By Jeffrey K. Shapiro –

There has been a lot of talk about hostage taking during the recent federal government budget impasse.  But Congress is not the only one taking hostages in Washington.  The recent draft Medical Device Reporting (MDR) guidance reminds us (pp. 4-5) about a long forgotten hostage moldering in FDA’s statutory implementation dungeon. 

To be specific, Section 227 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) amended Section 519 of the Federal Food, Drug, and Cosmetic Act (FDCA) to ease the burden of malfunction MDR reporting by requiring only summary quarterly reporting for most class I and II devices.   

Congress directed that revised malfunction MDR reporting shall be “in accordance with criteria established by [FDA] for reports … which criteria shall require the reports to be in summary form and made on a quarterly basis.”  519(a)(1)(B)(ii).  

This change does not apply to class III devices, class II devices that are permanently implantable, life supporting, or life sustaining, and such other devices as FDA may designate in a “notice published in the Federal Register or letter to the person who is the manufacturer or importer of the device.”  Section 519(a)(1)(B)(i)(III).

Unfortunately, a full six years has passed, and nothing has happened.  In 2011, FDA issued a notice reminding industry that malfunction MDR reporting should continue as usual.  76 FR 12743.  In 2013, FDA has now reminded everyone again in the draft MDR guidance that nothing has changed.

Interestingly, the FDAAA Implementation Chart on FDA’s website does not even show the malfunction MDR reporting change as an item intended for implementation.  There should be a row for Section 227, but the chart skips from Section 226 to 228, with not a word about implementation of Section 227.  

Is this long delay really necessary?  According to the federal register notice, FDA is delaying implementation of the quarterly MDR reporting change until:

1. The agency publishes a federal register notice listing the additional class I and II devices not eligible for quarterly reporting pursuant to Section 519(a)(1)(B)(i)(III) of the FDCA; and
2. The agency conducts a rulemaking to establish the criteria for summary quarterly reporting for most class I and II devices pursuant to Section 519(a)(1)(B)(ii) of the FDCA.

Thus, implementation of the change is being held hostage to the agency’s own inaction.

As to the first item, Section 519(a)(1)(B)(i)(III) was intended to give FDA the regulatory flexibility to designate additional devices ineligible for quarterly reporting.  Nothing in the statute indicates that FDA’s designation of a complete list of such devices is a threshold requirement for implementation of quarterly reporting.  FDA’s failure to issue this list is not a valid basis for holding up implementation of quarterly reporting for the majority of class I and II devices.

As to the second item, keep in mind that even when FDA finally initiates a rulemaking, it typically takes several years until a final rule is issued.  With no rulemaking even begun, FDA appears on track to exceed 10 years in implementing this simple statutory requirement.  This delay is unacceptable.

Furthermore, the statute merely says that quarterly reporting shall be under criteria to be “established” by FDA.  The word “established” does not require a rulemaking, but could be achieved by a guidance.  Given the six year delay, at this point, it would be prudent for FDA to issue a guidance.  Even that process would probably require one to two years.  A benefit to issuing a guidance would be to allow FDA to gain some experience with widespread quarterly reporting before codifying  the requirements in a regulation.  It would also allow the agency to actually implement quarterly reporting inside of a decade.

By the way, Section 226 of FDAAA amended Section 519 to require FDA to establish a system of unique device identifiers.  This provision directs FDA to “promulgate regulations establishing a unique device identification system.”  Thus, Congress knew how to direct FDA to initiate a rulemaking when one was desired.  The absence of a similar requirement to “promulgate regulations” in Section 227 bolsters the interpretation that Congress did not intend for FDA to conduct a rulemaking to establish criteria for quarterly summary MDR reporting.

Congress has made the judgment that quarterly malfunction MDR reporting is sufficient to protect the public health for most class I and II devices.  Six years later, it is long past time for FDA to let this hostage go.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Kermit L. Jones, J.D., M.D. has joined the firm as an Associate.  Prior to joining the firm, Dr. Jones served as a 2012-2013 White House Fellow assigned to the Secretary of Health and Human Services, the Honorable Kathleen Sebelius.  In this role, Dr. Jones briefed the Secretary on issues of importance to senior leadership at the Department of Health and Human Services, such as the arguments and positions in the Supreme Court case, Assoc. for Molecular Pathology v. Myriad Genetics, Inc. (133 S. Ct. 2107 (2013)).  He helped lead the Secretary’s efforts to engage states, licensing bodies and federal government agencies working to secure private sector licensing for military medical personnel. 

Dr. Jones also assisted stakeholders at the NIH, FDA, and within the non-profit and pharmaceutical sectors in evaluating the effectiveness of several recent initiatives that increase private-public collaboration in the rescue and repurposing of therapeutics.   Prior to the White House Fellowship, Dr. Kermit Jones served as a Navy Flight Surgeon with the Marine helicopter casualty evacuation squadron, the HMM-364 Purple Foxes, in Al Habbaniyah, Iraq.  While in Iraq, he provided medical care for U.S. service members and Iraqi citizens. 

Dr. Jones is a graduate of the Columbia University School of International and Public Affairs (2012), and both the Duke University School of Law (2005) and School of Medicine (2005). While at Duke, Dr. Jones was a Mordecai Scholar and spent semesters abroad at the London School of Hygiene and Tropical Medicine and the Christian Medical College and Hospital, in India.  He is conversational in Hindi and Urdu and admitted to practice law in Pennsylvania and medicine in New York.  His application to practice law in the District of Columbia is pending.

By Riëtte van Laack & Ricardo Carvajal –

On September 19, 2013, Cargill entered into a $5 million settlement agreement to dispose of a class action lawsuit regarding its advertising for Truvia® products as “natural.”  Plaintiffs charged that the products are not natural because they contain ingredients that are “‘highly processed,’ synthetic and/or derived from GMOs,” and that the descriptions of the products and their ingredients, namely stevia leaf extract and erythritol, are inaccurate or misleading.  In the agreement, Cargill denies that its marketing, labeling, and advertising violate any legal requirement.

The agreement is intended to address all current and future claims concerning the marketing of the products as natural (for purposes of the settlement, Cargill recognized a nationwide class of consumers).  The agreement consists of four components: 1) the $5 million settlement to cover attorney’s costs (1.59 million) and consumer refunds, 2) an administration fund of 300,000 dollars, 3) modifications to claims on packaging and labels, and 4) modifications to the website.

Interestingly, the parties agreed that Cargill can continue the use of the tagline “Nature’s Calorie-Free Sweetener” on labels, as long as the tagline is linked to a statement referring consumers to FAQs on the website where they can obtain more detailed information on the product’s manufacture (more about that in a moment).  Cargill can also continue to describe erythritol as a “natural sweetener” on labels, but instead of stating that it is produced by a “natural process,” Cargill will state that it is produced by a “fermentation process.”

The FAQs on the website address the processing of stevia leaf in some detail.  In essence, the leaves are harvested, dried, and steeped in hot water, and the extract is then filtered, purified, and dried.  The FAQs also address the production of erythritol.  Notwithstanding the label changes described above, the FAQ agreed to for erythritol states that it is “produced through a natural fermentation process” – a reaffirmation of sorts that fermentation is a natural process.  The FAQs also include the following explanatory text on processing aids:  

Like in other finished foods, including sugar, processing aids suitable for use in food are used in the production of both stevia leaf extract and erythritol. These aids help either extract, isolate or purify components of the ingredients. Under the U.S. Food and Drug Administration regulations, our processing aids are not subject to labeling requirements because they have no technical or functional effect in the finished food and because they are either not present or are present at only insignificant levels in the finished product.

