By Kurt R. Karst –      

Last Friday, BioMarin Pharmaceutical Inc. (“BioMarin”) and FDA announced (here and here) the approval of a BLA for a new biological product for patients with Mucopolysaccharidosis type IVA, also known a “Morquio A syndrome”: VIMIZIM (elosulfase alfa) Injection.  The approval of VIMIZIM not only marks the first FDA-approved product for Morquio A syndrome, a rare, severely debilitating and progressive disease that previously had no standard accepted treatment other than supportive care, but also the first time a company has secured a Rare Pediatric Disease Priority Review Voucher (“Pediatric PRV”).

The Pediatric PRV was created by Section 908 of the 2012 FDA Safety and Innovation Act (“FDASIA”), which is codified at FDC Act § 529 (see our FDASIA summary at pages 54-56).  The Pediatric PRV program is intended to encourage the development of treatments for rare pediatric diseases.  The program was inspired by the existing Tropical Disease PRV (“TD-PRV”) program set forth at FDC Act § 524, as added by the 2007 FDA Amendments Act of 2007 (“FDAAA”) (see our FDAAA summary at page 45, and draft FDA TD-PRV guidance here), but differs from that PRV program in several respects.

A Pediatric PRV is a voucher issued to the sponsor of a “rare pediatric disease product application” that entitles the holder of such voucher to priority review (instead of a longer standard review) of a single NDA or BLA after the date of approval of the rare pediatric disease product application.  A qualifying rare pediatric disease product application is an NDA or BLA for a drug or biologic intended to prevent or treat a rare pediatric disease.  Such drug or biologic may not contain any active ingredient (including any ester or salt of the active ingredient) previously approved in any drug or biologic application.  The application must also be deemed eligible for priority review and rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.  A sponsor cannot seek an adult indication as part of a rare pediatric disease application.

FDA defines a “rare pediatric disease” similar to that as a “rare disease,” but in pediatric patients.  That is, a “rare pediatric disease” is a disease that affects fewer than 200,000 individuals primarily aged from birth to 18 years in the U.S.  The definition also extends to diseases that affect more than 200,000 individuals primarily aged from birth to 18 years in the U.S. but for which no drug or biologic treatments are available because a company cannot reasonably expect to recover the costs of developing and marketing such products.

Upon the request of a sponsor, FDA may designate a new drug or biologic as a product for a rare pediatric disease, and the application for such drug or biologic as a rare pediatric disease product application.  The request for designation must be made at the same time as a request for orphan drug designation or fast track designation; however, requesting orphan drug or fast track designation is not a prerequisite to receiving a PRV.  Within 60 days of receiving a request for a determination, FDA must determine whether a product qualifies as a new drug or biologic for a rare pediatric disease and whether an application qualifies as a rare pediatric disease product application.  PRVs are awarded upon approval.  FDA will publish notice of the issuance of a Pediatric PRV or the approval of a drug that used a Pediatric PRV within 30 days of the issuance or approval, respectively.  

FDA can revoke a Pediatric PRV if the product for which the voucher was awarded is not marketed within 1 year of approval.  In addition, a sponsor of an approved rare pediatric disease product must submit a report within 5 years of approval that provides information on the estimated population in the U.S. suffering from the rare pediatric disease, the estimated demand in the U.S. for the sponsor’s product, and the actual amount of such product distributed in the U.S. for the past four years.

An important limitation on the Pediatric PRV program is its sunset clause.  Under the statute, no further vouchers can be awarded “after the last day of the one-year period that begins on the date” that the third voucher is granted.   Therefore, less than a handful of vouchers will be issued.

A sponsor must notify FDA of its intent to use a pediatric PRV no later than 90 days prior to submitting a drug or biologic application, and “[s]uch notification shall be a legally binding commitment to pay for the [Pediatric PRV] user fee,” in addition to other applicable user fees.  Although FDA has not yet determined the Pediatric PRV user fee, the fee to use a TD-PRV, which is calculated using a similar formula, is substantial (see here and here).

In general, Pediatric PRVs may be sold or transferred, and there is no limit on the number of times a priority review voucher can be transferred.  The transferee or purchaser must notify FDA of a change of ownership within 30 days after such transfer or purchase.   A sponsor that provides notification of its intent to use a Pediatric PRV, while committed to pay the Pediatric PRV user fee, “may transfer the voucher after such notification is provided, if such sponsor had not yet submitted the human drug application described in the notification.”

The TD-PRV program is similar in many ways to the Pediatric PRV program, and, therefore, may provide a good example of how Pediatric PRVs might work.  However, not a lot of TD-PRVs have been granted thus far. 

When the TD-PRV program was introduced, many industry experts predicted that a market could be created for PRVs.  At the time, PRVs were speculated to be worth between a whopping $50 million and $500 million!  Despite their high valuation, only two drug sponsors have developed products that have received TD-PRVs: (1) Novartis’s COARTEM (artemether, lumefantrine), which was approved on April 7, 2009 for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least 5 kilograms; and (2) Janssen Therapeutics’ SIRTURO (bedaquiline), which was approved on December 28, 2012 for pulmonary multi-drug resistant tuberculosis.  The COARTEM PRV was used by Novartis when in 2011 the company submitted a supplemental NDA for ILARIS (canakinumab) to add an indication for gouty arthritis.  It is unclear whether Janssen has used its PRV.  A third TD-PRV may be granted if FDA approves a pending application for IMPAVIDO (miltefosine) for the treatment of visceral, mucosal and cutaneous leishmaniasis (see here). 

One takeaway from the TD-PRV program is that the value of PRVs is uncertain and has not encouraged large-scale development of new therapies for tropical diseases.  It is important to note, however, that there are at some key differences between TD-PRVs and Pediatric PRVs that may make the latter more appealing.  First, a sponsor using a TD-PRV is subject to a one-year notification requirement before submitting a human drug application for priority review, whereas a sponsor using a pediatric PRV is only subject to a 90-day notification requirement.  Second, transfer of TD PRVs is limited to a single sale or transfer, whereas a Pediatric PRVs can be traded or sold multiple times.  These differences, among others, may make the Pediatric PRV more appealing to companies.

By Kurt R. Karst – 

Although it’s been more than 10 years since the December 8, 2003 enactment of the Medicare Modernization Act (“MMA”) – or, more accurately, The Medicare Prescription Drug, Improvement, and Modernization Act, Pub. L. No. 108-173 – which created a new regime for 180-day generic drug marketing exclusivity, the pre-MMA version of the statute governing 180-day exclusivity is still alive and kicking.  In fact, because of how the pre-MMA-to-post-MMA changeover operates, pre-MMA 180-day exclusivity may be around for quite some time, frustrating some generic drug applicants along the way, but rewarding others.

