of shortage and for 30 days after the period ends.  When this draft guidance and guidance concerning repackaging biological products becomes final, Section 506F (hospital repackaging in times of shortages) will no longer apply. 

(3)        “Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application”

This draft guidance describes the conditions under which FDA intends to exercise enforcement discretion when pharmacies, federal facilities or outsourcing facilities mix, dilute or repackage specific biological products without an approved BLA, or when such facilities or physicians prepare prescription sets or allergenic extracts (used to treat allergies) without an approved BLA.

FDA notes that under the FDCA, such products otherwise may not legally be marketed, and the Act’s compounding provisions do not address biological products subject to licensure under Section 351 of the PHS Act.

The guidance addresses the following:  

• Except as provided for single-dose vials (as described in the guidance), repackaging must not conflict with approved labeling.
• For a single dose vial that is mixed/diluted/repackaged into multiple units, it must be done in a way that does not conflict with labeling other than statements designating product as a single-use vial/dose (page 9; 9 n.15). 
• Specifically concerning Avastin, which is packaged in a single-dose vials: “This condition could be satisfied even if Avastin is repackaged into multiple single dose syringes,” despite the fact that label of the approved product states, “single-use vial…discard unused portion.”  The repackager must adhere to other approved labeling (e.g., regarding the appropriate diluent and storage conditions) (page 9).
• Products must adhere to very stringent BUDs specified in the draft guidance due to susceptibility of biological products to contaminants (page 9). 
• If mixed, diluted or repackaged by a pharmacy or federal facility, the BUD cannot be longer than the in-use time indicated on the package or four hours (whichever is shorter); or up to 24 hours if microbial challenge studies are performed (as described in the guidance appendix);
• If mixed or diluted by an outsourcing facility, then the BUD cannot be longer than the in-use time or four hours (whichever is shorter); or up to 24 hours if microbial challenge studies are performed, as described in the guidance appendix.
• If repackaged by an outsourcing facility, then, as an alternative to the above, the BUD may not exceed the shorter of five days or the expiration of the biological product being repackaged, if the outsourcing facility performs container-closure compatibility studies consistent with 21 C.F.R. § 211.94.   
• Products may not be sold or transferred by an entity other than the facility that mixes the product, and must meet state requirements.  Sale or transfer does not include administration in a health care setting.
• Outsourcing facilities must comply with FDA reporting and labeling provisions, but the NDC number for the original licensed biologic product should not be placed on the repackaged  product (page 11, 12).
• Secondary packaging (i.e., the bag, box, or other package in which the products are distributed) must include active and inactive ingredients; directions for use, including dosage and administration and information to facilitate adverse event reporting.
• Must be accompanied by a copy of the prescribing information that accompanied the original FDA-licensed biological product (page 12).
• The outsourcing facility must reports serious adverse events to FDA.
• Concerning prescription sets and allergenic extracts, FDA does not intend to take action for violations of section 351 of the PHS Act or FDCA section 502(f)(1), if the pharmacist, federal facility or outsourcing facility meets conditions for extracts/BLAs in the guidance.  Conditions are set forth at pages 13-15. 

(4)         “Adverse Event Reporting For Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act” 

Under Section 503B, outsourcing facilities are required to submit adverse event reports to FDA. Failure to report is a prohibited act.  The draft guidance describes a “serious adverse drug experience” and “unexpected adverse drug experience” under 21 C.F.R. § 310.305.  It reminds registrants they must report all serious, unexpected adverse events “associated with” their compounded drugs.  It also “strongly recommends” reporting of all “serious adverse drug experiences” (assuming this means reporting whether or not such event is “unexpected”  (page 4). 

The guidance sets forth considerations for event reporting, which should include an investigation of the following four data elements and submission of an “Alert Report’ as soon as possible but not later than 15 calendar days after receiving information about the event:

1. An identifiable patient
2. An identifiable reporter
3. A suspected drug product
4. A serious adverse event

The guidance describes the four data elements in detail (pages 5-7) and tells how to report the events to FDA (pages 7-8).  FDA is currently modifying its processes to specifically identify and accept electronic reports from outsourcing facilities.  Until the electronic system is available, outsourcing facilities should provide reports of adverse events to FDA in hard copy (page 8).  Reports should be maintained by the facility for ten years. 

(5)         Draft Memorandum of Understanding Between a State and FDA Addressing Interstate Distribution of Compounded Human Drug Products under Section 503A 

Released with no accompanying guidance or explanation (which we hope is forthcoming), the draft MOU describes a state’s responsibilities for investigating and responding to complaints related to compounded human drug products distributed outside the state.  The MOU sets forth clear notification requirements for complaints. 

The draft also defines interstate distribution of “inordinate amounts” of compounded human drug products:  “The number of units of compounded human drug products distributed interstate during any calendar month is equal to or greater than 30% of the number of units of compounded and non-compounded drug products distributed or dispensed both intrastate or interstate during that month.”  FDA does not intend to include prescriptions dispensed to a patient/patient’s agent; if the patient/patient’s agent carries the drug across state lines after dispensing. (MOU  III(b)(4)).  Recall that the 1998 version of the draft MOU, which states never signed, used a 20% ratio.  The MOUN provides that states will review compounding records during inspections to determine compliance with the 30% ratio.  The MOU explicitly does not prohibit FDA from taking action against a non-compliant pharmacy, although the primary responsibility for investigations will lie with the state.    

Notwithstanding the interminable length of this blogpost, it is not a complete analysis of the draft guidance documents.  We will continue to update as more information becomes available.     

By Kurt R. Karst –

Earlier this month in a post concerning the Orange Book we mentioned our love of data and discussed how solid figures can reveal some interesting conclusions.  After all, it’s rather difficult – and dangerous – to come to a conclusion without having as many facts and as much data as possible.  Or, as Sir Arthur Conan Doyle wrote in The Adventure of the Copper Beeches, one of the Sherlock Holmes series of stories: “‘Data! Data! Data!’ he cried impatiently.  ‘I can’t make bricks without clay.’”  Indeed!  And the clay we have to play with today to make some bricks are the latest data from FDA’s Office of Orphan Products Development (“OOPD”) on orphan drug designations and approvals.