The agreement disclaims any intent to address the merits of the claims, but could still have an impact.  It would not be surprising to see a trend toward greater disclosure with respect to processing methods, especially given the continuing lack of clarity regarding the meaning and scope of “natural.”

The preliminary settlement hearing, in which the Court will consider whether it should approve the proposed settlement, is scheduled for October 23, 2013.

By Jay Cormier & Alan Kirschenbaum –

The Patient Protection and Affordable Care Act made extensive changes to the 340B drug discount program, which we have previously described.  Among other things, the statute expanded the categories of covered entities entitled to purchase drugs at the statutory ceiling price.  It also provided an exemption from the ceiling price for designated orphan drugs when purchased by certain of these covered entities (the so-called “orphan drug exclusion”). 

For readers not familiar with the 340B Program, section 340B of the Public Health Services Act requires drug manufacturers, as a condition of Medicaid and Medicare Part B coverage of their product, to sell outpatient drugs to “covered entities” at a price no greater than a statutory ceiling price.  Congress’ intent was to provide outpatient prescription drug assistance to vulnerable uninsured patients.  The list of covered entities, as expanded by the Affordable Care Act, includes certain federally subsidized clinics and certain safety net hospitals, including disproportionate share hospitals, children’s hospitals, certain free-standing cancer hospitals, critical access hospitals, rural referral centers, and sole community hospitals. 

The orphan drug exclusion in the Affordable Care Act provides that a drug eligible for 340B pricing “shall not include a drug designated by the Secretary under [section 526 of the Federal Food, Drug, and Cosmetic Act] for a rare disease or condition.”  42 U.S.C. § 256b(e).  This exception applies to cancer hospitals, critical access hospitals, rural referral centers, and sole community hospitals. 

In late July, the Health Resources and Services Administration ("HRSA") issued a final implementing rule, codified at 42 C.F.R. § 10.21, providing that the orphan drug exclusion applies only to orphan drugs that are “transferred, prescribed, sold, or otherwise used for the rare condition or disease for which that orphan drug was designated.”  76 Fed. Reg. 44,016 (Jul. 23, 2013) (see our previous post regarding the proposed rule).

As threatened in their comments on the proposed rule, the Pharmaceutical Research and Manufacturers of America ("PhRMA") has filed a complaint and application for a preliminary injunction in the U.S. District Court for the District of Columbia, with supporting memorandum, claiming that HRSA’s orphan drug rule violates the Administrative Procedures Act ("APA").  Specifically, PhRMA alleges that (1) HRSA did not have the authority to promulgate the final rule, and (2), even if HRSA did have such authority, the final rule conflicts with the plain statutory language of the Affordable Care Act, which, according to PhRMA, exempts all uses of designated orphan drugs from the ceiling price, not just those used for the orphan indication.  PhRMA is seeking a declaration that HRSA violated the APA, a preliminary injunction, and an order invalidating and enjoining the enforcement of the final rule.

Will PhRMA prevail on the merits of this case?  That is the question.  We will be following this case during the coming months and will provide you with updates.

The case is Pharmaceutical Research and Manufacturers of America v. US Department of Health and Human Services, et al., Civil Action No. 1:13-cv-01501 (D.D.C.).

By John R. Fleder –

On September 26, 2013, the United States Attorney for the District of Colorado announced that he had filed a six count criminal Information against Eric and Ryan Jensen.  The government alleges that the defendants violated the FDC Act by introducing adulterated cantaloupes into interstate commerce.  The government also alleges that the cantaloupes bore Listeria monocytogenes and 33 people died.  It is quite curious (we are being charitable here) that the government’s press release alleges that 147 people were hospitalized as a result of sales of the cantaloupes, but those allegations appear nowhere in the criminal Information!

The prosecution is a misdemeanor case, and does not allege any criminal “intent” on the part of the defendants.  There is no public indication that the defendants are prepared to plead guilty and/or cooperate with the government against others.  This fact pattern strongly suggests that this case is an old style Park criminal prosecution where the government files criminal charges under the FDC Act against company officials, without allegations that the defendants intended to violate the law and without a plea bargain that a misdemeanor prosecution is a settlement of more serious felony charges.  Our speculation is that a thorough government investigation here failed to turn up evidence that the defendants violated the FDC Act “with the intent to defraud or mislead,” which would be necessary to commence felony charges under the FDC Act.  In fact, the government used a grand jury to investigate this case, even though it can file a criminal Information involving misdemeanor charges without using a grand jury.

The second interesting twist in this case is that arrest warrants were issued for the defendants.  Arresting defendants charged only with misdemeanors was certainly not the norm with regard to old style Park prosecutions.  Typically, the defendants were simply notified of the charges and came to court voluntarily to enter their guilty or not guilty pleas.

By Kurt R. Karst –   

It was not a question of whether, but when FDA would issue its first Warning Letter to a facility covered by the Generic Drug User Fee Amendments of 2012 (“GDUFA”) that failed to self-identify its facility and pay applicable user fees.  That day has come.  In a September 17, 2013 Warning Letter posted on FDA’s website earlier this week, the Agency says that Feldkirchen-Westerham, Germany-based C.P.M. Contract Pharma GMBH & Co. KG (“CPM Contract Pharma”) failed to self-identify its Finished Dosage Form (“FDF”) manufacturing facility and pay applicable user fees.

GDUFA establishes four types of user fees that together generate funding for FDA each fiscal year.  One of the fees – the annual facility fee –  must be paid by both FDF and Active Pharmaceutical Ingredient (“API”) manufacturers.  Facility fees are the most significant of all GDUFA user fees, and FDF facility fees in particular (see our previous post here).  The API and FDF facility fees are based on data submitted by generic drug facilities through the so-called self-identification process (see here and here).  In a draft guidance document titled “Self-Identification of Generic Drug Facilities, Sites, and Organizations,” and in an accompanying Q&A, FDA lays out the so-called “self-identification process.”  As explained in the draft guidance:

Self-identification is required for two purposes.  First, it is necessary to determine the universe of facilities required to pay user fees.  Second, self-identification is a central component of an effort to promote global supply chain transparency.  The information provided through self-identification will enable quick, accurate, and reliable surveillance of generic drugs and facilitate inspections and compliance.

Facilities that fail to self-identify and pay applicable user fees are subject to some pretty significant penalties:

1. Identification of the facility on a publicly available arrears list, such that no new applications from the person that is responsible for paying such fee, or any affiliate of that person, will be received by FDA;
2. New generic drug submissions to FDA that reference a non-compliant facility will not be received unless the fee is timely paid; and
3. All FDFs or APIs manufactured in such a facility or containing an ingredient manufactured in such a facility are deemed misbranded under FDC Act § 502(aa).

These pentalties apply until the facility fee is paid or until the facility is removed from all generic drug submissions that refer to the facility.  The misbranding penalty is particularly harsh.  It was a point of contention during GDUFA negotiations, but we understand FDA demanded that it be included in the law to give it some teeth.

FDA’s Warning Letter to CPM Contract Pharma pulls out all the stops.  According to FDA:

The above-referenced facility is a drug manufacturing facility as defined under GDUFA.  It was identified as a finished dosage form manufacturer in [REDACTED] on the date for self-identification for fiscal year 2013 and fiscal year 2014 and on the due date for facility fees for fiscal year 2013, but has not self-identified or paid facility fees as required by that law.  Therefore, all finished dosage forms of drugs or APIs, as well as drug containing an API, manufactured at the facility are misbranded.
 
