By Jamie K. Wolszon –

FDA announced on August 19, 2010 in the Federal Register that the agency is reopening the comment period for comments related to FDA oversight of laboratory-developed tests ("LDTs"), and will now accept comments until September 15.  The comment period had closed August 15. 

LDTs are diagnostic tests developed and performed by a single laboratory.  They are widely used; virtually all genetic tests are LDTs, as are many tests for rare conditions and companion diagnostics.

Starting in 1992, FDA asserted that all LDTs are devices subject to regulation under the Federal Food, Drug, and Cosmetic Act.  Since then, the agency said it was exercising its enforcement discretion and not regulating LDTs.  Thus, the primary federal regulation of laboratories has been under the Clinical Laboratory Improvement Amendments of 1988 ("CLIA").

Until recently, FDA has departed from this position of enforcement discretion in relatively few instances.  For example, FDA advanced its controversial and now-defunct proposal to regulate a subset of LDTs, known as In Vitro Diagnostic Multivariate Index Assays (“IVDMIAs”).  (IVDMIAs are tests where the results of multiple markers are combined to generate an “index score.”)  

We previously reported that FDA announced in June that it was revisiting its years-long policy of exercising enforcement discretion over LDTs, and considering adopting a risk-based framework.  The agency announced that it was holding the July 19-20 workshop as a first step to gather comment on the regulation of LDTs. 

As we previously reported, FDA officials at the July 19-20 workshop indicated that they planned to end the enforcement discretion approach, and more actively regulate LDTs, but that they had not decided on the details of a regulatory scheme.

FDA is reopening the comment period to “update comments and receive any new information,” according to the August 19, 2010 Federal Register notice.  Explaining its decision to reopen the comment period, FDA stated:  “Following publication of the June 17, 2010, notice, FDA received a request to allow interested persons additional time to comment.  The requester asserted that the initial time period was insufficient to respond fully to FDA’s specific requests for comments and to allow potential respondents to thoroughly evaluate and address pertinent issues.”

The additional time also will provide interested parties with time to consider two preliminary reports regarding the 510(k) process and the use of science in the Center for Devices and Radiological Health (CDRH).  We previously reported that in early August, FDA unveiled preliminary reports from the 510(k) Working Group and the Task Force on the Utilization of Science in Regulatory Decision Making.  To the extent that FDA decides to require a 510(k) for any LDT, changes to the 510(k) process can significantly affect the future regulation of LDTs.  The reopened comment period will provide an opportunity for interested parties to comment in more detail on FDA regulation of LDTs, and incorporate the preliminary recommendations regarding 510(k)s into those comments.

In the July/August 2010 edition of FDLI Update, HP&M attorneys John R. Fleder and Cassandra A. Soltis authored an article, titled “Advertising and Promotion: FDA Is Not the Only Cop on the Beat.”  The article focuses on the various non-FDA groups that police alleged false or misleading claims in advertising and promotion: (1) the Federal Trade Commission (“FTC”), which has the statutory authority to commence court and administrative actions against companies and persons that the FTC believes have engaged in deceptive practices; (2) state Attorneys General, which regulate advertisements and promotional materials; (3) the National Advertising Division of the Better Business Bureau, which is not a governmental body and has no legal authority to order someone to cease particular advertising, but is nevertheless an important policing body; and (4) companies that use the Lanham Act to bring an action in federal court against a competitor which is alleged to have disseminated false or misleading advertisements.  “Collectively, these enforcement tools have resulted in many companies paying millions of dollars in monetary judgments,” say the authors.

By Kurt R. Karst –   

When does a patent expire?  When does pediatric exclusivity begin and end?  And when can FDA approve ANDAs (or 505(b)(2) applications)?  These are some interesting questions touched on in some recent court decisions.  But before we get to those cases, some law . . . .  

The patent statute at 35 U.S.C. § 154(a)(2) (post-GATT/URAA) states the following with respect to the term of a patent: “Subject to the payment of fees under this title, such grant shall be for a term beginning on the date on which the patent issues and ending 20 years from the date on which the application for the patent was filed in the United States.”  So, does a patent expire 20 years from filing, or is it 20 years plus one day?  Apparently, the answer is 20 years plus one day – as alluded to in various Patent and Trademark Office decisions on maintenance fee payment issues (here, here, and here) providing that a patent expires at midnight on the date of expiration.  Nevertheless, we note that FDA’s longstanding practice is to approve ANDAs on the patent expiration date specificed in the Orange Book – i.e., on the date that is 20 years from patent filing and not 20 years plus one day.  (This is consistent with how FDA treats the expiration of non-patent market exclusivity, where the periods listed in the Orange Book do expire on the date listed.)

With respect to generic drug approval, the patent statute at 35 U.S.C. § 271(e)(4)(A) states that “the court shall order the effective date of any approval of the drug or veterinary biological product involved in the infringement to be a date which is not earlier than the date of the expiration of the patent which has been infringed” (emphasis added).  In addition, for an ANDA (or a 505(b)(2) application) containing a Paragraph III certification, the FDC Act at § 505(j)(5)(B)(ii) states that “the approval shall be made effective on the date certified under [FDC Act § 505(j)(2)(A)(vii)(III)],” which is “the date on which such patent will expire” (emphasis added).  These provisions are consistent with FDA’s approval practices.

The pediatric exclusivity provisions at FDC Act § 505A add a wrinkle to the approval equation.  They provide that pediatric exclusivity applies to an Orange Book-listed patent covering a Reference Listed Drug such that FDA is prevented from approving an ANDA (or a 505(b)(2) application) containing a Paragraph II or a Paragraph III certification to such Orange Book-listed patent, or a Paragraph IV certification to such Orange Book-listed patent that a court has determined is valid and would be infringed, until “six months after the date the patent expires (including any patent extensions)” (emphasis added).

So, taking pediatric exclusivity out of the approval equation, FDA can approve an ANDA on the date of patent expiration listed in the Orange Book rather than on the day after patent expiration.  But including pediatric exclusivity in the approval equation could, some might argue, yield a different result – FDA approval on the day after expiration. 

(Interestingly, the tension between patent expiration and FDA approval was not resolved with respect to biosimilars in the Patient Protection and Affordable Care Act.  New 35 U.S.C. § 271(e)(4)(D) provides that:

the court shall order a permanent injunction prohibiting any infringement of the patent by the biological product involved in the infringement until a date which is not earlier than the date of the expiration of the patent that has been infringed under paragraph (2)(C), provided the patent is the subject of a final court decision, as defined in section 351(k)(6) of the Public Health Service Act, in an action for infringement of the patent under section 351(l)(6) of such Act, and the biological product has not yet been approved because of section 351(k)(7) of such Act. [(emphasis added)]

An earlier biosimilars legislative proposal sponsored by Rep. Anna Eshoo (D-CA) would have provided that FDA “shall make approval of the application effective on the day after the date of expiration of the patent that has been found to be infringed.  If more than one such patent is found to be infringed by the court, the approval of the application shall be made effective on the day after the date that the last such patent expires” (emphasis added).)

Now on to the cases . . . .