Under the pre-MMA version of FDC Act § 505(j), 180-day exclusivity is patent-based, such that an ANDA applicant is (or different applicants are) eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the Reference Listed Drug if such applicant submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent.  Pre-MMA 180-day exclusivity is triggered by the earlier of either the first commercial marketing (for all patents certified to as Paragraph IV by a first-filer), or by a court decision favorable to an ANDA applicant (with respect to a particular patent).  Of course, where there is no court decision (because, for example, an ANDA applicant was not sued for patent infrongement, or there was a settlement of litigation without a holding on the merits), the possibility of “parked” exclusivity arises . . . at least until there is commercial marketing of the drug or the patent(s) on which 180-day exclusivity is based expires. 

The MMA amended the FDC Act such that the first company to submit an ANDA to FDA containing a Paragraph IV certification to any Orange Book-listed patent covering the RLD – i.e., a “first applicant” – is eligible for 180-day exclusivity.  Post-MMA, 180-day exclusivity is considered drug product-based and is triggered by first commercial marketing of the drug product by any first applicant.  A first applicant can forfeit 180-day exclusivity eligibility under one or more forfeiture provisions created by the MMA. 

The MMA includes – at § 1102(b)(1) – an effective date provision for purposes of deciphering when the pre- or post-MMA 180-day exclusivity regime will apply.  That provision states: “the amendment made by subsection (a) shall be effective only with respect to an [ANDA] filed . . . after [December 8, 2003] for a listed drug for which no [Paragraph IV certification] was made before [December 8, 2003].”

As a result of the MMA’s effective date provision, a drug product subject to the pre-MMA rules on 180-day exclusivity is forever evaluated under the old version of the statute.  This includes, as FDA previously determined, so-called “MMA Straddles.”  An MMA-Straddle situation arises  when one or more ANDAs were submitted to FDA on or before December 8, 2003, but the first Paragraph IV certification was submitted to FDA after December 8, 2003.  A few known MMA Staddle drug products include Topiramate Sprinkle Capsules, 15 mg and 25 mg (TOPAMAX) and Methylphenidate HCl Extended-Release Tablets, 18 mg, 27 mg, 36 mg, and 54 mg (CONCERTA). 

Also included the pre-MMA category of drugs are brand-name products for which an ANDA was submitted to FDA on or before December 8, 2003 containing a Paragraph IV certification that may have already resulted in a period of 180-day exclusivity associated with that patent, and for which a new patent is issued post-MMA and information for which is listed in the Orange Book.  The new patent listing gives rise to the possibility of another period of 180-day exclusivity – either by operation of an amendment to a pending ANDA or through the submission of a new original ANDA – for a brand-name drug that went generic long ago.  It also means, however, that subsequent ANDA sponsors certifying to a newly listed patent cannot be approved until the first-filer’s exclusivity is over (or is otherwise lost).   Thus, for example, U.S. Patent No. 7,022,340 applicable to NDA No. 019955 for DDAVP Tablets (desmopressin acetate), 0.1 mg and 0.2 mg, has given rise to a new period of 180-day exclusivity eligibility and has blocked subsequent applicants from opbtaining final approval.  Similarly, U.S. Patent No. 8,476,010 applicable to NDA No. 019627 for DIPRIVAN (propofol) Injection, 10 mg/mL, has given rise to a new period of 180-day exclusivity eligibility for generic versions of that drug product.  (Another interesting case is the listing of U.S. Patent No. 7,091,236 for various Glycopyrrolate Tablet drug products approved in August 1961 under NDA No. 012827, and marketed under the ROBINUL trade name.  The patent is apparently the first patent listed in the Orange Book for those brand-name drug products.)  

Because of the pre-MMA patent-by-patent approach to 180-day exclusivity, FDA’s interpretation of when the pre-MMA statute applies in a post-MMA world, and the issuance of new patents for drugs approved long ago, any list of pre-MMA drug products is naturally fluid.  Drug products can move on or off of that list.  Although ANDAs with a number less than or equal to 076933 are applications submitted to FDA on or before December 8, 2003 (pre-MMA), and ANDAs with a number equal to or greater than 076934 are post-MMA applications, a post-076934 ANDA could be subject to (or be eligible for) pre-MMA exclusivity because of an older ANDA submission.  In some cases, that means a revision to a pre-MMA list of drugs to add a new drug.  In another situation, a brand-name drug for which an ANDA was submitted to FDA pre-MMA may be withdrawn for reasons of safety or effectiveness (e.g., TEQUIN, SELDANE, and “old” OXYCONTIN), or converted in a prescription-to OTC switch under a new NDA (e.g., MIRALAX).  Those products have to be removed from any pre-MMA list of drugs.

So what’s this all leading up to you ask?  You guessed it, as part of our celebration of the 30th anniversary of the Hatch-Waxman Amendments we put together a current list of all the drug products we think are subject to the pre-MMA 180-day exclusivity statute.  The list may not be perfect (after all, not all of the MMA Straddles are known), but it’s as complete a list as we have ever seen.  Here you go . . . and enjoy!

By Ricardo Carvajal –

FDA published a notice announcing the availability of a Draft Approach for Designating High-Risk Foods, and asking for comments and information to help the agency refine that approach.  Designation of a food as a High-Risk Food (HRF) would trigger additional recordkeeping requirements intended to facilitate product tracing (current recordkeeping requirements for purposes of product tracing are limited to identity of immediate previous sources and subsequent recipients of a food). 

As explained in the Draft Approach, FSMA section 204(d)(2)(A) sets forth a number of factors on which HRF designations must be based.  In light of those statutory factors, FDA proposes to rely on the following criteria:

1. Frequency of outbreaks and occurrence of illnesses;
2. Severity of illness, taking into account illness duration, hospitalization and mortality;
3. Likelihood of contamination; 
4. Growth potential/shelf life;
5. Manufacturing process contamination probability/intervention;
6. Consumption; and
7. Economic impact.

Throughout the Draft Approach, links to FDA’s other food safety initiatives and activities are evident.  For example, where data on the likelihood of contamination are not available, FDA proposes to rely on RFR reports, its recall database, and its compliance programs.   As an additional example, scoring of the probability of manufacturing process contamination would take into account lessons learned from implementation of preventive controls (i.e., “available control measures and interventions that have been validated… and can be applied during manufacturing to eliminate, reduce (to acceptable levels), or otherwise control a hazard”).

FDA’s notice emphasizes that the Draft Approach is open to revision based on comments submitted to the agency, and that it likely will be subject to peer review.   The notice also asks for comments a number of specific topics, including how food allergens should be considered in developing a list of HRF.  Comments are due by April 7, 2014.