Your facility has been placed on a publicly available arrears list.  Failure to correct these violations promptly may result in regulatory action, including but not limited to seizure or injunction without further notice.  Your facility may also be placed on import alert such that any drug the facility manufactures will be refused admission into the United States.

FDA’s Warning Letter is the latest in a string of events as the Agency continues to ramp up GDUFA implementation.  Not everything FDA has done has been welcomed by the generic drug industry (see our previous post here); however, other aspects are improvements vis-à-vis the pre-GDUFA era.  For example, earlier this week, FDA published a detailed draft guidance, titled “ANDA Submissions – Refuse-to-Receive Standards,” providing helpful insight on the circumstances under which the Agency may refuse to accept an ANDA submission, including failure to pay applicable GDUFA user fees.  

By Ricardo Carvajal & Kurt R. Karst –

According to contingency plans drawn up by the Department of Health and Human Services, 45% of FDA’s nearly 15,000 staff were to be furloughed in the absence of enacted annual appropriations – popularly referred to as a government shutdown.  Now that the shutdown has materialized, the effects will be felt throughout the agency, but the blow is likely to be softened (at least in the near term) for centers that operate programs funded by industry-paid user fees (e.g., drugs and tobacco products).  For those FDA components, carryover balances from user fees previously collected under the Prescription Drug User Fee Act, the Generic Drug User Fee Amendments, the Medical Device User Fee Amendments, the Animal Drug User Fee Act, the Animal Generic Drug User Fee Act, and the Family Smoking Prevention and Tobacco Control Act can be spent – until exhausted – on activities for which the fees are authorized under the statute.

That’s not to say programs funded by user fee carryover balances will escape unscathed.  As indicated in a notice posted on FDA’s website on the first day of the shutdown (referred to as "the lapse period"):

With respect to medical product user fees, during the lapse period, FDA will not have legal authority to accept user fees assessed for FY 2014 until an FY 2014 appropriation for FDA is enacted. This will mean that FDA will not be able to accept any regulatory submissions for FY 2014 that require a fee payment and that are submitted during the lapse period.

Hardest hit is FDA’s foods program, which is generally not funded by user fees.  By all accounts, the majority of activity in that program has ground to a halt.  In particular, notification programs such as those for GRAS uses of substances, food contact substances, and infant formula have ceased operation, leaving a number of submissions in limbo. 

The effects of the shutdown will also be felt in relation to services that are not center-specific.  For example, the Division of Dockets Management is shuttered and will remain so indefinitely.  It is not clear how, in the interim, any submissions that must be made in person at the Division of Dockets Management will be handled (e.g., original citizen petitions).  For routine docket submissions, the regulations.gov website says: "You can still submit comments to agencies using Regulations.gov during the shutdown."

Also, it appears that other operations, such as recall operations, have been significantly curtailed and that remaining resources will be focused as necessary for the protection of human life.

By William T. Koustas & Jessica A. Ritsick –

With California’s electronic pedigree requirement set to take effect in 2015, we have been following recent efforts by Congress to enact a national prescription drug track and trace system (see our previous posts here, here, here, and here).  The House passed a bill in June, H.R. 1919, that would create a national pedigree system and the Senate Committee on Health, Education, Labor, and Pensions (“the Senate Committee”) passed a similar bill, S. 959, in May.  Then, late on September 25, 2013, leaders from the Senate and House committees overseeing health care policy announced that they reached an agreement on bipartisan and bicameral legislation (“bicameral legislation”) that would amend the Federal Food, Drug, and Cosmetic Act (“FDCA”) to address compounding pharmacies and incorporate a national prescription drug track and trace system as well as national standards for prescription drug wholesale distributors (“wholesalers”) and third-party logistics providers (“3PLs”).  The House passed the bicameral legislation, the Drug Quality and Security Act (H.R. 3204), on September 28, 2013 by voice vote.  A detailed outline of the bicameral legislation prepared by Hyman, Phelps & McNamara, P.C. can be found here.

The track and trace system (i.e., pedigree) set forth in the bicameral legislation would preempt state pedigree requirements and eventually create a national interoperable electronic prescription drug track and trace system.  While the bicameral legislation is in many respects similar to the Senate Committee’s bill, it contains some significant differences.

The bicameral legislation provides specific track and trace requirements for manufacturers, wholesalers, repackagers, and dispensers (e.g., pharmacies) of prescription drugs.  Unlike the Senate Committee’s bill, it does not require 3PLs to be responsible for pedigrees.  Under the bicameral legislation, manufacturers would be required to include a product identifier number on each “package and homogeneous case” of prescription drug product they produce within four years of enactment, while repackagers would be required to include it within five years.    In the meantime, the bicameral legislation requires manufacturers, wholesalers, repackagers, to provide and/or receive pedigree by January 1, 2015, while dispensers are required to do so by July 1, 2015.  In addition, wholesalers would be required to accept and distribute only those prescription drug products that include product identifiers within six years, while dispensers would be required to only receive proscription drug products with a product identifier within seven years.  As such, other than for 3PLs, the timelines for incorporating and distributing drug products with a product identifier for manufacturers, wholesalers, dispensers, and repackagers remains unchanged from the earlier Senate Committee’s bill.

In addition to product identifier requirements, the bicameral legislation also mandates that manufacturers, wholesalers, repackagers, and dispensers implement a system to verify that prescription drug products under their control are legitimate (e.g., not counterfeit, diverted, stolen, or otherwise adulterated).  If a “suspect” drug product is determined to be illegitimate, the entity must take the necessary steps to purge it from the supply chain.  Both pieces of legislation allow FDA or any trading partner to request verification from a drug’s manufacturer. 

Both the Senate Committee’s bill and the bicameral legislation initially allow for pedigrees to be transmitted and maintained in either paper or electronic format.  However, both bills mandate that an interoperable electronic system be implemented within 10 years of enactment.  This interoperable electronic system must be able to track and trace prescription drug products at the package level in accordance with standards established through guidance.  As such, FDA would be required to issue guidance documents for each of the following:  1) standards for an interoperable electronic system (within one year of enactment); 2) suspect and illegal products (within 180 days of enactment); 3) unit level tracing (within 18 months of a public meeting); and 4) revisions to the interoperable electronic system guidance (within 18 months of a public meeting).  Some of these guidance documents cannot be issued before a series of public meetings which cannot be held prior to one year after the legislation is enacted.  Both the bicameral legislation and the Senate Committee bill also requires FDA to establish at least one pilot program to “explore and evaluate methods to enhance the safety and security of the pharmaceutical distribution supply chain.”  

The bicameral legislation also sets requirements for the licensing and operation of wholesalers and 3PLs.  This includes the creation of national wholesaler and 3PL licenses in cases where states do not license such entities.  However, similar to the Senate Committee’s bill, the bicameral legislation continues to allow states to collect licensing fees and direct administrative fines for wholesalers and 3PLs licensed by the state.  Additionally, wholesalers and 3PLs are required to submit annual reports to FDA beginning on January 1, 2015.  These reports would include information regarding each state where the wholesaler or 3PL is licensed, the name and address of each facility, and contact information.  Both the Senate Committee’s bill and the bicameral legislation preempt state pedigree requirements. 