Although FDA’s agency-wide performance management system, known as FDA-TRACK, provides some information on orphan drug designations and approvals, that system is not up-to-date.  So we have to get our data from other sources – primarily (though not exclusively) from FDA’s Orphan Drug Designations and Approvals database.  As we’ve done in some previous years, we culled information from that database, which OOPD populates with data on a rather frequent basis.   The database is also constantly being refined to better reflect what orphan drug designations have been granted, what orphan drugs have been approved, and what the relevant periods of orphan drug exclusivity apply to.   We understand that the database will be revamped soon (perhaps later this year) to make it a more useful and user-friendly resource. 

The three metrics we’ve historically followed are: (1) the number of orphan drug designation requests received by OOPD; (2) the number of orphan drug designation requests granted by OOPD; and (3) the number of orphan drugs approved.  In 2014, records were shattered for all three metrics, with an astounding 467 designation requests (a nearly 35% increase over 2013), an astonishing 293 orphan drug designations granted (a nearly 13% increase over 2013), and a whopping 49 orphan drug approvals (a 53% increase over 2013).  Wow!  That’s an amazing output for FDA’s orphan drug program (and, in particular, for OOPD).

Below are three tables – one for each metric – showing the year-by-year numbers since 1983.

When we add up all of the numbers since 1983, FDA has approved 511 orphan drugs, granted 3,280 orphan drug designations, and received 4,738 orphan drug designation requests.  Of the 511 approvals, some drugs have been approved for more than a single rare disease, and sometimes a single orphan drug designation has been the platform for multiple orphan drug approvals (and multiple periods of 7-year exclusivity).

So what does it all mean?  Well, clearly orphan drugs are trending up – way up!  And there’s no indication of a slowdown any time soon.  (In fact, we understand that OOPD is already on pace to break the 2014 record for the number of orphan drug designation requests received by the Office.)  The data also show that the Orphan Drug Act has been an overwhelming success (for both patients and the drug and biotechnology industries).  Of course, a successful program breeds copycats.  We’ve seen that with the creation of orphan drug programs in other countries modeled after the Orphan Drug Act.  It’s also happening on out own backyard, however.  Consider, for example, the Generating Antibiotic Incentives Now Act (“GAIN Act”) (FDC Act § 505E), and the Dormant Therapies Act provisions included in the draft 21st Century Cures Act (see our previous post here).  The roots for both of those items can almost certainly be traced back to the Orphan Drug Act. 

By James E. Valentine* & Anne Marie Murphy –

The National Institutes of Health (“NIH”) just extended the comment period for its Notice of Proposed Rulemaking on clinical trial registration and results submission (“NPRM”) until March 23, 2015.  As we previously reported, the NPRM proposes to expand and clarify many of FDAAA’s requirements for submitting registration and summary results information for specified clinical trials of drugs, biologics, and devices and for pediatric postmarket surveillances of a device to ClinicalTrials.gov. 

This month-long extension will provide current and future “responsible parties” of “applicable clinical trials,” as well as other stakeholders, additional time to weigh in on NIH’s proposed changes (e.g., requiring results for trials of products that are not approved), as well as areas where the Agency has requested specific feedback (e.g., whether to require lay and/or technical results summaries).  For a synopsis of the changes proposed in the NPRM, see our previous posts here and here.  Comments can be submitted to docket number NIH-2011-0003 at Regulations.gov.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.

By Kurt R. Karst –

For those in the generic drug industry who attended the Generic Pharmaceutical Association’s (“GPhA’s”) annual meeting in Miami, Florida earlier this week, the message from Office of Generic Drugs (“OGD”) Director Dr. Kathleen “Cook” Uhl in her Generic Drug User Fee Amendments (“GDUFA”) progress report was clear: We have a lot of work to do, but progress is being made.  Of course – and to borrow the tagline from one of the industry’s giants (Mylan) – “seeing is believing.”

We’re now well into the second quarter of Fiscal Year 2015, which corresponds to GDUFA year 3 cohort applications.  For that cohort, FDA agreed to review and act on 60% percent of original ANDAs within 15 months from the date of submission.  (Those goals are ratcheted up in Fiscal Year 2016 [year 4 cohort] and Fiscal Year 2017 [year 5 cohort] where FDA agreed to review and act on 75% of original ANDAs within 15 months, and 90% of original ANDAs within 10 months, respectively.)  GDUFA includes other performance goals for Fiscal Year 2015, including with respect to Prior Approval Supplements (“PASs”) and Controlled Correspondence.

Although we’re still far away from the first 15-month GDUFA goal dates for original ANDA submissions (i.e., January 2016), it’s clear that OGD has been working hard to put in place a system to ensure that goals will be met.  (And by meeting goals, we mean approvals, not complete response actions.)  For example, OGD has surpassed GDUFA hiring goals (as shown in the table below from Dr. Uhl’s presentation), enhanced the Office’s information technology systems to realize various efficiancies, made significant changes to the Office’s structure, aligned other FDA components necessary to a successful (and prompt) ANDA review system, and published numerous guidance documents and manuals of policies and procedures (see, for example, our previous posts here, here, and here). 

OGD’s efforts have thus far have resulted in some pretty impressive progress for cohort year 3 submissions and for other goal-related Fiscal Year 2015 submissions.  Consider, for example, the information in the slides below from Dr. Uhl’s presentation.

Two items in particular in these slides stand out to us: (1) the average time for FDA’s initial review and acceptance of an ANDA is now less than 30 days (specifically, 27 days); and (2) a large number of ANDAs are still the subject of Refuse-to-Receive (“RTR”) actions.  That last bit is something that folks should be able to correct with little effort.  Most of the RTR letters from FDA cite inadequate or improper payment of GDUFA user fees, inadequate stability data, dissolution data or bioequivalence data (even failed studies), and incomplete or untimely responses to minor deficiency communications. 

While OGD certainly seems to be progressing well with GDUFA year 3 cohort submissions, the Office’s ability to “move the freight” on pre-GDUFA submissions, as well as year 1 cohort (Fiscal Year 2013) and year 2 cohort (Fiscal Year 2014) submissions (the so-called “GDUFA donut hole”), is still a work in progress and an ongoing issue of concern for the generic drug industry. 