By Jennifer D. Newberger –

On February 5, 2014, CDRH released its 2014-2015 Strategic Priorities, in which it stated that the most important areas of focus over the next two years will be to “strengthen the clinical trials enterprise,” “strike the right balance between premarket and postmarket data collection,” and “provide excellent customer service.”

Clinical Trials Enterprise

The key component of this priority is to find ways to encourage sponsors of clinical trials to conduct those trials in the United States rather than overseas and to do so early in the device development process.  CDRH aims to achieve this goal by improving the efficiency, consistency, and predictability of the IDE process to reduce the time and number of cycles needed to obtain IDE approval, and to increase the number of early feasibility/first-in-human IDE studies submitted to FDA and conducted in the U.S.

CDRH has already taken steps over the last two years to improve the IDE and clinical trial processes.  For example, in 2012, FDA issued a guidance document that describes the factors it considers in making premarket risk/benefit determinations, including patient perspective on risks and the willingness to accept increased risk for certain conditions.  To build on this, CDRH states that as part of its strategic priorities it will “formalize the incorporation of [its] benefit-risk framework, including patient-specific factors such as tolerance for risk and perspective on benefit, into the IDE process.”  Such formalization will help sponsors better understand the various factors that might influence whether and how quickly an IDE might be approved, which could possibly, in turn, positively influence a decision about conducting the study in the United States.  CDRH should also address the amount of data needed to initiate a study, which can, in and of itself, be an insurmountable burden.

Premarket v. Postmarket Data Collection

The question of the appropriate amount of data to collect premarket versus postmarket generally applies to devices approved through the PMA process, and is an area that industry and FDA have long debated.  Industry’s position has been that FDA may request data that is too extensive to gather premarket, and will delay entry of potentially life-saving or highly beneficial devices to the U.S. market.  FDA has argued that without sufficient premarket data, it could be allowing products onto the market that have not demonstrated reasonable assurance of safety and effectiveness.

The strategic priorities indicate that CDRH recognizes that burdensome data requirements can adversely affect when patients in the U.S. will have access to a device, and notes that it is “critical” for CDRH to “strike the right balance between premarket and postmarket data collection.”  The “balance” is between improving patient access to devices while assuring postmarket data collection will occur in a timely fashion, thereby enabling a more rapid evaluation of safety of the device in use.

This strategic priority may be the first time CDRH has specifically put forth a plan for determining the devices for which data requirements may be shifted from pre to postmarket.  This plan involves reviewing all device types subject to PMA approval “to determine whether or not to shift some premarket data requirements to the postmarket setting or to pursue down classification, and communicate those decisions to the public.”  Certainly there is no guarantee that CDRH will find that a data shift or down classification is appropriate for any PMA device, or will do so in a meaningful time frame (another FDA Center just responded to a Citizen Petition almost 39 years after it was submitted) but it is encouraging to see CDRH recognizing this as a possibility and setting forth timeframes within which such a review should occur.  As part of the review, CDRH will seek public input on when data shifting is appropriate.  Hopefully, FDA and industry can work together to reach agreement with respect to when it is appropriate to shift data requirements to the postmarket setting, allowing the public earlier access to medical devices while continuing to assure the safety and effectiveness of those devices.

Provide Excellent Customer Service

This is perhaps the most interesting and unexpected of the strategic priorities.  Industry has long complained about the unresponsiveness of CDRH to its inquiries and the lack of transparency and consistency with respect to its decision-making.  Perhaps this priority is a sign that CDRH is finally considering how its interactions with industry impact whether manufacturers choose to pursue clearance or approval in the U.S.

To provide excellent customer service, CDRH will be implementing “customer service standards,” which include active listening, problem solving, seeking out the ideas of others, explaining the reason for CDRH’s decisions and requests for information, learning from its mistakes, and “doing our best.”  These are all sufficiently vague (particularly “doing our best”) that is not clear how the “customers” (industry and other stakeholders) will determine whether an adequate level of customer service has been obtained.  The strategic priorities indicate that there will be a survey tool in emails and on the website, and a CDRH program will be established to monitor and address feedback and improve quality and performance.  It is not clear how CDRH will ensure that it obtains feedback from a majority of “customers” or how those customers are intended to rank issues like whether CDRH did its best, or what CDRH will do with this feedback.  It is encouraging to see CDRH acknowledging that its interactions with stakeholders must be improved, but it is not clear from the information in the strategic priorities precisely how that will be accomplished or measured. 

In sum, CDRH’s strategic priorities seem to constitute positive steps.  Whether they will result in regulatory improvements or represent aspirations that will go unfulfilled remains to be seen.

By Delia A. Deschaine & Alan M. Kirschenbaum –

On January 31, 2014, the HHS Office of the Inspector General ("OIG") issued its Work Plan for FY 2014.  The Work Plan sets forth OIG’s priorities for evaluations, inspections, and audits to be conducted in FY 2014 (Oct. 1, 2013 through Sept. 30, 2014).  The 2014 Work Plan describes a number of new and continuing studies and reports on pharmaceutical issues to be conducted by OIG’s Office of Evaluations and Inpections, including the following:

Conflicts of interest involving compendia (p. 23):  Generally, Medicare covers drugs that are approved by FDA and used for indications that are either approved or supported in one or more drug compendia recognized by CMS. OIG explains that, while publishers are required to have “publicly transparent processes for evaluating anti-cancer drug therapies and or identifying potential conflicts related to inclusion of those therapies in the compendia,” there are no such requirements for non-anticancer drugs.  OIG will initiate a new study of the processes used by the publishers of these drug compendia to evaluate anticancer and non-anticancer drug therapies and identify conflicts of interest related to the therapies included in the compendia.

Medicaid Drug Rebate Program (MDRP) (pp. 34-35):  OIG intends to continue its ongoing evaluation of whether manufacturers are complying with average manufacturer price ("AMP") reporting requirements.  In addition, a new review will assess manufacturer compliance with MDRP requirements for calculating rebates for new formulations of existing oral dosage form innovator drugs.  The Affordable Care Act made significant changes to the statutory definition of AMP and added the new formulation provision, effective October 1, 2010.  However, CMS has not issued final regulations to implement these new statutory provisions, many aspects of which are subject to varying interpretations.  Manufacturers who have undergone OIG reviews of their AMP calculation methodologies in the past have faced the difficulty of being reviewed against ambiguous statutory requirements in the absence of written policies and interpretations from CMS.  In reviews of compliance with the new formulation provision of the statute, which is unclear at best, the regulatory void will be even more problematic.  CMS expects to issue its final MDRP rule in May 2014, but if the past is any indication, OIG will be reviewing manufacturer methodologies that predate the final rule.