The bicameral legislation appears to have the support of congressional leaders from both parties.  With passage secured in the House, it is expected that the full Senate will take up this legislation soon.  A national prescription drug track and trace system is closer to becoming a reality than ever before.

By William T. Koustas – 

We have previously reported (here and here for example) on the litigation between Regenerative Sciences, LLC (“Regenerative”) and FDA.  Regenerative is a Colorado company that owns a medical procedure known as the Regenexx Procedure.  It is a non-surgical procedure by which physicians take bone marrow and blood samples from a patient, culture and process the stem cells, and inject them back into the same patient in order to treat joint, muscle, tendon, or bone pain.  The Regenexx Procedure is exclusively licensed for use by the Colorado clinic where its inventors practice. 

As reviewed in more detail in our prior posts, FDA contends that, among other things, the stem cells processed in the Regenexx Procedure are a drug under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and must therefore only be created pursuant to a New Drug Application and under current Good Manufacturing Practices.  Regenerative responds that the Regenexx Procedure is the practice of medicine, which is outside of FDA’s jurisdiction and the stem cells are not introduced or delivered for introduction into interstate commerce since the entire process is performed in Colorado. 

The U.S. District Court of the District of Columbia ultimately sided with FDA, although it called the decision a “close question.”  The Court found that the stem cells used in the Regenexx Procedure are a drug as defined under the FDCA and that FDA has jurisdiction to regulate this procedure “because a component of the [Regenexx Procedure] shipped through interstate commerce prior to its administration to the patient,” thus satisfying the interstate commerce requirement in the FDCA.

However, with the case now pending before the U.S. Court of Appeals for the District of Columbia Circuit, a new report authored by Richard A. Epstein from the Manhattan Institute’s Center for Legal Policy (“the Report”) calls into question the legal and policy bases for FDA’s regulation of autologous stem cell procedures like the Regenexx Procedure.

The Report, titled “The FDA’s Misguided Regulation of Stem-Cell Procedures: How Administrative Overreach Blocks Medical Innovation,” contends that FDA “has taken the aggressive position that it has oversight authority over any stem-cell procedure that reinjects harvested stem cells into the same person from whom they were removed, so long as those cells were grown and cultured outside the human body.”  Among other things, the Report argues that FDA and the district court incorrectly interpret the interstate commerce provision in the FDCA while also improperly determining that the stem cells in the Regenexx Procedure are drugs rather than part of the practice of medicine. 

With respect to FDA’s position that is has authority to regulate autologous stem cell procedures pursuant to the interstate commerce provision in FDCA § 301(a), the Report contends that the statutory authority provided in the FDCA does not extend as far as the Constitution’s Commerce Clause.  The Report points to the fact that the interstate commerce language in the FDCA pre-dates the Supreme Court’s Wickard v. Filburn, 317 U.S. 111 (1942), decision and is therefore meant to reflect a pre-Wickard reading of interstate commerce.  As such, “the statutory requirement…is not whether a reagent used in the process has moved in interstate commerce but whether the dangerous (‘adulterated or misbranded’) article itself has moved in interstate commerce.”  Therefore, while the Constitution’s Commerce Clause would allow Congress to regulate autologous stem cells due to use of reagents that traveled through interstate commerce, the FDCA’s interstate commerce provision would not. 

In addition, the Report suggests that the “held for sale” language of FDCA § 301(k) only applies to articles that were themselves part of an interstate commerce transaction.  However, the stem cells used in the Regenexx Procedure were never part of an interstate transaction themselves and were therefore not held for sale in an interstate transaction.

The Report also makes the case that the Regenexx Procedure is the practice of medicine rather than the manufacture of a drug as FDA contends.  The Report analogizes the Regenexx Procedure to dental work by noting that, “[t]he process in question would normally be regarded as a provision of services for which the growth of the cells under these highly specified procedures would be regarded as, at most, an ‘incidental’ element to the transaction, just as a dentist who prepares mixtures for fillings is regarded as having supplied services and not as having manufactured and sold a mixture of silver and bonding solutions.”  The report also notes the basic differences between cultivating autologous stem cells and the mass production of drugs, arguing that the “…uniqueness [of the cultivating of stem cells] makes it relatively easy…to engage in the upstream regulation of these products” by state medical boards instead of FDA-approval.  In contrast, the Regenexx Procedure does not lend itself to FDA regulation as the process is slightly different for every patient.

The Report also seeks to rebut FDA’s argument that it is entitled to extensive deference in its interpretation of the definition of “drug.”  It points to the Supreme Court’s decision in FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120 (2000), in which “the Court pushed back on the FDA when it sought to include cigarettes and tobacco as drugs under the [FDCA]…”  The Report goes on to state that, “…even if it takes great skill to figure out how to regulate drugs, and the government’s broad claims for Chevron deference here should not override the ordinary meaning of ‘drugs’ versus ‘medicine.’”  

Given the arguments laid out in the Report, it will be interesting to see how the case is resolved in the Court of Appeals.     

By Jeffrey K. Shapiro –

As everybody has noticed, FDA finalized its guidance on Mobile Medical Applications earlier this week.  We blogged on the draft version here.

The final guidance is similar to the draft guidance – but with improved clarity.  Hence, it has expanded from 29 to 43 pages.  Most of the additional pages are appendices with examples and other supplementary information.  This guidance is sensible and well written.

FDA’s general approach to mobile medical applications (mobile apps) is to define large swaths of territory that will be either unregulated because they are considered outside of FDA’s jurisdiction or because FDA will simply refrain from regulation on the basis of low patient risk.  When FDA refrains from regulating products within its jurisdiction, it is called an exercise of “enforcement discretion.”

This general approach makes sense, because FDA and industry both have limited resources, so it is realistic to apply the expensive and burdensome FDA regulatory system only to mobile apps that pose a significant risk to patients.  In technical regulatory terms, this approach is known as getting the most bang for the buck.

Because much of the mobile apps industry is not very familiar with FDA regulation, this guidance has an unusually detailed description of the entities, mobile apps, and activities that will not be regulated.  These include:

• Platform products without medical device claims.
• Third party app distributors who do not develop apps.
• Providers of general development tools and hardware/software infrastructure.
• Licensed practitioners who develop their own apps for their own use.
• Mobile apps developed solely for non-clinical research, teaching or analysis and not introduced into commercial distribution.
• Mobile apps that are essential e copies of medical textbooks and reference material.
• Mobile apps used for provider or patient medical training and education.
• Mobile apps used to automate operations in a healthcare setting and not for use in the diagnosis or treatment of disease.
• Mobile apps that are generic aids or general purpose products.

There is also a description of entities and activities for which FDA will exercise enforcement discretion based upon low risk to patients.  Of note, the guidance provides welcome relief for the “health coaching” apps by placing them under enforcement discretion.  There has been a lot of innovation in this area, but also an overhang of regulatory uncertainty.  The enforcement discretion categories are:

• Mobile apps that help patients self-manage their disease or conditions without providing specific treatment suggestions.
• Mobile apps that provide simple tools for patients to organize and track health information.
• Mobile apps that provide easy access to information related to patients’ health conditions or treatments.
• Mobile apps that automate simple tasks for health care providers.
• Mobile apps that enable patients or providers to interact with electronic health records ("EHRs").

A few interesting examples: 

• Mobile apps that help patients diagnosed with psychiatric conditions.  
• Mobile apps that use patient characteristics to provide patient specific screening, counseling and preventive recommendations from well known and established authorities.
• Mobile apps that remind patients about pre determined dosing schedules (medication reminders). 