To give readers a sense of the amount of pre-GDUFA and donut hole freight OGD has to move, below is a series of slides from Dr. Uhl’s presentation showing some pretty large numbers:

The following two slides from Dr. Uhl’s presentation show that OGD is making some progress, but there’s clearly still a lot of work to be done.

So, how will OGD hold itself accountable and assuage generic drug industry concerns (and concerns that are likely growing with FDA’s recent announcement – here at page 65 – that the median ANDA approval time was a whopping 42 months in Fiscal Year 2014, and is predicted to remain at that level for the next two fiscal years)?  The answer seems to be: assign Target Action Dates (“TADs”) to all pre-year 3 cohort applications. 

TADs are a relatively recent OGD creation that the Office has reportedly been assigning to some ANDAs for several months now as a sort of dry run for meeting GDUFA performance goals.  A TAD is not a GDUFA action date, but rather an internal OGD deadline for action on an application.  At the GPhA annual meeting, Dr. Uhl announced that OGD will extend the TAD initiative to all pre-year 3 cohort applications – and notify  ANDA applicants of the assigned TAD.  OGD will roll out the enhanced TAD initiative over the next several months, as discussed in the slides below.

By Douglas B. Farquhar, Jennifer M. Thomas & Kurt Karst –

We can’t help celebrating a recent court victory in which Hyman, Phelps & McNamara, P.C. represented Mylan Pharmaceuticals, Inc. (“Mylan”), and which yesterday resulted in Final Approvals for Mylan and one other generic drug company to manufacture celecoxib, the active ingredient in Celebrex®.  That drug, which is indicated for the treatment of rheumatoid arthritis, osteoarthritis, short-term acute pain, and other conditions, is one of the highest-grossing drugs in the United States, with sales of about $2 billion in 2013.

We have reported on the case before (see here). But, to recap, the dispute centered on a reissue patent’s impact on 180-day exclusivity under the pre-MMA (the Medicare Modernization Act) statutory framework and FDA’s patent-by-patent approach to exclusivity.  Teva Pharmaceuticals USA, Inc. (“Teva”) was the only company to qualify as a first-filer of what is referred to as a Paragraph IV certification to an original patent for Celebrex®, U.S. Patent No. 5,760,068 (“the ‘068 patent”) when it submitted its celecoxib ANDA in early 2003.  In May 2008, a court decision invalidated the ‘068 patent, which Mylan, Watson Pharmaceuticals, Inc. (“Watson”) and Lupin Pharmaceuticals, Inc. (“Lupin”), argued triggered the running of Teva’s exclusivity tied to the ‘068 patent pursuant to the statutory “court decision trigger.”  Thus, as Mylan, Watson, and Lupin contended in court, Teva’s exclusivity period tied to the ‘068 patent expired in November 2008.  However, Pfizer, the company that sells the brand version of Celebrex®, later secured a reissue of the ‘068 patent from the United States Patent Office, U.S. Patent No. RE44,048 (the “‘048 patent” or the “reissue patent”).  Teva, Mylan, and Watson were all first-filers to the reissue patent.

On April 24, 2014, FDA, while agreeing that Teva, Mylan, and Watson were all first filers to the reissue patent, issued a letter decision stating that only Teva would be granted an exclusivity period – even though Mylan and Watson both had Tentative Approvals to market the drug – because FDA believed that Teva’s first-filing to the original ‘068 patent and its subsequent timely filing to the reissue ‘048 patent created a  “bundle of rights” that essentially preserved Teva’s exclusivity tied to the ‘068 patent.  Mylan sued FDA, arguing both that (1) Teva’s exclusivity period tied to the ‘068 patent had expired; and (2) the ‘048 patent was tied to a separate period of exclusivity that should be shared by all first-filers to that patent.  Watson intervened, along with Teva and Lupin.  The U.S. District Court sided with FDA and issued a final decision finding that, although Mylan’s, Watson’s, and Lupin’s position that the original exclusivity period had expired was plausible, FDA’s position must be afforded deference.  Teva received its Final Approval to market celecoxib on May 30, 2014, and began marketing the drug (pursuant to a settlement agreement with Pfizer) on December 10, 2014.

On December 16, 2014, the Fourth Circuit Court of Appeals reversed the District Court, agreed with Mylan’s, Watson’s and Lupin’s argument, and found that the statutory language was clear that the exclusivity period tied to the ‘068 patent had expired and could not be revived by a reissue patent.  Although the Court did not explicitly say it, they apparently agreed with our argument that there is no such thing as a “zombie” exclusivity period: one that can never die because it could be revived if an original patent was replaced by a reissue patent.  The Fourth Circuit also stated in its opinion that “[t]he plain language of the statute indicates that each patent that is the subject of a certification may trigger exclusivity,” indicating that first-filers to the ‘048 patent were entitled to a separate, shared period of exclusivity.

The Mandate on the Fourth Circuit decision issued Monday, and the District Court, at the request of the parties in the litigation, immediately remanded the case to FDA.  FDA yesterday granted Final Approvals to Mylan and Watson, permitting them to join in the exclusivity period that Teva began using about three months ago.  Although numerous companies have been selling what are referred to as “Authorized Generics” (licensed versions of Pfizer’s product, under Pfizer’s NDA) since mid-December, Mylan and Watson will now be able to distribute their own versions of the product, manufactured pursuant to their own ANDAs.

By Ricardo Carvajal –

Given the effort that FDA has put into FSMA implementation thus far, it comes as no surprise that the agency’s budget for 2016 places a heavy emphasis on the resources that the agency believes are needed to finish the job.  The focus on FSMA and food safety is established up front in the Commissioner’s cover letter, which gives primacy to FSMA implementation in the agency’s justification for a budget authority increase.  The remainder of the document doesn’t let up, with some 115 references to FSMA.