In an unpublished November 2009 decision from the U.S. District Court for the District of Delaware concerning the approval of a generic version of the acid reflux drug PREVACID (lansoprazole), the court ordered that the “effective date of any [FDA] approval of [certain ANDAs] shall be no later than November 11, 2009” – the day after the period of pediatric exclusivity applicable to U.S. Patent No. 4,628,098 (“the ‘098 patent”) listed in the Orange Book expired.  The court also clarified that “November 11, 2009 is the earliest effective date” upon which a generic applicant “may launch its commercial generic product.”  In what appears to be a case of first impression, the court issued its decision after the NDA holder, Takeda, argued in a Motion for Clarification of Final Judgment Order that the court’s previous ruling that ANDA approval “shall be no earlier than the date of expiration of claim 10 of the ‘098 patent and any pediatric exclusivity that applies to the ‘098 patent, if applicable,” needed greater clarity and could lead to ANDA approval and launch of the generic product one day too early – on November 10, 2009.

Citing the pediatric exclusivity provisions at FDC Act § 505A (i.e., ANDA approval shall not occur until “six months after the date the patent expires (including any patent extensions)”), Takeda argued that “the Orange Book captures the time period for which the FDA is barred from approving an ANDA; that period runs up to and through the date of expiration of the patent extension, in this instance, November 10, 2009.”  Although, the court’s Order reflected the November 11, 2009 date, FDA nevertheless approved an ANDA on November 10, 2009.  (Consistent with the court’s order, the generic version was presumably not launched until November 11, 2009.)

Two other recent court decisions – one concerning generic VIGAMOX (moxifloxacin HCl) and another concerning generic PROTONIX (pantoprazole sodium) – reached similar conclusions, although the decisions do not specifically grapple with the approval date issue as in the generic PREVACID case.  In the generic VIGAMOX case, Judge Sue L. Robinson of the U.S. District Court for the District of Delaware (the same Judge who issued the November 2009 generic PREVACID decision) ruled, apparently sua sponte, in an August 5, 2010 decision that FDA could not approve an ANDA until March 30, 2020, the day after pediatric exclusivity applicable to U.S. Patent No. 6,716,830 (“the ‘830 patent”) expires.  (The ‘830 patent is listed in the Orange Book with pediatric exclusivity expiring on March 29, 2020.)  And in a decision issued last week by Judge Jose L. Linares of the U.S. District Court for the District of New Jersey, the court ordered that the date of approval of a particular ANDA for generic PROTONIX  “shall be a date which is not earlier than January 20, 2011, the first day after the date on which Plaintiffs’ pediatric exclusivity period [with respect to U.S. Patent No. 4,758,579 (‘the ‘579 patent’)] ends” (emphasis added).  (The ‘579 patent is listed in the Orange Book with pediatric exclusivity expiring on January 19, 2011.) 

FDA has not yet been asked to opine on how the Agency’s ANDA (and 505(b)(2) application) approval practices mesh with the patent laws and the FDC Act’s various  provisions affecting generic drug approval.  And although there are, as explained above, some cases applying the pediatric exclusivity provisions of the FDC Act, we are not aware of a case challenging generic drug approvals without the involvement of pediatric exclusivity – that is, a challenge touched off by 35 U.S.C. § 271(e)(4)(A) and the term provisions of the patent laws.

By Carrie S. Martin –

Yesterday, the Federal Trade Commission (“FTC”) held a press conference in Chicago to announce a lawsuit against several companies, including Central Coast Nutraceuticals, iLife, Simply Naturals, Fit for Life, and Health and Beauty, for their marketing of acai berry weight-loss supplements and “colon cleansing” supplements in an allegedly false and defective manner.  The FTC also announced that the U.S. District Court for the Northern District of Illinois, Eastern Division, granted the FTC’s request for a temporary restraining order on August 6, 2010, requiring the companies to halt their Internet sales and freezing their assets.  

In the Complaint, the FTC states that the products, which were offered to consumers on a “free trial,” “risk free,” or “trial” basis with only a nominal charge, were not free.  Instead, the FTC alleges that the defendants charged consumers for various hidden and undisclosed costs, made it difficult to cancel during the trial period, and enrolled consumers into paying “membership” programs during the trial period that required affirmative action by the consumers to avoid and/or cancel.

The Complaint also states that products such as AcaiPure were advertised as inducing rapid and substantial weight loss and Colopure as preventing colon cancer, both without substantiation; and the companies falsely implied that their products were used or endorsed by celebrities such as Oprah Winfrey and Rachael Ray.

According to the FTC, since 2007, consumers have filed more than 2800 complaints with law enforcement agencies and the Better Business Bureau about these practices.  In addition, the FTC alleges that the companies scammed consumers out of $30 million or more in 2009.  The FTC plans to seek a permanent injunction against the defendants.

By Kurt R. Karst –   

On August 16, 2010, FDA announced that the Agency plans to follow through on previous correspondence threatening to withdraw approval of all marketing applications for the Subpart H (accelerated approval) drug Midodrine HCl.  FDA also issued a Notice of Opportunity for a Hearing (“NOOH”) to application sponsors proposing withdrawal because of the failure to complete required postmarketing studies with due diligence (Docket No. FDA-2007-N-0475).

As we previously reported (here, here, and here), FDA approved PROAMATINE (midodrine hydrochloride) Tablets in September 1996 under the Agency’s Subpart H (accelerated approval; surrogate endpoint) regulations for the treatment of symptomatic orthostatic hypotension.  FDA also subsequently approved several ANDAs for generic versions of the drug. 

Approval under FDA’s accelerated approval regulations is conditioned on a sponsor’s commitment to timely complete the required postmarketing studies to demonstrate the product’s clinical benefits.  FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if a sponsor “fails to perform the required postmarketing study with due diligence,” or if “[a] postmarketing clinical study fails to verify clinical benefit.”  In September 2009, the Government Accountability Office (“GAO”) issued a report, titled “FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints,” which found that  weaknesses in FDA’s monitoring and enforcement process have hampered the Agency’s ability to effectively oversee postmarketing studies conducted under FDA’s accelerated approval regulations.  The example used in the GAO report of a drug with uncompleted confirmatory studies is Midodrine HCl – the accelerated approval with the longest outstanding commitment.

An August 7, 2007 letter FDA sent to companies marketing approved versions of Midodrine HCL raised the possibility that generic sponsors might conduct the required confirmatory studies, and also raised the possibility of withdrawing approval for all Midodrine HCl applications if those studies are not conducted.  FDA stated in an August 2008 letter that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved soon, we will issue a Notice of Opportunity for a Hearing on the Center’s proposal to withdraw the approval of the midodrine hydrochloride new drug application (NDA) (and all ANDAs referencing that NDA) pursuant to 21 CFR 314.530.” 

FDA took an even more forceful tone in an August 2009 letter stating again that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved in a timely manner as described herein, we will issue a [NOOH] on the Center’s proposal to withdraw the approval of the midodrine hydrochloride NDA (and all abbreviated NDAs (ANDAs) referencing that NDA) pursuant to 21 CFR §§ 314.530; 314.150, and 314.151,” but adding that the required studies must have “50% enrollment by April 12, 2010,”  “100% enrollment by June 12, 2010,” and that full study reports of the requested trials must be submitted “on or before October 12, 2010.”