The last example is especially welcome.  For a number of years, FDA has been actively regulating medical reminders under 21 C.F.R. § 890.5050 (product code NXQ).  The active regulation of these products has created a headache for developers of health and wellness coaching apps, who risked device regulation by including this useful and low risk functionality in their products.  FDA’s decision to exercise enforcement discretion here is wise, and consistent with the overall approach of this guidance. 

The mobile apps that FDA will regulate are called “mobile medical apps.”  What mobile apps fall under this category?  FDA discusses the following broad types:

• Mobile apps that connect to medical devices to control them or to display, store, analyze or transmit patient specific medical device data.
• Mobile apps that transform a mobile platform with device functionality by using attachments, display screens, or sensors.
• Mobile apps that perform patient specific analysis and provide patient specific diagnosis or treatment recommendations.

This last type of mobile medical app looks very much like clinical decision support software (“CDSS”).  However, FDA expressly says that this guidance does not address CDSS.  FDA is expected to issue a draft guidance on that topic in the near future. 

At the same time, it would be odd for FDA to regulate a particular CDSS functionality if provided via mobile app but not if it is on some other platform.  That is especially true because FDA goes out of its way to say in this guidance that its oversight approach to mobile apps is focused on functionality and not platform.

Most likely, the CDSS draft guidance will take a similar approach to the mobile medical apps guidance, subjecting CDSS software with higher risk functionality to regulation while specifying CDSS functionality that is unregulated or under enforcement discretion.  This upcoming guidance will probably apply to CDSS functionality on any platform, mobile or not.

In this guidance, FDA provides only a few examples of mobile apps providing diagnosis or treatment recommendations that will be regulated.  The examples are:  apps that use patient specific parameters to calculate dosage or create dosage plans for radiation therapy; Computer Aided Detection (“CAD”) software; image processing software; radiation therapy treatment planning software. 

These apps are all examples of what FDA describes as “mobile apps that perform sophisticated analysis or interpret data (electronically collected or manually entered) from another medical device” (p. 15).  Unfortunately, FDA does not provide examples of mobile CDSS apps that are not regulated.  We will probably need to wait for the overall CDSS guidance to more fully clarify what mobile CDSS functionality will or will not be regulated.

The awkwardness here is probably due to the fact that FDA geared up development of a guidance for mobile apps before discovering, as the software industry developed, that the focus really needs to be on functionality rather than type of platform.  For anyone who needs to predict the likely regulatory status of stand alone software that is not a mobile app, this guidance should still be a valuable tool.  It is a fair inference that much of the substance here applies when the same type of functionality is placed on a non-mobile platform.

Finally, if a mobile app falls within one of the mobile medical app categories, that is only the beginning of the analysis.  The next step will be to determine its classification (Class I, II or III), because that will drive the determination of what regulatory requirements apply.  This guidance does not directly address the determination of regulatory classification.

By Allyson B. Mullen –

Have you ever heard of an “Immediately in Effect (IIE)” guidance document?  Thanks to a new draft SOP issued by CDRH, you may soon see this new species of guidance on a regular basis.

In section 405 of Food and Drug Administration Modernization Act of 1997 ("FDAMA"), FDA was authorized to issue guidance documents without public comment in certain circumstances.  Specifically, section 701(h)(1)(C) was added to the Food, Drug, and Cosmetic Act (the “Act”) and states that guidance documents “set[ting] forth initial interpretations of a statute or regulation, changes in interpretation or policy that are of more than a minor nature, complex scientific issues, or highly controversial issues” must have prior public participation before implementation “unless the Secretary determines that such prior public participation is not feasible or appropriate.”  (Emphasis added.)

In February 2000, FDA issued proposed implementing regulations.  The preamble to the proposed regulations suggests that FDA deems prior public participation “not feasible or appropriate” if: “(1) there are public health reasons for immediate implementation of the guidance document; (2) there is a statutory requirement, executive order, or court order that requires immediate implementation; or (3) the guidance document presents a less burdensome policy that is consistent with public health.”  65 Fed. Reg. 7321, 7324 (Feb. 14, 2000).  The proposed regulations were finalized in September 2000 and are codified at 21 C.F.R. § 10.115(g)(2). 

Nearly 13 years later, on September 5, 2013, CDRH announced a Draft Standard Operating Procedure ("SOP") “Level 1, Immediately in Effect Guidance Documents on Premarket Data Issues” (the “Draft SOP”).  78 Fed. Reg. 54655 (Sept. 5, 2013).  Some may wonder why FDA would propose an SOP setting forth the process for issuing guidance at this late date.  Could it be because they are intending to make greater use of such a process and implementing more written guidance without prior public participation?

The stated intent of the Draft SOP is to clearly and efficiently communicate changes in CDRH’s expectations and new scientific information that relate to or could impact Investigational Device Exemptions and pre-market submissions (e.g., 510(k)s, PMAs, HDEs).  Draft SOP at 1. The Draft SOP accomplishes this objective by creating a new category of guidance document, called, “Immediately in Effect (IIE) Guidance Documents.”  Id. at 1.  (The Draft SOP replaces CDRH’s earlier attempt in 2011 to establish such a process in its “‘Notice to Industry’ Letters” SOP. 78 Fed. Reg. 54655.)

The Draft SOP proposes a three-pronged assessment to determine if an IIE Guidance Document should be developed: (1) there is new scientific information identified, which raises “new, important safety risk or calls into question the adequacy of currently used test methods or clinical trial design to demonstrate or bear on safety, effectiveness, and/or substantial equivalence of a device type;” (2) as a result of such new information, CDRH needs to change its regulatory expectations  with respect to IDEs and premarket submissions; and (3) “prior public participation is not appropriate or feasible.”  Draft SOP at 2. 

Based on these criteria, it appears as though there could be a high bar for issuance of an IIE Guidance Document.  However, the Draft SOP does not define or put any parameters around what would constitute new scientific information (must it be actual or speculative?) and FDA has previously declined to limit the use of IIE Guidance Documents to “rare and extraordinary circumstances” or “where there is a real demonstrated public health emergency, not just a theoretical emergency.”  65 Fed. Reg. 56468, 56472 (Sept. 19, 2000). 

It seems possible that CDRH could be planning to put this SOP into routine use once finalized since the Draft SOP provides a fairly simple process for issuing IIE Guidance Documents.  The Draft SOP allows for CDRH staff and management to prepare a briefing summary for discussion of proposed IIE Guidance Documents with the Center Science Council ("CSC").  Draft SOP at 3.  The Draft SOP includes a sample (short) format for a briefing summary and states that the briefing summary should include 9 items:

• The new scientific information;
• How the risk/benefit profile of the particular device is changed by the new scientific information;
• The Center’s anticipated changes to regulatory policy in light of the new scientific information;
• Why such changes are necessary;
• The audience who should be made aware of such changes;
• The submission types affected by such changes (future and/or pending submissions) (Yes, you read that correctly – IIE Guidance Documents can impact not only future submissions, but also submissions pending with CDRH at the time the guidance is issued; how will companies keep up?);
• The existing guidance documents impacted by such changes;
• Why an immediate effect guidance document is the “only appropriate method for disseminating this information”; and
• Whether and to whom any further communication regarding the topic at issue is needed.  Id. at 3 & 7.