The budget acknowledges what was already evident to many observers – FSMA implementation has drawn resources away from other food-related priorities (“FDA has proactively reprioritized current resources, including the FY 2016 increase, to ensure they are directed to the highest priorities for food and feed safety modernization.”)  However, FDA makes clear that reprioritization won’t yield sufficient funds going forward:

Without the requested budget authority, FDA will be unable to:

• implement fundamental FSMA requirements for domestic food and feed safety on a timely basis
• acquire the technical staffing needed to support FSMA implementation
• train FDA and state inspectors in the new FSMA prevention paradigm and preventive controls system, as needed to ensure effective and consistent inspections 
• provide the necessary guidance and technical assistance to industry, particularly small producers and businesses, on how to meet the new requirements resulting from the shift toward preventing food and feed contamination
• adequately support the FSMA goal of strengthening state roles in a national integrated food safety system
• adequately assure the safety of imported food by building and implementing the import safety system mandated by FSMA.

The budget goes on to explain in detail the activities that would be supported by an increase in the agency’s budget authority (@ $84M), but that increase pales in comparison to the @ $169M increase that would be supported by proposed user fees.  In what is becoming an annual ritual, FDA is asking for a variety of user fees – for imports, food facility registration and inspection, cosmetics registration, and food contact substance notification.  In sum, if all of the proposed user fees were to be authorized and implemented, then user fees would go from accounting for less than 2% of the foods program budget in FY 2015 to accounting for almost 20% of that budget in FY 2016.

The budget acknowledges that the proposed user fees would be “contingent upon the enactment of authorizing legislation.”  Previous efforts to secure such legislation have foundered, and it’s not clear why the result this year would be any different.  That could put the agency in an interesting position as it seeks to comply with a court-supervised deadline for issuing the final rules to implement FSMA (see our previous post here). 

By Jennifer D. Newberger –

On February 9, less than a year after issuing the draft, FDA issued a final guidance document confirming its exercise of enforcement discretion with respect to medical device data systems (MDDS), medical image storage devices, and medical image communications devices.  In line with the draft guidance, on which we blogged here, FDA has confirmed its intent not to enforce compliance with the regulatory controls previously applicable to the named devices.  This means manufacturers of those devices will not be required to register and list, or comply with the quality system regulation (QSR) or medical device and recall reporting.

Perhaps the most important takeaway from the guidance is that FDA has stated that it will also exercise enforcement discretion with respect to the named devices even if the device is intended for assessing the risk of cardiovascular disease or for use in diabetes management.  With the influx of apps and web services available to aid in diabetes management, FDA’s official position will be welcome news to many in the industry.

FDA also issued an updated version of its Mobile Medical Applications guidance, first released on September 25, 2013 (here), to incorporate the position outlined in the MDDS guidance.  For example, the September 25, 2013 mobile apps guidance indicated that an app that acted as an MDDS would be subject to registration and listing, QSRs, and medical device and recall reporting.  Since FDA has stated that it will not enforce regulatory compliance for MDDS products, the mobile apps guidance has been revised to reflect that position.

FDA has continued to indicate its intent to focus its efforts on higher risk technology products.  Hopefully, this trend will continue.

By Dara Katcher Levy –

Last Friday, FDA issued the latest in a series of draft guidance documents (here and here) that address alternate ways companies can disclose risk information in consumer-directed print Rx drug promotion.  The most significant difference between the 2015 and 2004 draft guidances is in scope; the 2015 document addresses not only consumer advertising but consumer print labeling. 

FDA regulations require that advertisements and promotional labeling be accompanied by different types of information.  Advertisements are required to have a “brief summary” of risk information accompany the ad.  Labeling is generally required to be disseminated with the full FDA-approved prescribing information (PI).  In the 2015 draft guidance, FDA recognizes that the lengthy, technical PI is difficult for consumers to comprehend and provides companies with a path forward to disseminating consumer-directed print labeling with an abbreviated statement of risk (referred to as the “consumer brief summary”) as opposed to the full PI.  This abbreviated option would not only benefit consumers with “better and more actionable information” (according to FDA) but can streamline the regulatory requirements for promotional materials with having the same consumer brief summary accompany both ads and promotional labeling.  Further, the consumer brief summary could potentially translate to a significant cost savings to companies that promote products with lengthy PIs that, to date, must be reprinted and disseminated in their entirety with promotional labeling.   

The proposal is an interesting shift for FDA:  In 2008, FDA issued a Warning Letter to Boehringer-Ingelheim for violations related to the promotion of Mirapex.  Among the issues cited was the “Failure to Provide Adequate Directions for Use” in that the full prescribing information was not provided with their consumer-directed promotional labeling in violation of 21 C.F.R. § 201.100(d).  In a footnote, FDA acknowledged that, “the pieces appear to have been disseminated with the patient package insert (PPI); however, as indicated above, the regulations require that any labeling which includes claims about a drug product must contain the contents of the full FDA-approved product labeling (PI). We remind you that this includes (but is not limited to) the full text of the Mirapex FDA-approved patient labeling or PPI, which must be reprinted immediately following the last section of the required FDA approved prescription drug labeling for Mirapex or, alternatively, accompany the Mirapex prescription drug labeling (PI).”  FDA did not comment on the adequacy of the PPI to convey appropriate safety information to consumers – rather, simply cited the regulatory requirement that the full PI must accompany the materials.  It appears that the PPI for most drugs would generally meet the requirements of the consumer brief summary as set forth in the new draft guidance, although FDA recognizes that there may be certain relevant drug risks not included in the PPI that might need to be added.

We note that the 2015 draft guidance does not simply provide an alternate approach, but actively discourages companies from meeting the current regulatory requirements.  FDA states that it “strongly recommends against providing the full PI,” when disseminating consumer-directed promotional labeling, and that companies should adopt the content and format recommendations in the guidance.  The suggestion is that the guidance supplants rule-making – an overt continuation of the Office of Prescription Drug Promotion’s trend toward regulating through the issuance of guidance documents and enforcement letters. 

Beyond the regulatory issues, companies should carefully consider the potential product liability implications involved with implementing FDA’s recommended approach in terms of “failure to warn” cases.  Although we recognize that the FDA recommendations are limited to direct-to-consumer promotion (and not the learned intermediary healthcare professional facing pieces), the approach may nonetheless increase a company’s vulnerability in this area.  Before determining whether to adopt the approach, companies should also consider consistency issues in the development and dissemination of promotional materials for their portfolio of products.  Any policy decisions should evaluate the inherent product liability risks represented by the most dangerous, or most litigated, drugs in their portfolio.        