According to FDA’s August 2010 NOOH letter:

No application holder has satisfied the requirements set forth in our letter of August 12, 2009.  Specifically, no application holder submitted documentation of IRB approval or statistical analysis plans for the two required studies on or before February 12, 2009, had 50 percent enrollment by April 12, 2010, or completed enrollment by June 12, 2010.  To our knowledge, the required studies are not currently being conducted. In light of the foregoing and consistent with our authority under applicable provisions of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 301 et seq.) and implementing regulations, we now propose to withdraw approval of NDA 19-815.  Upon withdrawal of NDA 19-815, FDA will also withdraw approval of all ANDAs that reference NDA 19-815.

The Midodrine HCl NDA holder has 15 days from receipt of FDA’s August 2010 letter to request a hearing and ANDA sponsors (which may participate in the hearing only as non-party participants) have 30 days to submit comments.  “If an ANDA holder has submitted timely comments but does not have an opportunity to participate in a hearing because a hearing is not held, the submitted comments will be considered by the Agency,” and FDA will issue “preliminary decision whether there are grounds to withdraw approval of the listed drug and the ANDAs.”  After that, FDA will accept comments and may “hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions,” and then issue a final decision.  FDA notes in the NOOH letter that:

If the Agency proceeds to withdraw approval of these products, any future use of midodrine HCI in the United States will require submission of an investigational new drug application to FDA. FDA will explore, as appropriate, continued availability of midodrine HCl under our regulations governing expanded access, 21 CFR part 312, subpart I.

The Midodrine HCl NOOH follows another FDA announcement from earlier this year that another Subpart H drug, MYLOTARG (gemtuzumab ozogamicin for Injection), would be voluntarily withdrawn from the market after a required postmarketing study failed to demonstrate clinical benefit.  The MYLOTARG withdrawal appears to have been the first instance in which a product granted accelerated approval was withdrawn from the market – either because a postmarketing study failed to verify clinical benefit or because of a sponsor’s failure to complete a required postmarketing study with due diligence.

By Kurt R. Karst –   

A recent analysis of the Congressional Budget Office’s (“CBO’s”) cost estimate of legislation intended to curb patent settlements (or what opponents call “pay-for-delay” or “reverse payment” agreements) criticizes the estimated savings as “significantly overstated.”  As we recently reported, in late July, the U.S. Senate Committee on Appropriations approved the inclusion of the “Preserve Access to Affordable Generics Act” in the report (Senate Report No. 111-238; pages 144-148 & 150-151) accompanying the Fiscal Year 2011 Financial Services and General Government Appropriations Bill (S. 3677).  The version of the “Preserve Access to Affordable Generics Act” in Senate Report No. 111-238 is modeled after S. 369, which would make patent settlements, if challenged by the Federal Trade Commission (“FTC”), presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.”  In addition, under the pending legislation (as in S. 369), a violation can lead to “a civil penalty of not more than 3 times the gross revenue of the NDA holder from sales of the drug product that is the subject of the patent infringement claim for the period of the violation, starting with the date of the agreement.”  In June 2010, the CBO updated its previous cost estimate for S. 369, estimating that the bill, if enacted, would save the Federal government $0.9 billion (net) between 2010-2015 and $2.7 billion between 2010-2020 period.

According to the August 2010 analysis, which was suported by funding from PhRMA, the CBO’s cost estimate is “flawed,” and depends critically on at least three assumptions:

• First, based on an earlier “study” by the FTC, the CBO assumed that the bill would accelerate entry of generic drugs affected by the bill by an average of 17 months.

• Second, the CBO appears to have implicitly assumed that restrictions on reverse payment settlements in existing law will be entirely ineffective over the next 10 years and that anticompetitive settlements can only be prevented by the further restrictions in S. 369.

• Third, the CBO assumed that substantial restrictions on reverse payment settlements would decrease generic manufacturers’ incentives to challenge branded patents and as a result reduce generic entry in some cases.

As an initial matter, the analysis concludes that the 17-month delay settled on by the FTC in its January 2010 study, which is “critical to the CBO’s cost estimate,” is unreliable:

As a matter of economics, there is no sound rationale for assuming that the inclusion of a payment from the branded to the generic manufacturer as part of the settlement agreement caused the observed differences in entry dates by the generic manufacturers. . . . [I]f settlements with reverse payments occur more often when the branded manufacturer possesses a stronger patent than in settlements without reverse payments, later entry under the reverse payment settlements may just reflect the average difference in patent strengths rather than any payment for delay. Similarly, patent settlements with and without reverse payments may differ in the average patent life remaining or the point in time after an initial challenge at which the settlement is reached. Such differences would render invalid the comparison of entry delay between the two types of settlements.  By ignoring the fact that the universe of settlements that involved a reverse payment may differ in important respects from the universe of settlements without such payments, the FTC study (and thus, the CBO cost estimate) has oversimplified the analysis in a way that has material bearing on its utility and reliability for predicting generic entry or estimating costs under alternative rules.

Moreover, according to the study authors, “[t]he FTC study (and therefore the CBO cost estimate, when relying on it) ignores the fact that patent settlements with reverse payments may actually accelerate generic competition for numerous drugs.”  That is, “[t]o the extent that a reverse payment is essential to enable the parties to settle litigation, it can lead to generic drugs entering years before they would at the end of a protracted litigation.”  Thus, restricting patent settlements “would in fact cost the Federal government billions of dollars in increased expenditures on prescription drugs, in contrast to the billions of dollars in savings estimated by the CBO.” 

Second, according to the study authors:

the CBO’s cost estimate depends importantly on accurately estimating the extent to which patent settlement agreements that would be undeterred under the current legal environment would be prevented by the additional restrictions in S. 369. . . . . [T]he CBO appears to attribute all savings from reducing reverse payment settlements to the additional restrictions – implicitly assuming that none of these settlements would be caught or deterred under existing law.  Because existing law will catch or deter at least some anticompetitive reverse payment settlements, this assumption is inappropriate and is another reason why the CBO overstates savings from S. 369.

Finally, apparently agreeing with the CBO cost estimate, the study authors note that a decrease in patent challenges as the result of the enactment of an effective ban on patent settlement agreements will significantly increase Federal expenditures by slowing generic competition:

To the extent that further restrictions on reverse payment settlements reduce such expected rewards (e.g., by denying the generic manufacturer one option for exiting lengthy, costly litigation), then generic manufacturers would have reduced incentives to challenge branded patents in the future.  Patent challengers can be small pharmaceutical firms that may lack the capital to withstand a long, drawn-out patent fight in court.  Faced with a greater likelihood of expensive and protracted litigation, these firms may just forgo the challenge.  Well-resourced generic companies may also have different business assessments of challenging patents in the face of protracted litigation with little possibility of an out-of-court resolution.

This would lead to fewer generic entrants and, all else equal, higher drug prices.  Even if the effect on a particular generic manufacturer’s decision were relatively small, the collective impact on future generic competition could be substantial.

Several Senators raised similar general concerns a letter sent to Senate Majority Leader Harry Reid (D-NV) objecting to the inclusion of the “Preserve Access to Affordable Generics Act” in any Fiscal Year 2011 appropriations bill.