Based on the discussions facilitated by the briefing summary, the CSC is charged with determining whether the new scientific information warrants a change in the premarket regulatory expectations, whether the change should be communicated through an IIE Guidance Document, and whether additional expertise is needed before making a determination on a particular topic.  Id. at 3-4.

Once the CSC determines that an IIE Guidance Document should be issued, the guidance is drafted and should only be 1 to 2 pages in length, and generally not exceed 3 pages.  Id. at 4.  For information that is critical to industry, such as changing regulatory expectations, it seems that it may be difficult for CDRH to include all of the required elements (e.g., the nonbinding language disclaimer) and still find space in three pages (maximum) to clearly articulate its new expectations.  Once drafted, the IIE Guidance Document must be approved by a number of individuals within CDRH before it is published in the Federal Register.  Id. at 5.  Lastly, the Draft SOP provides for public comment during the 60-day period following issuance of the IIE Guidance Document; and in the 90 days following close of the comment period, CDRH will review the comments and revise the IIE Guidance Document, if necessary.  Id. at 5.
 
Only time will tell how CDRH will utilize this SOP, and whether it will become routine.  However, it appears as though CDRH is establishing a simple process to easily implement guidance without public input and without establishing parameters around critical steps in the process (e.g., what constitutes new scientific information).  Since when does a bureaucracy invest significant effort in developing a regulatory tool and then choose not to use it?  The odds are that you will soon become very familiar with IIE Guidance Documents.

By Kurt R. Karst –      

Anyone from the United States who has visited a foreign city – like São Paulo, Brazil or Mumbai, India – knows immediately upon exiting the sealed environment of their aircraft that they are no longer in the United States.  There’s an indescribable smell to the air.  It permeates everything.  After a few weeks though, the smell loses its force and seems to go away.  Of course, it doesn’t really go away (which you realize upon returning home and opening up your suitcase), you just become accustomed to it.  And you begin to wonder what newcomers and visitors are complaining about.  A similar smell appears to be permeating Rockville, Maryland, and, more specifically, the suite of buildings on Standish Place where the Office of Generic Drugs (“OGD”) is located.  Those of us who visit the OGD campus can smell the change in the air, though others who have grown accustomed to the smell may not. 

Over the past several months we’ve noticed and heard about small, but significant changes in the way OGD has traditionally operated.  Consider, for example, a recent article penned by Bob Pollock on the Lachman Consultants Blog.  In his August 19th post, Bob provides a useful snapshot of ANDA approval times for June.  Bob would have liked to provide information on July ANDA approvals, but he couldn’t.  “[W]e understand that OGD has temporarily stopped releasing its monthly statistics,” says Bob.  “Hopefully, that will be resolved soon because these numbers are the only concrete view that the industry has into OGD’s performance.  This certainly is one piece of information that makes transparency seem alive and well and, now, at least for the short term, that piece of information is not available.”

Then, earlier this week, FDA released a new 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.”  The stated purpose of the MAPP is to “clarify[y] the general principles for handling inquiries with respect to abbreviated new drug applications (ANDAs) from the authorized representative for an applicant with an ANDA submission (the authorized inquirer) by Regulatory Project Management (RPM) staff in [OGD].”  The MAPP is specifically tied to implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”), stating:

The Center for Drug Evaluation and Research (CDER) believes it is important to timely respond to industry inquiries.  Historically, OGD staff responded to a range of informal, ad hoc inquiries from industry regarding the status of ANDAs.  In order to systematically improve the predictability and timeliness of the ANDA review process, however, industry and FDA negotiated the Generic Drug User Fee Amendment (GDUFA). GDUFA was enacted by Congress and became effective as of October 1, 2012.  Pursuant to GDUFA, OGD implemented certain agreed-upon premarket review efficiency enhancements, such as complete response letters, and also committed to achieve certain agreed-upon application and backlog metric goals.  As OGD works to fulfill its GDUFA performance obligations, industry has an interest in clarity regarding the process for handling inquiries going forward.

After stating that the generic drug industry is responsible for designating “a single individual” to communicate with OGD and must “make all inquiries through that authorized inquirer,” the MAPP goes on to lay our various procedures.  For example:

• Reviewers, team leaders, discipline specific project managers, deputies, division directors, other OGD management or OGD immediate office staff should refer all inquiries from the authorized inquirer on the status of an ANDA or related submissions to the RPM for that ANDA.
• RPMs should not provide dates or time lines for when reviews will be completed, when letters will be issued, or when other actions will be taken. Because workload and competing priorities affect action times, time lines are especially difficult to predict and should not be provided.
• RPM should try to understand the reasoning behind the status inquiry. The underlying principle identified by the authorized inquirer may reveal valuable information to aid FDA in providing a timely review to address a public health need (e.g., patent expiration date, drug shortage). If the justification does reveal previously unknown information, the RPM will communicate this to OGD management and the review team.

It wasn’t long after the posting of MAPP 5200.3 that we began to receive phone calls and emails expressing shock, anger, and frustration.  We started to feel like a therapist for the generic drug industry.  “In return for collecting hundreds of millions of $ in GDUFA fees, OGD is now restricting inquiries to only the Regulatory Project Manager, who will not provide any specific information regarding timing or content of reviews.  To add insult, INDUSTRY is supposed to inform OGD as to WHY THEY NEED THIS INFORMATION!,” read one email.  “This is so obviously a self-serving bureaucratic attempt to hide continuing disastrous performance by OGD, I have started calling it The Dog Ate My DAARTS Log MAPP of 2013,” continued the email, referring to the Document Archiving, Reporting and Regulatory Tracking System FDA uses to track applications.  Another comment we received said that the “transparency that has taken place is like the transparency of a brick wall!”  Some other comments we received we cannot post here – we’re only a PG-rated blog.

So what’s going on?  We call it “UFAization”:  the process by which an FDA component, after the enactment of a User Fee Act, becomes focused on so-called process enhancements to meet goals and commitments at the expense (both literally and figuratively) of those who are subject to such user fees.  (Ok, maybe it’s not a term that will appear in the Oxford English Dictionary, but it’s better than “twerk!”).  While other FDA components have likely undergone similar changes though the years as User Fee Acts have been enacted and implemented, OGD – and the generic drug industry – has a character all its own.  Asking the generic drug industry to change its character is kind of like asking a tiger to change his stripes. 

GDUFA and the accompanying Performance Goals and Procedures FDA and the generic drug industry hammered out and agreed to have three key aims:

Safety – Ensure that industry participants, foreign or domestic, who participate in the U.S. generic drug system are held to consistent high quality standards and are inspected biennially, using a risk-based approach, with foreign and domestic parity.

Access – Expedite the availability of low cost, high quality generic drugs by bringing greater predictability to the review times for abbreviated new drug applications, amendments and supplements, increasing predictability and timeliness in the review process.

Transparency – Enhance FDA’s ability to protect Americans in the complex global supply environment by requiring the identification of facilities involved in the manufacture of generic drugs and associated active pharmaceutical ingredients, and improving FDA’s communications and feedback with industry in order to expedite product access.

What some in the generic drug industry appear to be saying with their criticism of recent changes at OGD is that these changes are not merely growing pains as a result of GDUFA implementation, but that FDA is not meeting the key aims of GDUFA, or worse, that the Agency is reneging on some aspects of them.  We’re certain that we’re not the only outlet for folks to vent their concerns.  The Generic Pharmaceutical Association ("GPhA") is probably getting an earful from its members.  Whether or not the generic drug industry will simply become accustomed to the unusual smell these changes seem to be creating, or whether there will be a call to action, remains to be seen.  A couple of upcoming events – the GPhA/FDA Fall Technical Conference and a House Energy and Commerce Committee hearing on FDA's implementation of FDASIA – might be good venues at which to raise concerns.