By Jay W. Cormier & Allyson B. Mullen –

Two years ago, FDA promulgated the Part 4 regulations that specify how manufacturers of combination products are to comply with current good manufacturing practice (cGMP) when making products whose constituent parts are from more than one type of product. Recently, FDA issued a draft guidance document that put a bit more color on these regulations.

For those who are unfamiliar, each type of FDA-regulated product (e.g., drug, biologic, device, etc.) has its own set of regulations that govern what constitutes cGMPs. For single-category products, this makes sense – while the types of manufacturing issues that a medical device and, a biologic present do overlap, there are some differences in how to approach these issues, both technically and in the existing regulations. As if compliance with cGMPs isn’t difficult enough even for companies with big budgets, add in the wrinkle of manufacturing a product that, for example, is both a medical device and a drug at the same time, and things get messy in a hurry.

Part 4 was intended to come to the rescue. At a high-level, Part 4 is rather straight-forward. The analysis begins with the general rule that each constituent part of a combination product must be manufactured in compliance with its respective cGMP requirements. 21 C.F.R. § 4.3. For combination products that are either co-packaged (i.e., two or more separate products that are packaged together) or single-entity (i.e., comprised of parts that are physically, chemically, or otherwise combined into a single product) combination products, Part 4 provides an alternative to the general rule: a facility can elect to fully comply with the cGMP requirements for one of the constituent types and supplement certain specified provisions of the other constituent type cGMP requirements. See 21 C.F.R. § 4.4. Such a manufacturing facility has three options:

1. Fully comply with each of Parts 210 and 211 with respect to the drug constituent and with Part 820 for the device constituent;
2. Comply fully with Parts 210 and 211 for the combination product and with 21 C.F.R. §§ 820.20 (management responsibility), 820.30 (design controls), 820.50 (purchasing controls), 820.100 (CAPAs), 820.170 (installation), and 820.200 (servicing) for all constituent device parts; or
3. Comply fully with Part 820 for the combination product and 21 C.F.R. §§ 211.84 (component and container-closure testing), 211.103 (yield calculations), 211.132 (OTC tamper-evident packaging), 211.137 (expiration dating), 211.165-211.167 (final product release and stability testing), and 211.170 (reserve samples) for all constituent drug parts.

At 46 pages in length, the Draft Guidance helps to put some additional details onto this regulatory scheme. For readers who are interested in specifically how to apply device QSR provisions to drug components (when using option 2, above) or how to apply drug GMP provisions to device components (when using option 3, above), the majority of the Draft Guidance is dedicated to walking through each of these cross-product type issues. These summaries may be particularly helpful to companies that are unfamiliar with the cGMPs for the other regulatory product types (e.g., a device company that does not currently follow drug cGMPs). Rather than summarizing the many statements made by FDA on these specific issues, this post will provide a few highlights of the general concepts and clarifications provided by the Draft Guidance.

• Options 2 and 3, above, only apply to those manufacturing steps that occur after the first instance where the two separate product-type constituent parts are first co-packaged or combined into a single product. Prior to this point in time, the individual constituent parts are subject to their respective cGMP requirements.
• With respect to inspections, if a manufacturer elects one of these “streamlined” approaches (options 2 and 3), FDA recommends that the manufacturer notify FDA of which approach it intends to adopt in their premarket submissions as well as at the time that an inspection begins. A 510(k) premarket notification typically would not discuss manufacturing.
• A manufacturer may elect either streamlined approach for a co-packaged or single-entity combination product, without regard to which product center has been assigned as the lead review center or what primary mode of action has been designated for the combination product.
• Part 4 does not change FDA’s expectations for cGMP compliance for investigational products: drugs are generally exempt from cGMPs during Phase 1 studies and investigational devices are generally exempt from Part 820 with the exception of design controls.
• Part 4 does not change the analysis of whether a device component manufacturer is subject to Part 820 requirements. The guidance does a good job of explaining the difference between a device component (as defined in Part 820) and a device constituent part of a combination product.
• As with all other cGMP regulations, only those regulations that are applicable to the manufacturing operations must be followed.
• Specific procedures designed to implement one set of requirements (e.g., discrepancy investigations under 21 C.F.R. § 211.192) can be used to satisfy part or all of the relevant additional requirement s (e.g., CAPA requirements under 21 C.F.R. § 820.100).

The Draft Guidance includes detailed hypotheticals for pre-filled syringes, drug-coated meshes, and drug-eluting stents. While these hypotheticals each only cover one of the available options under Part 4, they are illustrative of what FDA expects combination product manufacturers to do when designing and implementing their manufacturing processes.

As always, general agency guidance cannot anticipate every scenario used by industry, so while applying the Draft Guidance to many products may seem to be straightforward, undoubtedly there will be instances where reducing agency guidance to practice is anything but clear.

Comments on the Draft Guidance are due to FDA by March 30th.

By James E. Valentine* & Jim C. Shehan –

The 21^st Century Cures Act’s focus on patients is inescapable.  Title I of this nearly 400 page bill is entitled, “Putting Patients First By Incorporating Their Perspectives Into The Regulatory Process and Addressing Unmet Needs.”  When we reported on the 21^st Century Cures Initiative hearing on incorporating the patient perspective (see our previous coverage here), it was clear from stakeholder testimony and engagement by Energy & Commerce Committee members that such a legislative proposal would be included.

So what exactly do patients get in the proposed legislation?  Well, considering the entire document is devoted to the discovery, development, and delivery of new treatments and cures, potentially quite a lot (see our broader coverage of the Act here and its proposed expansion of clinical trials data sharing here).  But specifically, we’ve identified two provisions that are patient centric: (1) Patient-Focused Drug Development and (2) Expanded Access.  Neither are new concepts.  In fact, both are current programs at FDA.  So let’s break down what’s new.