By Ricardo Carvajal –

Late on August 12th, the U.S. Senate Committee on Health, Education, Labor, and Pensions (“HELP”) announced the release its 225-page compromise agreement of the Food Safety Modernization Act (S. 510).  The Congressional Budget Office simultaneously released its estimate of the bill, stating that it would increase spending by about $1.4 billion between 2011 and 2015.

Among the new requirements in the compromise version of S. 510 that would be imposed on industry:

• Domestic and foreign food facilities would have to conduct a hazard analysis and establish risk-based preventive controls, and maintain associated records (dietary supplement facilities in compliance with dietary supplement good manufacturing practice requirements would be exempt);

• Facilities subject to registration under FDC Act § 415 would have to register biennially (but pay no registration fees);

• Facilities subject to reinspection would have to pay resinpection fees.

Among the new authorities that FDA would gain under the compromise version of S. 510:

• Enhanced authority to access records under FDCA § 414;

• Mandatory recall authority (and firms that fail to comply with a recall order would have to pay fees);

• Enhanced authority to administratively detain food under FDCA § 304(h).

Of special interest to importers, FDA would be directed to:

• Implement import certification requirements;

• Establish a program to facilitate importation of food that conforms to safety and security guidelines;

• Require importers to perform “risk-based foreign supplier verification activities” established by regulation.

Among the provisions of specific interest to the dietary supplement industry:

• FDA would be directed to notify the Drug Enforcement Administration if information in a new dietary ingredient notification suggests a potential safety issue due to the presence of an anabolic steroid or analogue thereof;

• FDA would be directed to issue guidance on new dietary ingredient notifications within 180 days of enactment.

There are numerous other provisions that would have significant effects on the food industry, not the least of which is the establishment of whistleblower protections for employees who notify the government of “any” violation of the FDC Act.  Notwithstanding the HELP Committee’s action on the legislation, the prospects for passage of the legislation this year appear to remain uncertain.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Karla L. Palmer will join the Firm as a Director on Monday. Karla brings significant experience in civil and administrative litigation matters. At Hyman, Phelps & McNamara, she will focus on a wide range of litigation, investigation, and enforcement matters.

“Karla’s extensive litigation and courtroom experience is an excellent complement to our growing litigation practice, ” said A. Wes Siegner, Jr., Managing Director.

Karla is a member of the Virginia and District of Columbia Bars. She is admitted to practice before the U. S. Court of Federal Claims, the U.S. Court of Appeals for the Federal Circuit, the U.S. Tax Court, the U.S. District and Bankruptcy Courts for the Eastern and Western Districts of Virginia, the U.S. Court of Appeals for the Fourth Circuit, the U.S. District Court for the District of Columbia, and the U.S. Court of Appeals for the District of Columbia Circuit.

Prior to joining the Firm, Karla was a partner in the law firm of McDermott Will & Emery LLP, where she was the head of the Washington, D.C. Trial Department and co-head of National Recruiting. She has represented clients in federal, state, and administrative courts.

Karla  is a 1992 graduate of the University of Richmond School of Law. While in law school, she was associate editor of The University of Richmond Law Review, a member of the McNeill Law Honor Society, and a legal writing teaching assistant. Upon graduation from law school, Karla clerked for the Honorable Claude M. Hilton, formerly Chief Judge of the U. S. District Court for the Eastern District of Virginia.

By Kurt R. Karst –   

The 60 Plus Association, a senior advocacy group and alternative to AARP, has joined the debate over marketed unapproved drugs, asking FDA to step-up enforcement action and starting its “Keep Seniors Safe” initiative, which “advocates the removal of unapproved drugs from the market for the safety and welfare of the public who unknowingly put themselves at risk of an adverse reaction.” 

According to a letter the association sent to FDA:

60 Plus was troubled by reports in the New York Times, Wall Street Journal, and other news sources that millions of unapproved nitroglycerine, morphine, and colchicine prescriptions were written and filled for patients across the country.  Seniors make up a substantial portion of the market for these unapproved drugs.  As such, 60 Plus is astounded by the FDA’s lack of consumer protection enforcement in the area of unapproved drugs. . . .  60 Plus urges the FDA to enhance its management of unapproved drugs and implement more stringent guidelines in mandating drug manufactures to seek FDA approval under its Unapproved Drug Initiative.

FDA kindly thanked 60 Plus for expressing its concern and detailed some of the Agency’s enforcement efforts under the Unapproved Drugs Initiative.

60 Plus joins a growing number of advocacy groups that have requested greater FDA enforcement action.  As we previously reported, the National Minority Quality Forum and MANA (a self-described national Latina organization) also sent letters to FDA asking for increased enforcement action.  And LegitScript, a self-proclaimed “leading source of information for patients, Internet users, physicians, businesses and other third parties who need to know if an Internet pharmacy is acting in accordance with the law and accepted standards of ethics and safety,” sent a letter to leading pharmacies (and FDA) noting that “[p]harmacies and distributers have the ability to change the unapproved drug market by encouraging drug manufacturers to seek FDA approval, and to refuse to fill prescriptions with unapproved drugs.”

Interest in marketed unapproved drugs has been high over the past few months.  During debate of the Patient Protection and Affordable Care Act, Senator Charles Grassley (R-IA) proposed an amendment that would have required FDA to publish a list of marketed unapproved drugs and that would have prohibited Medicaid payments for such products.  Although the amendment was not voted on, Sen. Grassley has since testified on the issue at a House of Representatives Committee on Appropriations Agriculture Subcommittee hearing, and reportedly plans to pursue legislative action at some point to further support FDA’s oversignt of marketed unapproved drugs.  More recently, FDA won a case in what appears to be the first challenge arising from the Agency’s Unapproved Drugs Initiative.  In that case, the U.S. District Court for the District of Wyoming denied a Motion for Temporary Restraining Order and Preliminary Injunction involving marketed unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL products. 

By William T. Koustas –

We have previously written that Regenerative Sciences (“Regenerative”), a Colorado-based stem cell company, filed a complaint in the U.S. District Court for the District of Columbia against FDA in order to enjoin it from regulating Regenerative’s use of cultured stem cells to treat patients for a variety of ailments (“Regenexx Product”).  In response, FDA recently filed a complaint with the U.S. District Court for the District of Columbia on August 6, 2010 seeking to permanently enjoin Regenerative from using stem cells to treat patients. 

In its June 22nd complaint, Regenerative essentially argued that its Regenexx Product was part of the practice of medicine and thus beyond FDA’s regulatory authority while also noting that the procedure did not involve interstate commerce.  However, in its complaint, FDA has responded by insisting that  Regenerative manufactures a biological product (stem cells) that is adulterated because it is not manufactured according to current good manufacturing practices (“cGMP”) while using components that are shipped in interstate commerce.  FDA v. Regenerative Sciences, LLC et. al., Untied States District Court for the District of Columbia, August 6, 2010 (“Complaint”) at 3, 5.