Coupons for Part D drugs (p. 31):  Continuing a study begun in FY 2013, the OIG will identify the safeguards that drug manufacturers have in place to ensure that Medicare beneficiaries do not use copay coupons to obtain drugs paid for by Part D.  OIG explains that a recent survey suggests that copay coupons for brand drugs cause Medicare to pay more than necessary when less costly versions of the drug are available, and that the use of copay coupons in Federal health care programs “implicates the anti-kickback statute.”

Medicare coverage of off-label uses (p. 22):  Medicare Part B generally covers approved drugs for on-label indications and also off-label indications that are supported in recognized compendia or supported by clinical evidence reported in medical literature.  OIG will conduct a new study of the oversight of CMS and its contractors to ensure that payments for Part B drugs meet the appropriate coverage criteria.

Manufacturer reporting of Average Sales Price ("ASP") (p. 21):  ASPs reported quarterly by manufacturers are used by CMS to set payment rates for drugs covered under Medicare Part B.  OIG previously found that a number of manufacturers were not reporting ASP to CMS, either because they were not required to (because they did not have a Medicaid Rebate Agreement, on which the ASP reporting requirement is predicated), or because they were violating the requirement to report.  OIG will conduct a new study to “determine the potential effect on average sales price reporting if all manufacturers of Part B-covered drugs were required to submit ASPs to CMS …. [and] whether CMS has improved its process for collecting ASP data ….”

Payment for compounded drugs (p. 23):  OIG will conduct a new study to examine the policies and procedures of Medicare Administrative Contractors for processing Part B claims for compounded drugs and assess the appropriateness of such claims.  Medicare pays for compounded drugs only when they are prepared in compliance with the Federal Food, Drug, and Cosmetic Act.  The Drug Quality and Security Act, which was enacted on November 27, 2013, imposes conditions for the lawful compounding of prescription drugs.

By Kurt R. Karst –       

A couple of weeks ago we announced a massive and unprecedented undertaking by FDA’s Office of Generic Drugs (“OGD”) to address an outpouring of concern about, among other things, a Manual of Policies and Procedures (“MAPP”) – MAPP 5200.3 – titled “Responding to Industry Inquiries with respect to Abbreviated New Drug Applications in the Office of Generic Drugs” that FDA published in September 2013 and that was criticized as restricting communication between OGD and ANDA sponsors concerning pending applications.  The fruits of OGD’s undertaking are beginning to rollout, and ANDA sponsors should expect to begin receiving correspondence from the Office. 

What will that correspondence look like?  Below is a representative letter from OGD (with fictitious products) detailing the status of various application components.   Applicants may receive multiple communications based on the number of ANDAs pending in OGD.  OGD emphasizes in the letter that “[t]his is a one-time communication intended to assist [applicants] to ascertain the current status of submissions.”  And while ANDA sponsors will certainly be tempted to contact OGD for further information – because in some cases the correspondence may raise more questions than provide answers – OGD says they should not do so: “Please do not respond to this communication by asking FDA or your Regulatory Project Manager for additional or more detailed information. . . .  It is not feasible for us to respond to a high volume of follow up inquiries.”  

DATE: February 12, 2014

TO: Generic Drugs, Inc.

ATTN: Responsible Company Official

E-Mail:

FAX:

RE: Update summary of filed and pending original ANDA(s)

Dear Sir or Madam:

The Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research, Food and Drug Administration (FDA), is providing you with this one-time communication on the status of your filed and pending original abbreviated new drug application(s) (ANDA) submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act. OGD is providing these updates as an interim measure to help applicants assess the status of their current submissions as we transition towards predictable goal times pursuant to the Generic Drug User Fee Amendments of 2012 (GDUFA).

Your status update is limited to available review information as of January 29, 2014. Any additional information regarding your ANDA collected after this date is neither considered nor provided. Furthermore, your ANDA status is subsequently subject to revision pending additional information or concerns raised by any of the discipline reviews (bioequivalence, clinical, chemistry, microbiology, labeling, facility), other unforeseen legal, scientific or regulatory issues, or inspectional results, which can also impact the status or ability to issue a complete response. Any applicable fees can also affect the status of your ANDA.

OGD is providing your ANDA status update in the attached chart with a list of applicable acronyms. The chart only contains current information regarding discipline review and does not forecast if and when OGD will issue a complete response, tentative approval, or final approval letter.

Please do not respond to this communication by asking FDA or your Regulatory Project Manager for additional or more detailed information. This is a one-time communication intended to assist you to ascertain the current status of submissions. It is not feasible for us to respond to a high volume of follow up inquiries.

Sincerely yours,

CAPT Aaron W. Sigler, USPHS
Chief, Review Support Branch

CHART ACRONYMS

Column Headings

ANDA - The application number for your Abbreviated New Drug Application
DRUG NAME - The official filed name of the drug associated with the ANDA number
CHEM - Product Quality Chemistry Review
BIO - Bioequivalence Review, typically including OSI, if applicable
MICRO - Microbiology Review
LABEL - Labeling Review
CLINICAL - Clinical Review
FACILITY – Overall Facility inspections summary. All facilities must be acceptable at the time of 29 JAN 14 in order to warrant an adequate notation. If one of more facility is not acceptable then the FACILITY column will be marked as such. OSI information is not considered.

Discipline Notations

IQ – Inadequate. This particular discipline is currently found to be inadequate.

AQ - Adequate. This particular discipline was found to be adequate when the information was gathered for this communication.

UR - Under Review. This particular discipline is currently assigned OR under review with the discipline team.

NR – Not Reviewed. This particular discipline is either currently not under review or assigned.

NA – Not applicable. This particular discipline is not required for the approval of this ANDA.

Facility Notations

PN – Pending, i.e., one or more facilities have been inspected and are pending an outcome.

AC - All facilities are acceptable at the time of this publication.

*Please note that you may receive your updates in multiple communications over time, based on the number of ANDAs pending in OGD.

At the Food and Drug Law Institute’s (“FDLI’s”) 2014 Medical Device Conference – Key Legal and Regulatory Developments, which will take place in Washington, D.C. on February 27, 2014, top FDA officials will discuss their most significant recent activities and forecast upcoming medical device activities.  Experts will analyze the most important cases of 2013 and predict what legal and policy developments to expect in 2014.  In addition, panelists will analyze pressing compliance issues, including regional warning letters and off-label promotion issues. This conference will cover hot topics in the medical device realm, including mobile medical apps, combination products and the Sunshine Act.