Additional Reading:

• Bob Pollock, The MaPP to Nowhere (Sept. 26, 2013)

By Jeffrey N. Wasserstein & Alexander J. Varond –

Last week, ahead of the September 23, 2013 compliance deadline for its HITECH final rule (also referred to as the “Omnibus Final Rule”), the Department of Health and Human Services issued guidance  entitled “The HIPAA Privacy Rule and Refill Reminders and Other Communications about a Drug or Biologic Currently Being Prescribed for the Individual.”  In prior posts, we discussed the HITECH final rule here, here, and here.  The guidance, as you guessed it, addresses the refill reminder exception, from the Omnibus Final Rule, and its two prongs:  (1) whether the communication is about a “currently prescribed drug or biologic,” and (2) if the communication involves financial remuneration, whether the remuneration is “reasonably related to the covered entity’s cost of making the communication.”

Addressing the issues in Adheris, Inc. v. Sebelius

HHS’s guidance sheds light on key issues raised in the lawsuit filed by Adheris, Inc. against HHS, which we blogged about here and here.

At issue in Adheris is whether the company, whose main business involves sending refill reminders and medication adherence communications to patients about their prescribed treatment regimens, and is paid for by pharmaceutical companies, can continue to provide its services under the Omnibus Final Rule.  In its complaint, Adheris argued that the Omnibus Final Rule violated the First Amendment and misconstrued the HITECH Act.

The HHS guidance clarifies the refill reminder exception and provides an example of permissible communications that is applicable in Adheris: “a pharmacy hires a business associate to assist in administering a medication adherence program that involves mailing adherence communications to patients about their currently prescribed drugs, even though the business associate is paid by the pharmaceutical manufacturers, provided the payment does not exceed the fair market value of the business associate’s services.”  HHS’s guidance does not define “fair market value,” but does note that permissible remuneration includes “reasonable direct and indirect costs . . . including labor, materials, and supplies, as well as capital and overhead costs.”  We haven’t heard anything yet, but we expect that this will likely take the wind out of the sails of Adheris’s suit.

Additional points addressed in HHS’s guidance

Also, of interest to many of our readers, HHS’s guidance makes clear that communications about specific new formulations of a currently prescribed medicine are not permitted under the Omnibus Final Rule.  However, the guidance does permit more general communications about new formulations.  So, while a covered entity or business associate can’t say to a patient on an immediate release formulation “Try the new extended release formulation” they can say “speak with your pharmacist about more convenient dosage forms.” 

The guidance also addresses:

• Recently-lapsed prescriptions;
• Drug delivery systems;
• REMS and other “government-mandated” communications; and
• Face-to-face discussions with individuals about specific products or services.

By Kurt R. Karst –    

FDA’s latest Report to Congress, required by FDC Act § 505(q)(3), on the Agency’s experience with so-called “505(q) citizen petitions” during Fiscal Year 2012 (“FY2012”) is largely a rehash of the FY2011 Report to Congress (see our previous post here on the FY2011 report, and our posts here, here, and here on reports from previous years).  FDA continues to express certain concerns about the petitioning process, such as serial petitioning, and continues to say that it is monitoring “the number and nature of 505(q) petitions submitted and [analyzing] whether section 505(q) is effectively discouraging petitioners from submitting petitions primarily to delay the approval of applications.”  But FDA, in the latest report, is more emphatic than in previous reports about expressing frustration with how responding to 505(q) petitions interferes with other Agency work, particularly in light of the enactment of the FDA Safety and Innovation Act (“FDASIA”), which shortened FDA’s response deadline.  The latest report also provides updated numbers and new statistics on the petitions received by and acted on by FDA.

By way of background, FDC Act § 505(q) was added to the law by the 2007 FDA Amendments Act (“FDAAA”) and is intended to prevent the citizen petition process from being used to delay approval of pending ANDAs and 505(b)(2) applications.  The law was amended by § 301 of Pub. L. No. 110-316 (2008), and again by FDASIA § 1135, which, among other things, changed the original 180-day response deadline to 150 days, and made the law applicable to citizen petitions concerning biosimilar applications submitted to FDA pursuant to PHS Act § 351(k).  (See our FDASIA summary here.)  In June 2011, FDA issued final guidance on FDC Act § 505(q).  In January 2012, FDA proposed regulations to amend the Agency’s citizen petition regulations.  FDA is reportedly evaluating the impact of FDASIA § 1135 on both the final guidance and proposed regulations.

Under the current version of FDC Act § 505(q), which was in effect for part of FY2012, the statute says that FDA shall not delay approval of a pending ANDA, 505(b)(2) application, or 351(k) biosimilar application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  Under FDC Act § 505(q), which FDA has interpreted to apply only to certain petitions submitted to the Agency after September 27, 2007 (when FDAAA was enacted), “[FDA] shall take final agency action on a petition not later than 150 days after the date on which the petition is submitted.”  FDA may not extend the 150-day period “for any reason,” including consent of the petitioner, and may summarily deny a petition submitted with the primary purpose of delaying ANDA, 505(b)(2) application, or 351(k) biosimilar approval.  FDA has never summarily denied a 505(q) petition.  Instead, FDA seems to have resorted to a form of public shaming (see our previous post here) when the Agency suspects delay tactics.

FDC Act § 505(q)(3) requires that each annual report to Congress specify: “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”  FDA says in its Fifth Annual Report that:

Between September 27, 2007, and September 30, 2012, FDA determined that a delay in approving an ANDA was necessary to protect the public health in the case of five ANDAs with related 505(q) petitions.  FDA has not delayed approval of any 505(b)(2) applications or biosimilar biological product applications based on 505(q) petitions.

During the FY 2012 reporting period, the agency approved 42 applications submitted under section 505(b)(2), 517 ANDAs, and no biosimilar biological product applications.  No approvals for any 505(b)(2) or biosimilar biological product applications were delayed because of the filing of a 505(q) petition in this reporting period.  No ANDA approvals were delayed in this reporting period because of pending 505(q) petitions.

During the FY 2012 reporting period, 24 petitions considering 505(q) petitions were submitted to the agency.  FDA did not miss the statutory deadline for responding to any 505(q) petitions during this reporting period.

FDA explained in previous reports that five ANDAs have been delayed because of pending 505(q) petitions.  That number will increase when FDA presents its Sixth Annual Report.  In an August 2013 denial of a March 2013 petition (Docket No. FDA-2013-P-0247) concerning the approval of generic Zoledronic Acid Injection, FDA noted that the petition caused a 25-day delay in ANDA approvals. 

In previous reports, FDA explained that the Agency has timely responded to all but two of the 505(q) petitions within the statutory timeframe.  Although FDA did not blow the statutory deadline in FY2012, FDA’s track record of timely responding to 505(q) petitions within the applicable statutory period will be tarnished in FY2013.  Earlier this month, FDA passed the 150-day deadline for responding to a citizen petition (Docket No. FDA-2013-P-0471) submitted by Bayer HealthCare Pharmaceuticals Inc. requesting that the Agency award 5-year new chemical entity exclusivity for the oral contraceptive NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (see our previous post here).