FDA’s Complaint states that the Regenexx Product is a drug under the FDC Act as it is intended to cure, treat and mitigate disease while also affecting the “structure and function” of the body.  Complaint at 5.  FDA supports this point by referring to Regenerative’s own website and promotional material, which claim that the stem cell procedure “prevents the need for surgery,” is “an Alternative to Traditional Surgery,” and is “shown to be safer than traditional surgical techniques…” Complaint at 6, 7.  FDA further argues that the stem cells are a prescription drug as they should only be used under the supervision of a practitioner as well as a new drug as they are not generally recognized as safe and effective.  Complaint at 7.   

Additionally, FDA’s complaint argues that the Regenexx Product is a biologic under the Public Health Service Act, but not a Human cell, tissue or cellular or tissue-based product (“HCT/P”).  It is a biologic because it is an “analogous product” under the definition of biological product in PHSA 42 U.S.C. § 262(i) as it is used to treat and cure a multitude of conditions, such as osteoarthritis and non-healing fractures.  Complaint at 8.  However, the Regenexx Product is not a HCT/P as the stem cells are more than “minimally manipulated” as required by 21 C.F.R. § 1271.10(a).  Complaint at 9.  Rather, the “expansion of cells in culture does not qualify as ‘minimal manipulation’.”  Complaint at 10. 

Finally, FDA argues that the Regenexx Product is adulterated and misbranded under the FDC Act.  The product is adulterated because it is not manufactured in compliance with cGMP standards (as noted by the prior FDA inspections of Regenerative’s facility) and it is misbranded because the label does not “bear adequate direction for use.”  Complaint at 11, 14.  FDA also points out that, since it asserts that it is a prescription drug product, the label should also note that Regenexx is “Rx only.”  Complaint at 14. 

Though FDA sought an injunction in part based on the fact that Regenerative refused to voluntarily comply with FDA’s request that the company stop manufacturing the Regenexx Product, however, a FDA news release on this issue noted that Regenerative has agreed to discontinue production of the Regenexx Product while this case is pending.  The Court has since issued an order denying Regenerative’s motion for a temporary restraining order in the case filed on June 22, 2010 as moot and entered a stay of that entire case until this case is resolved.

This case is one of the very few injunction suits that the Justice Department, on behalf of FDA, has ever filed in the District of Columbia.  The reason for filing the action here is almost certainly that Regenerative Sciences filed its earlier action here.  Had the Government filed the suit where it normally files injunction cases, namely where the defendant is incorporated or has its principle place of business (Colorado), Regenerative Sciences could have successfully argued that the case needed to be transferred to the District of Columbia.

By Michelle L. Butler & Alan M. Kirschenbaum –

On August 3, CMS issued final versions of three agreements to implement the Medicare Coverage Gap Discount Program.  We previously described the guidance CMS developed with regard to this program as well as the draft agreements CMS published for comment.  CMS has now issued final versions of the Model Manufacturer Agreement and the Model Third Party Administrator ("TPA") Agreement.  In a cover memorandum, CMS describes the revisions it made to the agreements in response to industry comments.  and describes the signing process and deadlines.  In order to participate in the Coverage Gap Discount Program in 2011, a manufacturer must complete and return to CMS the signed agreements, as well as a labeler code worksheet, by 11:59 pm Eastern Time on September 1, 2010.

CMS made the following notable revisions to the Model Manufacturer Agreement:

• Payment deadline:  CMS revised the payment timeframe in section II(b) so that Manufacturers are now required to pay each Part D sponsor within 38 calendar days after receipt from the TPA of the electronic invoice and supporting data.  Manufacturers had vigorously objected to the 14-day deadline proposed in the draft agreement.  In addition, the deadline for manufacturers to electronically notify the TPA that it has paid Part D plans has been extended from one to five business days.

• Level of detail of data provided to manufacturers:  In response to manufacturer comments, CMS has increased the level of information that will be provided to manufacturers from summary-level information to claims-level information, including, among other things, date of dispensing, prescription number, and pharmacy identifier.  Exhibit A to the Agreement provides list of data elements that will be provided to manufacturers.

• Audits:  The final agreement expands considerably on the audit rights of both manufacturers and the TPA.  Audits may not be conducted more frequently than annually.  The party requesting the audit is required to give the other party 60 days notice of the reasonable basis for the audit and a description of the audit.  Manufacturers are limited to auditing specified data for a statistically significant sample of Prescription Drug Events ("PDEs") to determine the applicable discounts.  Exhibit B to the Agreement identifies the PDE data elements available for audit.  The manufacturer is limited to auditing the data and information made available by the TPA and is not permitted to audit CMS records or the records of Part D sponsors.

• Payment of disputed amounts:  Rejecting manufacturer requests that they be permitted to withhold disputed amounts, at least where there are egregious errors, CMS decided not to revise the requirement in the Agreement that Manufacturers must pay invoices in full pending dispute resolution.  However, CMS did provide a narrow exception where an invoice contains NDCs that are not subject to the Agreement.

• Limitations period for claimed discounts:  CMS added a limitation that manufacturers may not be invoiced for drugs dispensed over three years before the date of invoice.

• Monitoring for errors:  Provisions have been added for CMS or the TPA to reconcile discrepancies with discounts reported by Part D sponsors prior to invoicing manufacturers, and to notify manufacturers of any errors discovered after the invoicing.

• Data use provisions:  The data use provisions, which were contained in a separate draft agreement, have now been incorporated into the main Agreement as Exhibit C.  In response to manufacturer objections, the final data use provisions no longer require manufacturers to provide data security of a level and scope required of federal government agencies under OMB and NIST standards.    Instead, manufacturers will be held to a less exacting standard of establishing “appropriate administrative, technical, and physical safeguards . . . .”  In addition, a provision has been added that permits manufacturers to grant access to data to contracted third parties for the purpose of assisting the manufacturer in evaluating the accuracy of claimed discounts, resolving disputes, and otherwise exercising its rights and responsibilities under the Agreement.

Manufacturers who do not sign an agreement by September 1 will not have any of their drugs covered by Part D in 2011.  CMS advises that no extensions will be granted, and encourages companies who are uncertain whether they have covered Part D drugs to sign an agreement, since no discount will be due if the company’s drugs turn out not to be covered.  Similarly, CMS invites companies who are not yet marketing any products to sign an Agreement, which can be updated if products later become available.

By Kurt R. Karst –   

For years now, folks (of the Hatch-Waxman type) have clamored for a full list of 180-day exclusivity decisions.  FDA has not put together such a list, so we decided to try and put together our own list – the 180-Day Exclusivity Tracker.  And now we know why nobody has previously put together such a list.  Like all things Hatch-Waxman, it is quite complicated and takes a lot of time to figure out.  Imagine, if you will, coming across a cache of 5,000-piece puzzles in your grandmother’s attic.  You’re a puzzle fanatic, so you decide to take on the task of putting them together.  But you quickly realize that all of the puzzles are pictures of similar forestscapes and that some of the pieces are missing.  That’s the type of situation we faced when we decided to build the 180-Day Exclusivity Tracker.  We needed to consult many sources, including historical Orange Book listings, Drugs@FDA (where many ANDA approval letters are not linked to), FDA’s first generic approvals database, other government databases (e.g., EDGAR), court documents, and press reports – sometimes to no avail.  But in the end, it is all worth the effort.  