Hyman, Phelps & McNamara’s Jeffrey K. Shapiro will present with CDRH Ombudsman David Buckles, PhD, FACC in a session covering two FDA guidance documents issued last year – one on  Medical Device Reporting (“MDR”) requirements and the Appeals Process (see our previous posts here and here).

To register for the conference and to obtain additional details, please go to the FDLI website.  FDA Law Blog readers can obtain a discount by using the code MEDDEV14.

By Kurt R. Karst – 

The Electronic Age has changed nearly every aspect of our daily lives, and the day-to-day operations of the U.S. Federal Government are no different.  The government is no longer open for business from 9-5, but rather 24 hours a day by virture of electronic media.  This 24-hour business day cycle is reflected in a new guidance for industry FDA published earlier this week, titled “Providing Regulatory Submissions in Electronic Format — Receipt Dates.”  In that guidance, FDA details not only the Agency’s current policy for assigning receipt dates for Electronic Submission Gateway (“ESG”) (and in-person) submissions (as well as explaining the important distinctions between drug and biologic submissions and receipts), but provides myriad helpful examples of scenarios in which FDA applies that policy and the potential ramifications of submission and receipt date timing.  Submission timing is, of course, an important consideration for any drug or biologic company; however, timing is particularly important in Hatch-Waxman World when 180-day generic drug marketing exclusivity is at stake.  And in that regard, FDA’s new guidance does not let us down.  But we’re getting ahead of ourselves . . . .

FDA’s Receipt Date Guidance first lays down some ground rules and definitions.  It identifies the drug and biologic (but not medical device) submissions to which it applies, such as INDs, NDAs, BLA, and ANDAs (including amendments and supplements to them).  It also starts out with the basic proposition that “[w]hen FDA receives a submission, the submission is assigned a receipt date.”  But that’s important, because the receipt date of a submission has legal and regulatory significance in several contexts.  For example, the receipt date of a submission determines the review performance goal date established under the applicable UFA (User Fee Act).  Then the guidance goes into the murky territory of “receipt,” “receipt date,” and ANDAs:

It is important to recognize, however, that the “receipt date” as defined under this guidance may . . . differ from the date of “submission” of an ANDA.  It is also important to distinguish . . . the “receipt date” as defined under this guidance from the decision by FDA whether or not an ANDA will be “received” within the meaning of the statute and FDA regulations. . . . 

FDA regulations set forth criteria for the receipt and initial review of NDAs, BLAs, and ANDAs to determine whether they may be filed (in the case of NDAs and BLAs) or received (in the case of ANDAs) and placed into review.  The decision whether or not [an] ANDA may be received depends both on whether appropriate fees have been paid and whether the applications are found to be adequate for review.  The receipt date for a premarket application, as described in this guidance, is the date on which an application is deemed to have arrived at FDA.  It should not be confused with our subsequent decision to . . . receive an ANDA for review.

With that important distinction explained, FDA states its receipt date policy:

For the purpose of assigning receipt dates, if an electronic submission covered in this guidance arrives via the ESG Monday through Friday, it is deemed to have arrived at FDA on the date and time corresponding to the Official Center Acknowledgment (second acknowledgment) that is automatically sent to the submitter by the ESG.  However, except [when a reporting deadline is established in terms of calendar days], if such a submission arrives through the ESG on a weekend, a federal holiday, or another day on which the FDA office that will review the submission is not open for business [(including during a givernment shutdown)], it is deemed to have arrived at FDA on the next day when that office is open for business.  If a submission covered in this guidance is submitted in physical media (e.g., paper or CD-ROM), it is deemed to have arrived at FDA on the date on which it arrived physically at the appropriate receiving unit, while open for business, for the FDA center that will review the submission.

In terms of the hours during which FDA can receive a submission, FDA’s receipt date policy translates into the following table (all times Eastern Standard Time/Eastern Daylight Time):

So, for electronic submissons, FDA is now running on a 24-hour business day clock beginning at midnight.  This is different from how FDA had previously counted days.  It was not too long ago that electronic submissions made to FDA after 4:30 PM Eastern were considered to have been submitted to FDA on the next business day.  Indeed, this is still reflected on at least one FDA webpage:

Q. What is the format of the Official Center Acknowledgement (second acknowledgment)?

A. The Official Center Acknowledgement is a text file that is sent to the sender via the FDA ESG (it is not an email).  This text file contains:

1. the original Message ID for the submission;
2. the date/timestamp for when the submission arrived at the Center;
3.  a unique identifier (called the CoreID) which the FDA ESG assigns to every submission and uses for reference purposes; and
4. a description of the Center business rules for processing of submissions.

An example of the Official Center Acknowledgement is shown below.
MessageId: 666168.1122063776231.JavaMail.rmyneni@mnhu
CoreId: 1122063551533.777@appserver7
DateTime Receipt Generated: 4:25:17,7-22-2005

The date and time stamp contained in this message conveys when (Center name or Programmatic entity) received your submission from the Electronic Submission Gateway.  If your submission was received at (Center name or Programmatic entity) after 4:30 PM EST, the official receipt date for the submission is the next government business day.

The now-abandoned 4:30 PM “pencils down” deadline was critical to The Medicines Company winning a court case concerning the availability of a Patent Term Extension (“PTE”) for ANGIOMAX (bivalirudin).  As we reported at the time, the district court, in its decision, relied on FDA’s 4:30 PM deadline to justify a next business day interpretation of the PTE statute at 35 U.S.C. § 156.  That decision was ultimately incorporated into the PTE statute by Section 37 of the Leahy-Smith America Invents Act (see our previous post here).

Although perhaps best saved for another day, we wonder how (if at all) the change from a 4:30 PM deadline to a Midnight deadline for electronic submissions affects previous submissions, and, in particular, 180-day exclusivity-bearing Paragrpah IV certifications.  For example, under the old system, if an ANDA sponsor submitted a Paragraph IV certification to a newly issued patent by submitting an amendment to its pending ANDA via FDA’s ESG at 4:35 PM on a given day, and the NDA sponsor submitted information on that patent to FDA on the next day at 2:30 PM, FDA would treat the 4:35 PM EST ANDA amendment to have been submitted to the Agency on the next business day, thereby making it effective.  If, however, in this scenario, the ANDA sponsor submitted its Paragraph IV certification amendment to FDA via the Agency’s electronic portal at 4:35 PM on the same day FDA received information on the patent, the Paragraph IV certification would not be considered effective until the next day.  This could be one day too late if another ANDA sponsor, for example, submitted its patent certification amendment to FDA via the Agency’s electronic submission portal at 4:23 PM on the same day FDA received information on the patent and the ANDA amendment was processed by FDA’s servers at 4:29 PM.  