Patient-Focused Drug Development

This provision, Section 1001, drafted by Health Subcommittee Chairman Joe Pitts (R-PA) and Representative Cathy McMorris Rodgers (R-WA), would build off FDA’s Patient Focused Drug Development.  FDA would be required to implement the structured benefit-risk framework it took on in PDUFA V, and develop processes for incorporating “patient experience data” into the framework to be used in its regulatory decision-making with respect to the benefits and risks of new drugs.

“Patient experience data” broadly includes information about the experience of patients with a disease, including specifically the impact of the disease on their lives and their caregivers.  This information can take the form of complete data and summaries and analysis of the data, and may be incorporated into “draft guidances” that patients groups submit to the agency. 

To facilitate “patient experience data” collection, the provision would have FDA publish guidance on (a) methodological considerations for collecting this information, (b) assessing patients’ beliefs of benefits and risks in the management of their disease, and (c) experimental designs for patient-reported outcomes.  FDA is also asked to include timeframes for review of documents containing this information and how it will use the documents and data.  Interestingly, the guidance would also cover establishing and maintaining patient registries designed to improve understanding the natural history of a disease.  A pre-draft workshop and post-draft public meeting would facilitate guidance development.

So in summary, this one provision endorses three tools for fostering patient participation in the regulatory process: patient registries, patient-reported outcomes, and “patient experience data,” including benefit-risk preferences.

Expanded Access

Another heavily patient centric section of Title I of the 21st Century Cures Act is Subtitle G, entitled “Expanded Access.”  This subtitle almost replicates H.R. 8505, the Andrea Sloan Compassionate Use Reform and Enhancement (CURE) Act, introduced at the end of last year by Representative Michael McCaul (R-TX) and blogged on by us previously.  Among changes worth noting, Subtitle G makes some slight changes to the scope of products covered, adding designated orphan drugs and dropping drugs approved under accelerated approval and drugs whose sponsors receive priority review vouchers.  Also, the task force assigned to look for ways to improve expanded access has grown from nine to thirteen members and is specifically asked to look at compliance with adverse event reporting requirements in expanded access programs.

There was another significant development in expanded access last week – FDA issued a draft guidance containing its new form for individual patient expanded access INDs.  Checking in at two pages and containing only eight sections that the patient’s physician needs to complete, the, new draft form, designated Form FDA 3926, appears to accomplish the FDA’s stated purpose  to “greatly simplify and accelerate the process by which a physician can request” expanded access.  The most significant pieces of information that physicians will need to provide are:

1. The patient’s initials;
2. Clinical information, including indication, brief clinical history of the patient, and the rationale for requesting the proposed treatment, including an explanation of why the patient lacks other therapeutic options
3. Treatment information, including the investigational drug’s name and treatment plan, that is, the planned dose, route and schedule of administration, planned duration of treatment, monitoring procedures, and planned modifications to the treatment plan in the event of toxicity.
4. A letter of authorization from the investigational drug’s manufacturer
5. Information about the physician’s qualifications;
6. The physician’s name, address and contact information;
7. A check box authorizing use of the form, which amounts to a request for a waiver of additional requirements under 21 C.F.R. Part 312; and
8. The physician’s signature and certification that treatment will not begin until 30 days after FDA receives the application unless there is earlier notification from FDA; that the physician will obtain informed consent; that IRB review of the expanded access use will be obtained; and that in the case of an emergency request treatment may begin without prior IRB approval provided the IRB is notified of the emergency treatment within 5 working days of treatment.

According to a post on FDA Voice, FDA expects that the new form can be completed within 45 minutes.  Comments on the guidance and the draft form may be submitted to FDA within 60 days.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.

By Kurt R. Karst –      

There was some big news out of FDA today.  Yes, there was the news that FDA Commissioner, Dr. Margaret Hamburg, one of the longest-serving FDA commissioners in the modern era (see here), has decided to resign her post effective next month.  But even bigger than that (at least for this blogger) was some other news.  For quite some time now this blogger has opened the pre-publication website of the Federal Register hoping to see posted a notice of FDA’s long-awaited proposed regulations to implement the December 8, 2003 Medicare Modernization Act (“MMA”).  We were disappointed when the proposed regulations – which have been in the works for many years – did not get published by the MMA’s 10th anniversary.  That was day 3,655 in our Hatch-Waxman diary (see our previous post here).  Fast-forward to day 4,079, February 6, 2015, and the proposed regulations will make their official debut in the Federal Register. 

The pre-publication version of the proposal is a massive 341 pages (and includes a slew of tables), while the official version printed in the Federal Register comes in at a cool 96 pages.  And this is only part one of what will likely be a two-part series.  Part two, which we don’t think will come out any time soon, will deal with forfeiture of 180-day exclusivity eligibility.  Part one largely deals with the MMA’s provisions concerning Paragraph IV notice, 30-month litigation stays, amendments to ANDAs and 505(b)(2) applications, the types of bioavailability and bioequivalence data that can be used to support ANDAs and 505(b)(2) applications, as well other changes “to facilitate compliance with and efficient enforcement of the FD&C Act.”  What does that last passage mean?  FDA provides an example: “we are proposing to clarify requirements for the NDA holder’s description of the patented method of use (the “use code”) required for publication in [the Orange Book] to avoid overbroad use codes that may delay approval of generic drugs.” 

We’re still poring over the behemoth of a proposal.  And because this is Hatch-Waxman we’re talking about, there’s a lot of nitty-gritty to consider.  Nevertheless, below are a few goodies to whet you Hatch-Waxman appetite (taken from FDA’s highlight summary).  We’re sure to have more to say on the proposal in the coming weeks.

Submission of Patent Information – In addition to revising and streamlining the requirements related to submission of information for certain patent types, FDA’s proposed rule tackles reissued patents and describes the Agency’s approach to treating original and reissued patents as a bundle of patent rights.  As FDA later explains in the proposal:

Proposed § 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) would provide that an NDA applicant or holder is required to include information on whether a patent submitted for listing is a reissuance of a patent previously submitted for listing for the NDA or supplement. . . .  [T]he timely filing of patent information for a reissued patent (including a reissued patent with a broadened scope of claims) does not alter the patent certification obligations of a 505(b)(2) or ANDA applicant whose application was pending when the original patent was filed by the holder of an approved application for listing more than 30 days after patent issuance (“late listed”).  In other words, if a 505(b)(2) or ANDA applicant is not required to provide a patent certification or statement to the original patent pursuant to § 314.50(i)(4) or § 314.94(a)(12)(vi) because the patent was late listed, the 505(b)(2) or ANDA applicant would not be required to provide a patent certification or statement to the reissued patent even if timely filed following reissuance.