The 180-Day Exclusivity Tracker appears on the right-hand side of the FDA Law Blog along with our other popular trackers – the FDC Act § 505(q) Citizen Petition Tracker, REMS Tracker, and FDA Legislation Tracker.  (It is a large file and might take a minute to download.)  The 180-Day Exclusivity Tracker is in Excel Spreadsheet format and is based on FDA’s Paragraph IV Certification List, although we added some drugs to the list, including drugs for which old exclusivity determinations from the 1980s (pre-Mova) were made, and others that were likely mistakenly omitted from FDA’s list.  Once you open the tracker, you should see lettered tabs at the bottom of the document – one for each letter of the alphabet.  (If you do not see the lettered tabs, then minimize the document.)  There are 8 columns of information for each drug listed: “Drug,” “Dosage Form,” “Strength,” “RLD,” “Date of Submission,” “ANDA Approval Date,” “Approval Letter,” and “Exclusivity Decision.”  In some cases, the “Date of Submission” for a particular drug is blank (just as in FDA’s Paragraph IV Certification List), because it is unclear to us what the date is.  We have filled in some of the blanks on FDA’s list with a pre- or post-Medicare Modernization Act (“MMA”) notation, which dictates whether or not the MMA’s forfeiture provisions come into play.  Under the “Approval Letter” column, we include a particular ANDA number and a link to the approval letter (when available).  Under the “Exclusivity Decision” column we note for each drug (when possible) whether exclusivity has been granted, whether it is pre- or post-MMA exclusivity, whether exclusivity has been forfeited, shared, waived, or relinquished, as well as other information (e.g., suitability petitions, tentative approvals).  We also provide a link to relevant FDA decisions.  Additional bells and whistles might be added as time goes on.

The information included in the 180-Day Exclusivity Tracker is based on the best publicly available information we could find.  In some instances we make an assumption.  For example, when the first generic for a particular drug product is approved after the last expiring Orange Book-listed patent, we assume that FDA did not grant any first applicant 180-day exclusivity – 180-day exclusivity dies with patent expiration.  In other cases, there is not enough information for us to come to any conclusion on what happened to 180-day exclusivity and there is a blank in the tracker.  In many other cases, there are blanks because FDA has not yet made an approval decision (e.g., for ANDAs for which the “Date of Submission” is in 2009 or 2010).  We will try to update the tracker on a regular basis – at least once a month – as new approval and exclusivity decisions are made.  The “last updated” date will appear in the “A” tab heading.

We kindly request from our loyal FDA Law Blog readers who have made us such a success (we recently ranked about 2,000 out of 1.19 million blogs on Technorati) that if you are able fill in any of the missing information in the 180-Day Exclusivity Tracker (or if you think we should clarify information we have filled in) that you contact us by sending an e-mail to kkarst@hpm.com.  Thank you, and enjoy the 180-Day Exclusivity Tracker!

By Carrie S. Martin –

On July 28, a district court in the State of Washington granted a motion for summary judgment in favor of Plaintiff which sought coverage of Medicare claims for a medical device.  International Rehabilitative Sciences, Inc. v. Sebelius, No. C08-5442-RBL (W.D. Wash. Jul. 28, 2010).  At issue were four denials of coverage by the Medicare Appeals Council (the Appeals Council), the highest level of administrative appeal, of the Bionicare Stimulator System, Model 1000 (BIO-1000).  FDA cleared BIO-100 as a Class II medical device in July 1997 for the treatment of osteoarthritis of the knee. 

Medicare Part B pays for outpatient care and durable medical equipment, like BIO-1000, unless the item or service is “not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member,” among other exclusions.  42 U.S.C. § 1395y(a)(1)(A).  Initial coverage decisions for a particular item or service are governed by “national coverage determinations” issued by Health and Human Services (“HHS”), “local coverage determinations” issued by a local Medicare contractor if no national coverage determination exists, or by regional contractors if neither a national nor local determination exists.  Coverage and payment of BIO-1000 was governed by regional contractors.  One can appeal a coverage decision through an administrative chain, with the Appeals Council being the final arbiter.

In upholding the denial of the four claims at issue, the Appeals Council concluded that Plaintiff failed to show conclusively that the device was not “experimental or investigational,” and hence not “reasonable and necessary” for the treatment of osteoarthritis.  According to an HHS Medicare Manual, an item is not “reasonable and necessary” if it is “experimental or investigational.”  In addition, the item must be “safe and effective” and “appropriate.”  Accepted proof of “reasonable and necessary” is “authoritative evidence” or general acceptance of the service in the medical community as safe and effective for the condition for which it is used. 

In reviewing the denial of the four claims, the district court noted that the Appeals Council “discounted the FDA’s approval of the BIO-1000” as evidence of “reasonable and necessary.”  The district court pointed to a statement by HHS in 2003 that said, in making national coverage decisions, “CMS adopts FDA determinations of safety and effectiveness.”  68 Fed. Reg. 55,634, 55,636 (Sept. 26, 2003).  According to the district court, the Appeals Council’s denials either considered FDA clearance simply a prerequisite for Medicare coverage or did not consider FDA’s clearance at all.  Although the district court admitted that HHS is entitled to substantial deference in coverage decisions, the court concluded that the Appeals Council’s failure to “give FDA approval any weight at all” was arbitrary and capricious.

The district court did not cite any judicial decisions to support its conclusion, but industry may want to consider this decision as an example of how courts may handle similar cases in the future. 

By Carmelina G. Allis –

Since September 2009, the Center for Devices and Radiological Health (“CDRH”) has been reviewing the operation of the 510(k) program and the way CDRH uses science in the decision making process.  This week, the 510(k) Working Group and the Task Force on the Utilization of Science in Regulatory Decision Making each released a preliminary report with a series of recommendations. 

The preliminary reports are now open for public comment.  You can find them here.  Once CDRH has assessed public input, it will announce which recommendations it will adopt, along with projected timelines for doing so. 

It is clear that the proposals would have a significant impact on the process by which industry brings devices to market.  Dr. Shuren’s cover letter summarizing the reports restated the agency’s goals in this review process as looking at ways to foster medical device innovation, enhance regulatory predictability, and improve patient safety.  It is an open question whether all of the proposed changes would actually serve these goals.  Some of the proposals seem likely to increase industry’s regulatory burden without much improvement in patient safety, such as, for example, a requirement that manufacturers provide regular, periodic updates to CDRH listing any device modifications that were implemented without the submission of a new 510(k).

The reports do acknowledge the importance of enhancing innovation.  The twin goals of protecting patients from harm and promoting the development of safe and effective devices are given equal billing.  However, in our view, the majority of the recommendations will result, if implemented, in an increased burden on manufacturers, CDRH reviewers, and the 510(k) regulatory program.  It is not apparent that the recommendations, if implemented, will foster medical device innovation or enhance regulatory predictability.  If anything, these recommendations may add new scientific requirements, new regulatory hurdles, and additional uncertainty to a regulatory process that is already non-transparent and unpredictable.

The reports assert that the recommendations are preliminary and have not been implemented.  However, CDRH staff in recent months appear to already be following some of these recommendations.

Below we discuss the most significant recommendations issued by the 510(k) Working Group:

(1) “CDRH should clarify the meaning of ‘substantial equivalence’ through guidance and training for reviewers, managers, and industry.”