Although FDA’s Receipt Date Guidance does not address any potential complications arising from the changeover from a 4:30 PM deadline to a Midnight deadline, it does address some interesting ANDA Paragraph IV certification issues.  Here’s the set-up:

When an application is submitted electronically, the submission and receipt occur at almost the same time. . . .  For most submissions, the distinction between submission and receipt will have no significance.  In rare instances, however, the date of submission thus determined may differ from the date of receipt, and certain significance may attach to the date of submission.

It’s those “rare instaces” we’re particularly interested in, because if there’s one thing we’ve learned from Hatch-Waxman, it’s that no scenario is too “left field.”  So here are two rather interesting examples of determining receipt date included in an appendix to the guidance:

Example No. 1

Three substantially complete ANDAs are sent to FDA electronically on April 20, all relying on the same reference listed drug and all containing paragraph IV certifications challenging a patent for the reference listed drug.  No applicant has previously challenged the patent.  Of these three ANDAs, the last to arrive is transmitted to the ESG and that transmission is completed at 11:55 pm EST, but that ANDA does not completely arrive at CDER until 12:01 am EST the next day, April 21, according to the second acknowledgment automatically generated by the ESG.  Assuming they pass technical validation, the first two ANDAs will be assigned a receipt date of April 20, and the third will be assigned a receipt date of April 21.  In accordance with GDUFA, however, all three ANDAs will be assigned a submission date of April 20 because the transmission of all three to the ESG was completed on April 20.  Consistent with the guidance 180-Day Exclusivity When Multiple ANDAs are Submitted on the Same Day, all three applicants are regarded as first applicants and may be eligible for shared 180-day generic drug exclusivity. 

Example No. 2

As in the last example, three substantially complete ANDAs are sent to FDA electronically on April 20, all relying on the same reference listed drug and all containing paragraph IV certifications challenging a patent for the reference listed drug.  No applicant has previously challenged the patent.  The third applicant begins transmission to the ESG at 11:55 pm EST on April 20.  Due to a slow connection, transmission to the ESG is not completed until 12:05 am April 21.  Assuming they pass technical validation, the first two ANDAs will be assigned a receipt date of April 20, and the third will be assigned a receipt date of April 21 (receipt dates corresponding to the ESG’s second acknowledgment).  In accordance with GDUFA, the first two ANDAs will be assigned a submission date of April 20, and the third will be assigned a submission date of April 21, the date on which transmission to the ESG was completed.  Consistent with the guidance [in the previous example], the first two applicants are regarded as first applicants and may be eligible for shared 180-day generic drug exclusivity.  The third is not.

So how does a potential first applicant ensure that Example No. 1 and not Example No. 2 plays out for itself?  FDA has some words to the wise: Applicants are “encouraged to make their submissions with time to spare, taking into account possible unexpected delays in transmission time to the ESG.”

By Riëtte van Laack –

On Friday, February 7, 2014, the FTC filed its long-awaited brief in the D.C. Circuit action concerning POM Wonderful LLC’s (“POM’s”) advertising for its pomegranate products (see our previous post here). 

Not surprising, the FTC asserts that POM’s ads were deceptive.  First, the FTC earlier determined that POM’s claims did not constitute “general health benefit” claims but claims (direct and indirect) that POM products fought specific diseases, i.e., atherosclerosis, prostate cancer, and erectile dysfunction.  According to the FTC, the Court may rely on and should give deference to the FTC’s “reasoned analysis” of POM’s advertising claims, asserting that the FTC need not conduct surveys or obtain consumer testimony to support its interpretation of claims.  Moreover, in this case, the FTC asserts that its interpretation is supported by POM’s internal documents produced during discovery.  Second, according to the FTC, there is no question that the claims were false and misleading.  FTC alleges that not only did POM not have one RCT to support its claims but several of POM’s studies showed no or a negative effect.  Yet, according to the FTC, POM continued citing the single study supporting its claims without mentioning the subsequent studies that allegedly showed no or a negative effect. 

As, according to the FTC, POM’s ads were misleading, POM’s First Amendment argument fails; false and misleading claims are not protected.  The FTC acknowledges that First Amendment protection is available to potentially misleading claims that could be presented in a non-misleading manner by adding an effective disclaimer.  However, this case does not concern future potentially misleading claims but past claims that, according to the FTC, were actually misleading, despite disclaimers or disclosures. 

The FTC defends the requirement of two RCTs in the proposed order as a fencing-in provision.  It claims that, under long-standing precedent, fencing-in provisions may be broader than the conduct that is declared unlawful; the FTC may “impose substantiation requirements that are reasonably related to preventing unlawful conduct even though those requirements may exceed what would be required of companies that have not been found liable for deceptive advertising.”  The FTC justifies its choice of the remedy as a method to ensure that POM would not continue “its long track record of distorting scientific evidence when portraying the disease benefits of its product.”  The FTC stresses that the two-RCT requirement applies only to POM’s future claims for disease prevention, risk reduction, and treatment, not to any future claims of general health benefits and not to disease claims that are effectively qualified. 

The FTC did not discuss whether POM should have had positive results from more than one RCT because, in the underlying liability ruling, the FTC concluded that POM lacked positive results from even one RCT. 

POM’s reply brief is due on February 21, 2014.  On February 10, 2014, Public Citizen, Inc. filed a notice of its intent to submit an amicus curiae brief in support of the FTC.  No date for oral argument has been set.

By Riëtte van Laack –

FDA published a proposed rule to implement the Sanitary Food Transportation Act of 2005 (“SFTA”) in the Federal Register on February 5.  FDA also published Questions and Answers related to the sanitary transportation of human and animal food. Enacted in 2005, the SFTA shifted responsibility for safe transportation of food from the U.S. Department of Transportation (“DOT”) to FDA.  The SFTA created new sections of the FDC Act providing that failure to comply with the sanitary food transportation regulations renders the transported food adulterated and is a prohibited act.  It further added section 416, which requires FDA to develop regulations addressing sanitation, packaging, limits on transport vehicles, information exchange among carriers, manufacturers and other persons involved in transportation of food, and transportation-related record keeping.  Five years later, in April 2010, FDA issued both an advance notice of proposed rulemaking and a guidance addressing transportation of food.  Apparently unhappy with FDA’s progress in SFT rulemaking, Congress in FSMA directed FDA to issue SFT regulations by a specific date.  Although FDA failed to meet that deadline, it did meet a court deadline imposed pursuant to litigation regarding FDA’s failure to meet FSMA’s deadlines. 