The Fifth Annual Report provides some consolidated petition numbers from FYs 2008-2012.  According to FDA, the Agency has received a total of 116 petitions subject to FDC Act § 505(q).  The annual number of petitions has remained relatively steady at around 20 petitions, with the exception of FY 2009, when there were 31 petitions:

New to the Fifth Annual Report is a table summarizing the outcomes for the 505(q) petitions – 97 of them – that were resolved as of September 30, 2012:

That means that as of the conclusion of FY2012, FDA denied about 64% of 505(q) petitions, denied in part and granted in part another 27%, and granted only 7% of the 97 petitions.  (Another almost 2% were voluntarily withdrawn by the petitioner.)

FDA has consistently expressed frustration with how responding to 505(q) petitions interferes with other Agency work.  FDA’s frustration is amplified in the Fifth Annual Report, however, now that the Agency has had experience with the 30-day haircut to the original 180-day deadline.  According to FDA:

The enactment of FDASIA has increased the agency resource requirements for responding to 505(q) petitions.  Section 1135 of FDASIA significantly shortened the time frame by 30 days and has given FDA less time to evaluate the issues, articulate its scientific and legal reasoning, and formulate a response on the issues referenced in the petition.  As a result, FDA has needed to direct resources away from other important initiatives to attempt to comply with the new shorter deadline.

Not included in the Fifth Annual Report (and not required to be) is FDA’s progress with meeting the new 270-day timeframe at FDC Act § 505(w) covering discontinuation petitions submitted pursuant to 21 C.F.R. § 314.161.  That provision was also included in FDASIA.  A quick look at our FDA Citizen Petition Tracker, however, indicates that the Agency is doing well in meeting that statutory mandate.  ANDA suitability petitions are another story altogether.  FDA has regularly failed to meet the 90-day statutory decision deadline for those petitions for years.  We’ll save that analysis for another day.  But in all fairness, we note that FDA does appear to be taking steps to address the situation.  FDA recently published new procedures that are intended to bring the Agency back into compliance. 

By Jennifer D. Newberger –

At long last, it is here: FDA has issued the final rule implementing the unique device identifier (UDI) requirements, originally required by the Food and Drug Administration Amendments Act of 2007 (FDAAA) and then again by the Food and Drug Administration Safety and Innovation Act (FDASIA), enacted in July 2012 (see here at pages 39-40).  The stated purpose of the rule is to “lead to more accurate reporting of adverse events by making it easier to identify the device prior to submitting a report. . . [and to] allow FDA, health care providers, and industry to rapidly extract useful information from adverse event reports, pinpoint the particular device at issue and thereby gain a better understanding of the underlying problems, and take appropriate, better-focused, corrective action.”  Product information will be maintained in FDA’s Global Unique Device Identification Database (GUDID), unless subject to an exemption.  On the same day FDA issued the final rule, it also released a draft guidance, Global Unique Device Identification Database (GUDID), to provide information to device labelers about submitting information to the database.

Each medical device subject to the UDI requirements will be required to bear a UDI on the label and device package of each medical device.  Each UDI must be provided in a plain-text version and in a form that uses automatic identification and data capture (AIDC) technology.  If a device is intended to be used more than once and to be reprocessed before each use, it must also be directly marked with the UDI, so that the identifying information is available even when separated from the original label or packaging. 

Some of the principal changes between the amended proposed rule of November 19, 2012 (see our previous post here) and the final rule include:

• FDA may grant a one-year extension of the compliance date applicable to a Class III device or a device licensed under the Public Health Service Act (PHS Act) when in the best interest of the public health.
• The final rule provides an exception for a finished device that is manufactured and labeled prior to the compliance date that applies to the device, but the exception expires three years after the compliance date.
• A Class I device labeled with a Universal Product Code (UPC) may use the UPC as its UDI, but is still subject to GUDID reporting requirements.
• Each device constituent part of a combination product need not bear a UDI so long as the combination product bears a UDI.  Additionally, any combination product that properly bears an NDC on its label need not bear a UDI.
• Unlike the proposed rule, which would have required the label and device package of each device packaged in a convenience kit to bear its own UDI, distinct from that of the convenience kit, the final rule does not require devices contained within a convenience kit to bear a UDI but does require the label and each device package of every convenience kit to bear a UDI.
• The proposed rule would have required an implantable device to bear a permanent marking providing the UDI; the final rule removed this provision, and does not require an implantable device to be directly marked with a UDI.
• Legacy FDA identifiers for devices, such as National Health-Related Item Code (NHRIC) and NDC numbers, will be rescinded by September 24, 2018.  However, continued use of a labeler code issued under an FDA-accredited system for the issuance of UDIs will be permitted, so long as the use is permitted by the issuing agency that administers the system, and the label submits a request for continued use of the code.  FDA must receive requests for continued use of labeler codes no later than September 24, 2014.
• The proposed rule would have exempted Class I single use devices from the UDI requirements; the final rule extends that to all classes of single use devices, except implants.
• Stand-alone software would have been subject to direct marking in the proposed rule; the final rule does not require direct marking, but is subject to certain specified requirements.  For example, stand-alone software that is not distributed in packaged form (e.g., downloaded from a website), will meet the UDI requirements if a plain-text statement of the UDI is displayed whenever the software is started or through a menu command.  When distributed in package form, the label and device package of the software must include a UDI in plain text and AIDC.
• In addition to the device identifier and production identifier required on the majority of devices, HCT/Ps regulated as devices will also have to include the distinct identification code required by 21 C.F.R. § 1271.290(c). 

The compliance dates for the final rule are unchanged from those described in the amended proposed rule of November 19, 2012, and are as follows:

• September 24, 2014
  • The labels and packages of Class III devices and devices licensed under the PHS Act must bear a UDI;
  • Class III stand-alone software must provide its UDI;
  • Data for these devices must be submitted to the GUDID database.
• September 24, 2015
  • The labels and packages of implantable, life-supporting, and life-sustaining devices must bear a UDI;
  • A device that is a life-supporting or life-sustaining device that is required to be labeled with a UDI must bear a UDI as a permanent marking if the device is intended to be used more than once and intended to be reprocessed before each use;
  • Stand-alone software that is a life-supporting or life-sustaining device must provide its UDI;
  • Data for implantable, life-supporting, and life-sustaining devices that are required to be labeled with a UDI must be submitted to the GUDID database.
• September 24, 2016
  • Class III devices required to be labeled with a UDI must bear a UDI as a permanent marking if the device is a device intended to be used more than once and intended to be reprocessed before each use;
  • The labels and packages of Class II devices must bear a UDI;
  • Class II stand-alone software must provide its UDI;
  • Data for Class II devices required to be labeled with a UDI must be submitted to the GUDID database;
• September 24, 2018
  • A Class II device required to be labeled with a UDI must bear a UDI as a permanent marking on the device if the device is intended to be used more than once and intended to be reprocessed before each use;
  • The labels and packages of Class I devices and unclassified devices must bear a UDI;
  • Class I stand-alone software must provide its UDI;
  • Data for Class I and unclassified devices must be submitted to GUDID.
• September 24, 2020
  • Class I devices and unclassified devices that are required to be labeled with a UDI must bear a UDI as a permanent marking if the device is intended to be used more than once and intended to be reprocessed before each use.

This phased-in approach should allow device manufacturers sufficient time to comply with the rule.  There will undoubtedly be complications, questions, and challenges as manufacturers begin to comply with the rule.  After all the waiting and debating, it will be interesting to see what the impact of the UDI system will be on FDA, industry, and the public.