The 510(k) Working Group found that there is confusion both within CDRH and the public at large as to what constitutes the “same” versus a “new” “intended use,” and about when “different technological characteristics” raise “different questions of safety and effectiveness.”  As a remedy, the Working Group first recommends that the concepts of “indication for use” and “intended use” be consolidated into a single term, “intended use.”  (The dual terms “indications for use” and “intended use” have created confusion for years.)

Second, the Working Group recommends that CDRH better train reviewers and managers on how to determine “intended use” based on information available in the 510(k) submission.  The main intent of these proposals is to “reduce inconsistencies in [the] interpretation and application” of the term “intended use.”

Third, the Working Group recommends that CDRH explore the possibility of amending the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to provide the agency authority to consider an off-label use of the proposed device when determining its “intended use.”  The declared intent of this proposed measure is to ensure that the manufacturer of the device does not seek clearance for a use that is not the actual use for which the device was intended to be marketed.

If FDA has sufficient evidence that the manufacturer is going to market the device for an intended use different from that proposed in its 510(k) submission, then the agency would likely deny 510(k) clearance or require that additional information be submitted in support of the off-label use.  This proposal would effectively revert to the days prior to the Food and Drug Administration Modernization Act of 1997 (“FDAMA”) when FDA would allege an “implied” intended use based upon off label capabilities of a device.  Since FDAMA, FDA has been required to accept the manufacturer’s characterization of its intended use, absent a finding by the CDRH Director that there is a reasonable likelihood that the device will be used for an intended use not identified in the proposed labeling for the device and that such use could cause harm.

It is not clear whether the agency would apply this change to a general class of devices or target specific device manufacturers based, for example, on their compliance history or publicly available information on their product development and marketing intentions.  It also raises the question as to whether FDA could unfairly subject a manufacturer to additional unnecessary pre-clearance scrutiny due to the bad acts of manufacturers of devices of the same type.

Fourth, the report alleges that FDA existing guidance does not “fully articulate a clear standard that may be applied consistently by reviewers and managers in determining which ‘technological characteristics’ to consider in their decision making, and how to determine whether such characteristics raise ‘different questions of safety and effectiveness.’”  The Working Group acknowledges that such lack of standard or criteria has resulted in inconsistencies in the 510(k) decision making process.  In fact, FDA’s determination whether technological differences raise different questions of safety or effectiveness has been notoriously subjective.

The report recommends revising existing FDA guidance to ensure conformance with language in the FDC Act regarding “different technological characteristics” and “different questions of safety and effectiveness.”  In addition, the Working Group proposes to revise existing FDA guidance to provide clear criteria for identifying different questions of safety and effectiveness, and to identify a core list of technological changes that generally raise different questions.  The goal of providing greater clarity is laudable, but achieving at will be challenging.  Unfortunately, it seems likely that, unless the revisions are device-specific, the proposed guidance, like existing guidance, will have to be written at a high level of abstraction given the heterogeneity of devices regulated as Class II.  It also seems unlikely that revised guidance could make this determination any less subjective and may result in ad hoc decision making.

(2) “CDRH should explore the development of guidance and regulation to provide greater assurance that any comparison of a new device to a predicate is valid and well-reasoned.”

Currently, all devices with 510(k) clearance are potentially available as predicate devices with no time limit.  The Working Group raised concerns about the continued availability of predicate devices that have either been withdrawn from the market for safety reasons or that have become obsolete due to technological advances.  The Working Group also recognized that the public 510(k) database often does not provide sufficient information to help submitters identify an adequate predicate device – and, according to the report, an adequate predicate device is one which raises no safety and/or effectiveness issues, does not have substandard performance, and has not been withdrawn from the market.  (This is not the definition in the FDC Act.)  The recommendations provided in the report include the development of a guidance document to address when a device should no longer be available for use as a predicate device.

The Working Group believes that rescission authority would be useful to eliminate inappropriate predicate devices.  Although the FDC Act does not state that the agency has 510(k) rescission authority, FDA believes that this authority is implicit in the statute.  The Working Group therefore recommends that CDRH consider issuing a regulation to define the scope, grounds, and procedures for exercising its authority to rescind a 510(k). 

FDA issued a proposed rule in 2003 allowing rescission of 510(k)s.  The proposed rule has languished ever since.  This proposal essentially revives the idea.  The problem is that the FDC Act did not really contemplate rescission of 510(k)s, and the withdrawal of a 510(k) creates a potentially cascading effect on other devices cleared in reliance upon that predicate, and also potentially compromises the regulatory status of devices remaining in the field.  What if the manufacturer has discontinued sale of a device with a rescinded 510(k), but still needs to ship accessories to the installed base?  Would that be lawful?  These kinds of practical issues have the potential to create a great deal of mischief.  It will be interesting to see if the agency can make rescission work without significant statutory changes.

The Working Group report also discusses the need to develop guidance on the use of more than one predicate device to establish equivalence, such as when the proposed device combines the intended use and technological characteristics of multiple devices.  One concern with the use of multiple predicate devices is that an analysis conducted for the report shows a greater mean rate of adverse event reports for those devices that cited more than five predicates in the 510(k) submission, something which the Working Group recommends that CDRH analyze further.  (The data used to support this conclusion are not described in the report.)  Recently, we have seen the agency require that manufacturers identify no more than two predicate devices, often times preferring that only one predicate be identified.

Moreover, the Working Group recommends that CDRH no longer allow the use of “split predicates,” which refers to those submissions where the manufacturer uses one predicate to claim intended use and another predicate to claim technological characteristics.  As stated in the report, “[c]oncerns have been raised that the use of a ‘split predicate’ may not allow for a valid comparison of safety and effectiveness because no such device exists . . . and therefore there is no real-world information about its risks and benefits.”  We believe that the agency has already started to implement this recommendation.  This approach may prove to be a formidable obstacle to technological innovation.  The report does not analyze the impact on innovation of a ban on “split predicates,” and, in the absence of “split predicates,” some devices may be inappropriately placed in Class III, requiring premarket approval.  On the other hand, if FDA improves the de novo process, making it less cumbersome and available more often, then a prohibition against “split predicates” might be more palatable.

(3) “CDRH should reform its implementation of the de novo classification process to provide a practical, risk-based option that affords an appropriate level of review and regulatory control for eligible devices.”

The Working Group recognized that CDRH’s implementation of the de novo classification process has been inefficient and has not been utilized optimally across the Center.  CDRH has averaged only about four de novos per year; the last de novo clearance was over a year ago.  One of the reasons is that the FDC Act requires a full 510(k) review prior to initiating the process, even when it is clear that there is no predicate for the proposed device.  Another challenge has been reviewers’ reluctance to agree to de novo review at the outset of the discussions.  Also, the agency develops device-specific guidance to serve as special controls for each device classified into Class II through the de novo classification process, which is a time-consuming process.

The Working Group recommends that CDRH revise existing guidance to streamline the de novo classification process, and proposes the use of pre-submission meetings to discuss the type of information that should be submitted to facilitate the de novo classification process.  The report also said that the Center should consider establishing a generic set of controls that could serve as baseline special controls for devices classified into Class II through the de novo classification process.