In addition, to “restrain overbroad use codes,” FDA’s proposal “would expressly require that if the scope of the method-of-use claim(s) of the patent does not cover every approved use of the drug, the NDA holder’s use code must describe only the specific portion(s) of the indication or other method of use claimed by the patent.” 

Timing of Submission of Patent Information – FDA expressly describes the Agency’s current practice with respect to the late listing of patent information, and proposes “to expand the category of untimely filed patent information to include certain amendments to the NDA holder’s description of the approved method(s) of use claimed by the patent, if such changes do not relate to a corresponding change in approved labeling or are submitted more than 30 days after such labeling change.”  According to FDA, this revision “is intended to reduce delays in approval related to manipulation of patent use codes. . . .”

Correction or Change of Patent Information – Among other things, FDA wants to enhance its response to challenges to the accuracy or relevance of Orange Book patent information.  FDA’s current regulation at 21 C.F.R. § 314.53(f) to challenge Orange Book patent information is rather toothless.  “If, in response to such a challenge, the NDA holder confirms the accuracy of the information, fails to timely respond, or submits a revision to the use code that does not provide adequate clarity for FDA to determine whether the scope of a proposed labeling carve-out would be appropriate based on the NDA holder’s use code and approved labeling,” says FDA, then “we are proposing to review proposed labeling carve-out(s) for the 505(b)(2) application or ANDA with deference to the 505(b)(2) or ANDA applicant’s interpretation of the scope of the patent.”

Notice of Paragraph IV Certification (Timing) – FDA proposes to delineate the two limitations on the timeframe within which Paragraph IV certification notice can be provided to the NDA holder and patent owner: “(1) [t]he date before which notice may not be given (reflecting FDA’s long-standing practice) and (2) the date, established by MMA, by which notice must be given.”  In addition, FDA reiterates that pramature notice is inavalid “and will not be considered to comply with the FD&C Act’s notice requirement.”  The Agency is also proposing “administrative consequences” for ANDA applicants who fail to send Paragraph IV notice within the statutory timeframe.  Specifically, “[t]he date the ANDA was submitted would be deemed to be delayed by the number of days by which the time frame was exceeded, which may result in the applicant losing eligibility for 180-day exclusivity.”  This is a topic on which we previously posted.

In addition, FDA's proposal would, if implemented, get rid of those pesky “serial certifications” – a practice many ANDA applicants have used throughout the years in an attempt to secure first-filer status and eligibility for 180-day exclusivity by preemptively sububmitting a Paragraph IV certification each day (sometimes for several months) until (or in case) a patent is listed in the Orange Book.  According to FDA's proposal: 

We are proposing to establish a date (the first working day after the day the patent is published in the Orange Book) before which an ANDA applicant cannot send valid notice of a paragraph IV certification to a newly listed patent.  This approach is intended to promote equity among ANDA applicants seeking eligibility for 180-day exclusivity and to reduce the burden on industry and FDA associated with serial submissions and multiple notices of paragraph IV certifications related to a newly issued patent.

Notice of Paragraph IV Certification (Content and Methods) – FDA is proposing to expand the acceptable methods of sending Paragraph IV notice beyond the now archaic registered or certified mail routes to include “designated delivery services.”

Amended Patent Certifications – In an effort to codify FDA’s current practice of not removing a withdrawn patent from the Orange Book until the resolution of 180-day exclusivity issues, the Agency proposes to “clarify the requirements for a 505(b)(2) or ANDA applicant to amend a paragraph IV certification after a judicial finding of patent infringement to reflect statutory changes made by the MMA,” and to “clarify the circumstances and time frame in which a 505(b)(2) or ANDA applicant must submit an amended patent certification after an NDA holder has withdrawn a patent and requested removal of the patent from the Orange Book.”

Amendments or Supplements (Patent Certification Requirements) – FDA’s proposal would augment the current regulations on patent certification requirements for amendments and supplements (for both ANDA and 505(b)(2) applicants) by “requiring a new patent certification with an amendment to make other-than-minor changes in product formulation or to change the physical form or crystalline structure of the active ingredient.”  That is, FDA finally addresses the issue of when an applicant must recertification and renotification. 

Limitation on Submission of Certain Amendments and Supplements to a 505(b)(2) Application or ANDA – FDA’s proposal codifies the Agency’s current interpretation of the statutory prohibition on amending or supplementing an application to refer to a different listed drug (see our previous posts here, here, and here).  “We are implementing these parallel restrictions on submission of certain types of changes in an amendment or a supplement to a 505(b)(2) application or ANDA in a manner that is consistent with the statutory text and preserves a meaningful opportunity for a single 30-month stay,” says FDA. 

505(b)(2) Applications – Turning to an issue that is part of ongoing litigation (see our previous post here), FDA proposes “to require a 505(b)(2) applicant to identify a pharmaceutically equivalent product, if already approved, as a listed drug relied upon, and comply with applicable regulatory requirements.”  FDA later explains that:

If a pharmaceutically equivalent drug product has been approved before a 505(b)(2) application is submitted, then we consider the 505(b)(2) applicant to be implicitly relying on the approval of such drug product.  We are proposing to revise § 314.54(a)(1)(iii) to require that the listed drug or drugs identified as relied upon by a 505(b)(2) applicant must include any approved drug product that: (1) Is pharmaceutically equivalent to the drug product for which the 505(b)(2) application is submitted and (2) was approved before the 505(b)(2) application was submitted.