The proposed rule applies to food shippers, carriers and receivers, “whether or not the food is offered for or enters interstate commerce.”  For purposes of the SFTA food includes human food, dietary supplements, animal food, raw materials, and ingredients (including packaging), and food subject to the Federal Meat Inspection Act, the Poultry Products Inspection Act, and the Egg Products Inspection Act.

FDA's proposed regulation would not apply to:

• Transportation of shelf-stable food that is completely enclosed by a container. 
• Transportation of raw agricultural commodities that is performed by a farm (“farm” is defined in the SFT regulations). 
• Transportation of compressed food gases.
• Transportation of live food animals.

The regulation would affect shippers (a person who initiates a shipment of food by motor or rail vehicle), carriers (the persons who owns, leases, or otherwise are ultimately responsible for the use of a motor or rail vehicle to transport food), and receivers (persons who receive food after transportation, whether or not they represent the final point of receipt for the food) that are engaged in “transportation operations” for food.  It establishes requirements for:

• Vehicles and transportation equipment
• Transportation operations
• Information exchange
• Training
• Records
• Waivers

Shippers, carriers, and receivers must employ effective measures to protect food during transportation.  For example, shippers must inform their carriers about the requirements for the transported products, such as temperature control, and verify cleanliness of the transportation equipment before shipment.  Carriers will have to supply vehicles that meet the shipper’s requirements, implement procedures to govern their SFT activities, and train employees.

Under the FDC Act, FDA has the authority to waive any of the SFT requirements “with respect to any class of persons, vehicles, food, or nonfood products” for which the Agency determines that a waiver will not (1) result in transportation of food under unsafe conditions and (2) be contrary to the public interest.

The proposed regulation includes a process by which a party may request a waiver.  In addition, FDA has tentatively determined that it is appropriate to waive the SFT requirements for:

1. Shippers, carriers, and receivers who hold valid permits and are inspected under the NCIMS Grade “A” Milk Safety Program, only when engaged in transportation operations involving Grade A milk and milk products.
2. Food establishments (as defined in the Food Code) holding valid permits, only when engaged in transportation operations as receivers, or as shippers and carriers in operations in which food is relinquished to consumers after transportation from the establishment.

To what extent these regulations will have a noticeable effect on safety of food remains to be seen.  In Questions and Answers regarding the proposed regulations, FDA acknowledges that the risk of contamination from transportation is low. Moreover, the Agency indicates that although it has funding to issue the rule, it will need additional funding to fully implement the rule.  For enforcement, the Agency will depend on assistance from the DOT and state personnel.

Comments may be submitted until May 31, 2014.  In part, FDA requests comments on: 

• whether the provisions should be applicable to activities that are intrastate in character;
• FDA’s tentative conclusion that shelf stable food that is completely enclosed by a container, compressed food gases, and live food animals should be excluded from the scope of the proposed rule;
• the proposed waivers.

By Jennifer D. Newberger & Alan M. Kirschenbaum –

Last Friday, CMS issued a notice announcing the opening of registration for electronic Open Payments reporting under the physician payment sunshine provisions of the Affordable Care Act.  (A previous post on the sunshine provisions and our memo summarizing CMS’s final implementing rule can be found here.)  According to the final rule, issued almost one year ago, applicable manufacturers and GPOs must complete their reports by March 31, 2014 for payments and transfers of value made during the August 31-December 31, 2013 timeframe.  However, in today’s notice, CMS indicates that the reporting will occur in two phases, the second of which will not be completed until June or later.

The CMS notice states that its registration portal will be available beginning February 18.  During the first phase, from February 18 to March 31, users are to register and submit corporate profile information and “aggregate 2013 payment data.”  The second phase, beginning in May and extending for no fewer than 30 days, will include the completion of registration, “submission of detailed 2013 payment data,” and attestation to the accuracy of the data. 

Prior to this notice, CMS had not indicated that Open Payments reporting would be a two-phased process, nor that reporting of payments would be bifurcated into “aggregate payment information” followed by “detailed payment information.”    The notice does not explain what is to be included in the former.  Presumably, this question will be addressed in a webinar that CMS says will be announced next week, which will be “aimed at providing extensive discussion of the phased approach to Open Payments registration and data submission.”

By John A. Gilbert & Delia A. Deschaine –

As previously reported here, late last year, CDER Director, Janet Woodcock issued a statement indicating FDA’s intent to recommend that DEA reclassify hydrocodone-combination products in Schedule II.  (We note that scheduling recommendations are made to DEA by the Assistant Secretary for Health at HHS, but in practice FDA is generally responsible for drafting the recommendation.)  And, as also previously reported here, on December 26, 2013, a Citizen Petition (“CP”) was filed with FDA requesting that the agency modify any such recommendation to exclude lower strength hydrocodone-bitartrate products.  The CP was intended to at least put HHS and FDA on notice of concerns about the rescheduling of these products; it seems to have also had the effect of smoking out where HHS and DEA are in the rescheduling process.  

In an article published on February 7th by FDA Week/Inside Health Policy, a DEA Spokeswoman is quoted as saying that the agency has received the recommendation from HHS and the proposal is under review.  DEA did not state when the recommendation was received by the agency.  Both agencies have traditionally considered such communication as inter-agency communications not subject to public disclosure.  Further, it appears that neither HHS nor DEA has disclosed what the recommendation is at this point.  It is fair to assume that the recommendation is consistent with CDER Director’s statement – that all hydrocodone-combination products be reclassified in Schedule II. 

At some point DEA will have to issue a Notice of Proposed Rulemaking.  At that point the industry will have the opportunity to comment on any proposed change in the scheduling.   

By Wes Siegner –

On January 21 we posted on FDA’s unusual decision to reopen the comment period for the final guidance on INDs with respect to food and cosmetic research.  Subsequently we learned that 60 university department heads submitted a comment to FDA’s Final IND Guidance on November 6, 2013.  The comment vigorously opposed implementation of the guidance with respect to food research, and was likely a significant reason for FDA’s decision to reopen comment on a final guidance.   Today, FDA published a Federal Register Notice reopening the comment period on the IND Guidance for 60 days.

Quoting from the department heads’ comment:

Foods and drugs are statutorily defined by the Federal Food, Drug, and Cosmetic Act (FD&C Act).  Recommending a “drug-level” approach to research for foods through the filing of INDs:

• would have a paralyzing effect on clinical research in the U.S. and stifle innovation and product development;
• is unnecessarily burdensome to academic and organization institutional review boards; 
• is outside the scope of current laws/regulations and inconsistent with the FDA’s charter;
• contravenes the statutory and regulatory definition for foods; and
• represents the creation of regulatory guidance that was not developed through a transparent and open process.