Date of Approval of a 505(b)(2) Application or ANDA – With respect to application approval and 30-month patent litigation stays, FDA, among other things in the proposal, codifies the MMA’s provisions on the type of court decisions that will terminate a 30-month stay.  FDA also brings up other scenarios in which a 30-month stay may be terminated (e.g., written consent to approval by the patent owner or exclusive patent licensee, a court order terminating the stay, or a court order of dismissal without a finding of infringement). 

Notification of Commercial Marketing – Under FDA’s proposal, an ANDA applicant’s failure to timely notify the Agency about the date of commercial marketing (and thus the trigger for the start of 180-day exclusivity) can have significant consequences:

A first applicant would be required to submit correspondence to its ANDA notifying FDA within 30 days of the date of first commercial marketing of the drug product.  If the first applicant does not notify FDA within this time frame, we are proposing to deem the date of first commercial marketing to be the date of the drug product’s approval.  This may have the effect of shortening the 180-day exclusivity period in a similar manner to the current regulatory consequence for failure to provide “prompt” notice of first commercial marketing.

Notification of Court Actions or Documented Agreements – In what appears to be an effort by FDA to be better informed of the patent infringement litigation landscape, the Agency proposes to “expand the scope of documentation that an applicant must submit to FDA regarding patent-related court actions and documented agreements to ensure that FDA is promptly advised of information that may affect the timing of approval of a 505(b)(2) application or ANDA.”  This includes a copy of any judgment (or settlement order or consent decree signed and entered) by a court (district court or mandate of the court of appeals) finding a patent invalid, unenforceable, or not infringed (or finding the patent valid and infringed).

By James C. Shehan –

The new Congress has been very busy introducing legislation that affects FDA and regulated industry, including the 21st Century Cures Act (see our previous post here); the Limited Population Pathway for Antibacterial Drugs Act (PATH) (here) and the Improving Regulatory Transparency for New Medical Therapies Act, which aims to speed up DEA’s scheduling of new drugs (see our previous post here).  While these bills have been favorably received by many in the regulated industry, there’s another recently introduced bill that has found a less welcoming reception among industry: the Medical Innovation Act of 2015 (“MIA”) (S. 320), introduced by Senators Elizabeth Warren (D-MA), Ben Cardin (D-MD), Sherrod Brown (D-OH), and Tammy Baldwin (D-WI).  (Senator Warren’s press release, floor introduction video, and a bill summary are available here.)  Characterized by the sponsors as a bill that would boost funding for critical medical research, MIA does indeed provide for substantial NIH and FDA funding, estimated at $6B per year.  But that funding is provided via a novel mechanism – drug companies that market blockbuster drugs and enter into certain settlements with the federal government would be required to pay portions of their net profits for a five year period to the two agencies, a mechanism Senator Warren likens to a “swear jar.”  Delving into the bill, we see some proposals likely to be opposed on both policy and legal grounds, and perhaps capable of generating some swearing by those subject to it.

Here’s how the bill works.  A “covered blockbuster drug” is defined as one for which a manufacturer realizes $1B in net sales (presumably global sales) and developed in whole or part through federal government investment in medical research.  Federal government medical research investment is to be determined by the HHS Secretary considering whether information included in any patents that claim the drug or a method of use for the drug  relate to (1) “prior science conducted, in whole or in part, by a person” funded by the federal government; (2) “a signaling pathway, cellular receptor, ion channel, protein, DNA or RNA sequence or mutation, virus, or any other scientific information discovered, in whole or in part”, through such funded research; or (3) “the manufacturing process or testing process of the covered blockbuster drug, technology derived, in whole or in part,” through such funded research.  Given the breadth of this definition, especially clause 2, it appears that many products will meet the definition.

“Covered manufacturers” are those who hold the NDA or BLA for the covered blockbuster drug or who are a licensed partner of the holder.  “Covered settlement agreement” is one between an agency and a covered manufacturer with a payment of at least $1M and related to an alleged violation of the anti-kickback statute, the False Claims Act, the Federal Food, Drug, and Cosmetic Act, or any other federal civil or criminal law.  This is a very broad definition but the bill contains an exception that narrows it – “covered settlement agreement” does not include any settlement that the HHS Secretary determines does not involve an alleged criminal violation and does not involve fraud resulting or potentially resulting in loss of taxpayer dollars or allegations of conduct having an adverse or potentially adverse impact on the public health. 

Covered manufacturers that enter into covered settlement agreements after the MIA is passed and that have net income of at least $1B will be required to pay1 the federal government each year for five years an amount equal to 1% of their net income multiplied by the number of covered blockbuster drugs sold by that manufacturer in that year. 

Funds equivalent to the payments would be allocated by the HHS Secretary every year between NIH and FDA to “meet urgent needs in medical research.”  NIH’s funding would be used to support “research that fosters radical innovation,” “research that advances fundamental knowledge,” “research related to diseases that disproportionately account for Federal health care spending” and “early career scientists.”  FDA’s funding would be used to support its implementation of Section 1124 of FDASIA and other research to promote the public health and advance innovation in regulatory decision-making.  Between NIH and FDA, funds would be allocated according to the ratio of discretionary Congressional funding that each receives in that year.  MIA also contains mechanisms to prevent the funds from being used to replace budget cuts.

Among possible concerns about the bill is that it punishes settlements instead of fault.  Indeed although the bill summary states that it applies to companies that “[b]reak the law and enter into a settlement” with the government, by its text it applies to settlements and alleged violations, not actual violations of the law.  Indeed, somewhat perversely, the payments would not be owed by companies that went to trial and were actually found guilty of breaking the law. 

The bill may also be subject to legal as well as policy challenges as imposing an unconstitutionally excessive fine, given that the payments are not linked to any degree of culpability but instead to the size of corporate profits. 

Coverage of the bill in the media has been limited.  But PhRMA is reported to have offered the following point of view: “Pursuing misguided policies that siphon funding from the groundbreaking medical research happening in the biopharmaceutical industry will have devastating consequences for patients and society.  The proposed legislation would result in fewer medicines for patients and lost jobs at a time when our economy can least afford it.” 

Introduced by minority party Senators and lacking bipartisan support, unlike the other bills referenced at the start of this blog, it’s difficult to see this bill gaining much traction.  But if the situation changes, we are likely to blog on it.