For these reasons, we urge you to take immediate action to stop implementation of the new confusing and contradictory IND Guidance. 

The Department Heads urged FDA to open a dialogue with stakeholders to “review and consider the potential impact on the public, health care providers, academia, government and industry.”  It appears that FDA, in reopening the comment period, may have heeded this message.  Regardless, it is important, now that the comment period has been reopened, for others who are negatively impacted to submit comments on this guidance.

By Larry K. Houck –

The National Association of Boards of Pharmacy (“NABP”), along with a coalition of healthcare stakeholders, recently announced collaborative steps to address prescription drug abuse and practitioner compliance with federal and state corresponding responsibility requirements while ensuring that patients receive needed medical care.  Thirteen healthcare stakeholders, including NABP, the American Medical Association, Federation of State Medical Boards, National Association of Chain Drug Stores, Cardinal Health, CVS Caremark, Rite Aid and Walgreens met twice late last year to discuss these important, sometimes conflicting, issues.  The stakeholders will issue a consensus document that identifies “red flags” or circumstances under which actions “should be initiated to ensure the legitimacy of a controlled substance prescription.”  A second consensus document will provide industry guidelines concerning how to “engage in and improve the dialogue and collaboration among stakeholders” to address so-called red flags and to eliminate confusion caused by the “diversity of current proprietary policies.” 

Much has been written about the Drug Enforcement Administration’s (“DEA’s”) recent focus away from non-legitimate prescribing by medical practitioners to an increased focus on dispensing pharmacists, drug manufacturers and distributors as controlled substance “gatekeepers” or “chokepoints” further up the distribution chain.  The Agency has increasingly held these non-prescribers accountable for dispensing controlled substances pursuant to prescriptions not issued for a legitimate medical purpose.  DEA regulations have long established that a corresponding responsibility rests with pharmacists to ensure that a prescription has been issued for a legitimate medical purpose by an individual practitioner acting in the usual course of professional practice.  21 C.F.R. § 1306.04(a).  And, relying on the vague requirement that manufacturers and distributors design and operate a system to disclose to the registrant and report suspicious controlled substance orders (21 C.F.R. § 1301.74(b)), DEA has held them accountable for their pharmacy customers’ dispensing of controlled substances for other than legitimate medical purposes.  DEA has taken administrative actions against, and U.S. attorneys’ offices have sought and obtained millions of dollars in civil penalties, from pharmacies, manufacturers and distributors for their alleged failure to comply with DEA regulations concerning controlled substance dispensing and distribution.

The collaborative efforts by the NABP and the healthcare stakeholders are a positive development for everyone.  Clarifying prescription “red flags” and how stakeholders should communicate and collaborate with one another will benefit everyone, particularly patients in legitimate need of opioids and other controlled substances.

By William T. Koustas –

The litigation between Regenerative Sciences, LLC (“Regenerative”) and FDA may have come to an end on Tuesday, February 4th, when the United States Court of Appeals for the District of Columbia Circuit ruled against Regenerative, concluding that FDA has the authority to regulate certain autologous stem cell procedures.  The D.C. Circuit affirmed the lower court’s decision granting summary judgment to the government, dismissing Regenerative’s counterclaims, and permanently enjoining Regenerative’s operations.  

Regenerative is a Colorado company that owns a medical technique known as the Regenexx Procedure, which for the purposes of this case we understand is limited to a non-surgical procedure by which physicians take bone marrow and blood samples from a patient, culture the stem cells, mix the cultured cells with doxycycline, and inject the stem cell mixture back into the same patient in order to treat joint, muscle, tendon, or bone pain.  This procedure is exclusively licensed for use by a Colorado clinic where its inventors practice.

Our prior blog posts on this case provide more background (see here and here for example), but in essence, FDA’s litigation stance was that the stem cell mixture used in the Regenexx Procedure was a drug under the Federal Food, Drug, and Cosmetic Act (“FDCA”), thus imposing current Good Manufacturing Practices (“cGMP”) and labeling requirements applicable to all drugs.  On the other side, Regenerative argued that FDA had no authority over the Regenexx Procedure because it involved the practice of medicine, which is outside of FDA’s purview, and because the stem cell mixture was not introduced or delivered for introduction into interstate commerce.

The D.C. Circuit upheld the district court’s decision, frequently relying on long-standing principles of food and drug law.  The court first found that the stem cell mixture met the definition of drug contained in the FDCA as it was “an article derived mainly from human tissue intended to treat orthopedic diseases and to affect musculoskeletal function.”  Slip Op. at 6.  In addition, and perhaps of more consequence, the court disagreed with Regenerative’s argument that FDA was interfering with the practice of medicine by preventing physicians from performing autologous stem cell procedures.  The D.C. Circuit described this argument as “wide of the mark,” clarifying that FDA was seeking to regulate the stem cell mixture and not the procedure itself.  Id. at 7.  

The court also rejected Regenerative’s argument that FDA lacked jurisdiction over the stem cell mixture given that the Regenexx Procedure is performed entirely within the State of Colorado.  Unsurprisingly, the court restated the well-known principle that the interstate commerce requirement of the FDCA is satisfied if a component of a product is shipped in interstate commerce prior to its administration to a patient.  Id. at 9.  The court also seemed to agree with FDA’s position that the interstate commerce requirement could be satisfied simply because the stem cell mixture would “undoubtedly have effects on interstate markets for orthopedic care . . . .”  Id. at 8.   

The D.C. Circuit also dismissed Regenerative’s argument that the stem cell mixture was a human cell, tissue, or cellular and tissue-based product (“HCT/P”), and thus exempt from manufacturing and labeling requirements.  The court found that the stem cell mixture was likely more than “minimally manipulated” “[b]ecause [Regenerative] concede[d] that culturing [stem cells] affects their characteristics and offer[ed] no evidence that those effects constitute only minimal manipulation, they fail to carry that burden as a matter of law.”  Id. at 12.  

After summarily rejecting Regenerative’s arguments, the D.C. Circuit ruled that the stem cell mixture was adulterated and misbranded.  The court found that the stem cell mixture was adulterated because it was not “manufactured” in conformance with cGMP requirements, and that they were misbranded because the information on the “label” on the syringe that contains the stem cell mixture did not include “adequate directions for use” or bear the “Rx only” symbol.  Id. at 14-15. 

Although the court upheld the permanent injunction, it did so only after analyzing whether there was a reasonable likelihood of further violations in the future.  Id. at 18.  While the court determined that such likelihood existed in this case, this suggests that a violation of the FDCA, in and of itself, does not automatically necessitate injunctive relief but must be considered based on the facts of each case.