(4) “CDRH should take steps through guidance and regulation to facilitate the efficient submission of high-quality 510(k) device information, in part by better clarifying and more effectively communicating its evidentiary expectations through the creation, via guidance, of a new ‘class IIb’ device subset.”

One of the agency’s concerns is its inability to sometimes determine whether a predicate device identified in a submission is a modification of the original cleared device, therefore raising the question of whether it is a valid predicate.  To address this issue, the Working Group made several recommendations for the agency to have better control of unreported device modifications.

The Working Group recommends that CDRH revise existing guidance to clarify the types of changes to a device that do or do not warrant submission of a new 510(k).  Although this would be valuable, it will be impossible for the guidance document to capture all types of changes for all device types regulated via the 510(k) requirements.  Therefore, it is unclear that a revision to existing guidance will help streamline the 510(k) process, facilitate the submission of high-quality device information, or even enhance the agency’s control over unreported device modifications.  There is also a risk that CDRH will use the occasion to revise guidance to require more device modifications to undergo 510(k) clearance, which could slow iterative innovation and improvement in devices, to the detriment of patients.

Another recommendation suggests that CDRH require each manufacturer to provide regular, periodic updates to CDRH listing any device modifications that were implemented without the submission of a new 510(k).  It is unclear how this would be implemented or in what way submitting these tens of thousands of reports annually would foster medical device innovation, but it is certain to burden manufacturers and increase the workload on CDRH reviewers and managers.

The Working Group further recommends that FDA develop guidance to explain manufacturers how to make adequate, structured, and well-supported predicate comparisons in their 510(k)s.  Moreover, CDRH should explore the possibility of requiring each 510(k) submitter to provide as part of the 510(k), non-proprietary photographs and schematics of the device, as well as samples of the device so that CDRH staff could examine the device hands-on as part of the review of the device itself, or during future reviews in which the device in question is a predicate.  The prospect of release of proprietary information is of considerable concern to industry.

The Working Group also recommends providing additional guidance and training for submitters and reviewers on the appropriate use of consensus standards.  In addition, the Working Group recommends that CDRH consider revising Part 807 regulations to require, as is required for the more burdensome PMA applications, a list and brief description of all scientific information regarding the safety and/or effectiveness of the device reasonably known to the submitter.  While generating these summaries may sound like a minor task, for some devices the process will require substantial effort.

Another recommendation is the proposal to develop guidance to define a subset of Class II devices, called “Class IIb” devices, for which clinical information, manufacturing information, pre-clearance manufacturing site inspections, and/or additional post-market surveillance requirements would likely be required to support a substantial equivalence determination.  In addition to delineating the Class IIb types of devices, the Working Group recommends that the same guidance discuss what type of clinical data would be adequate to support clearance.  The Working Group also recommends that the agency continue its ongoing effort to implement a unique device identification system, and consider using “real world” clinical data, such as data from electronic health record systems, as a requirement for future 510(k) submissions.

These recommendations, if implemented, would not likely foster medical device innovation, as it would subject certain Class II devices to more stringent regulatory requirements.  It is unclear that these would be offsetting benefits in improved effectiveness or safety.  The purpose of the 510(k) process is to allow devices fast access to market.  Requiring the submission of clinical and manufacturing information for 510(k) clearance would defeat the purpose of the 510(k) program, making it into a lengthy and burdensome process, similar to that for PMAs, and seems better calculated to hinder, not foster, device innovation.  The review of manufacturing information currently is only required for a very small subset of devices; the intent here seems to apply this requirement more widely.  A small silver lining would be that companies would at least have greater certainty up front as to whether clinical data will be required.
 
(5) “CDRH should take steps to enhance its internal and public information systems and databases to provide easier access to more complete information about 510(k) devices and previous clearance decisions.”

Some of the most useful recommendations include: developing procedures and guidance for the development and assignment of product codes and developing a publicly searchable database for each cleared device that includes a 510(k) Summary, non-proprietary photographs/schematics of the cleared devices, and information identifying the predicate device and corresponding data in support of the clearance.  The Working Group also recommends developing a standardized electronic template for 510(k) Summaries to ensure they contain all information required by regulation.  Another recommendation involves requiring manufacturers to submit final device labeling post-clearance and periodic labeling updates.  The Working Group also recommends developing guidance and regulations to document 510(k) transfers of ownership, which is currently not required by the agency.

Implementing those changes would enhance a manufacturer’s ability to identify an adequate predicate device and provide accurate and up-to-date information on the intended use and technological characteristics of predicates.  All of these reforms are much overdue.  The current CDRH 510(k) database lacks meaningful data to help manufacturers identify adequate predicates.  For example, most 510(k) Summaries do not contain a detailed description of the cleared device, or a discussion of the data submitted in support of clearance.  Without that information, it is difficult and sometimes impossible to identify a predicate device or to determine the likely data support requirements.  And a lack of information on predicate devices introduces unpredictability and uncertainty to the decision-making process.

(6) “CDRH should enhance training, professional development, and knowledge-sharing among reviewers and managers, in order to support consistent, high-quality 510(k) reviews.”

The Working Group recommends that CDRH explore new avenues to enhance the professional development of its review staff and engage outside experts.  Most of these recommendations are reasonable reforms not likely to be controversial within industry.

A specific proposal is to establish a Center Science Council to serve as a cross-cutting oversight body to facilitate knowledge-sharing across offices.  The report also recommends developing a process for regularly evaluating the third-party program; for enhancing third-party reviewer training programs; and for sharing more information with third-party reviewers.  They currently are at an informational disadvantage compared to CDRH reviewers.

The Task Force also made several recommendations which, for the most part, are general in applicability to all of CDRH’s pre-market review programs.  For example, there is a proposal for CDRH to revise its 2002 “least burdensome” guidance to clarify the Center’s interpretation of the “least burdensome” statutory provisions, evaluate the success of the pre-IDE program and agency-industry interactions during the pre-IDE process, and create a mechanism whereby review offices can assemble an ad hoc team of reviewers from different divisions to accommodate unexpected surges in workload. 

In addition, the Task Force recommends that CDRH develop better data sources, methods, and tools for collecting and analyzing post-market information, and take steps to develop a model to help the agency respond to new scientific information, such as using “Level 1- Immediately in Effect” guidance documents or “Notice to Industry” to address a public health concern or a change in regulatory expectations regarding a particular type of device.  The “Notice to Industry” suggestion highlights one of the fundamental challenges for CDRH.  The concept is commendable.  The problem is that communicating “expectations” after they have been set is not very helpful.  Companies need advance notice of changes, and in at least some instances, the opportunity to comment on the changes.  Learning about “evolving expectations” that already have been set is too late for a company that has completed its 510(k) development program.

By Dara Katcher Levy -

In what we believe is DDMAC’s first foray into tackling one of the “gray-areas” created by social media, on July 29, DDMAC issued an Untitled Letter to Novartis Pharmaceuticals for Rx drug content “grabbed” by a Facebook Share widget. 

For those that aren’t familiar with Facebook Share (yes, we know you’re out there), it is a widget placed on a webpage by the webpage operator that allows users to share a link and brief description of that page on Facebook.  The brief description and link are often fed through a “news feed” and shared with Facebook friends.  Although users can add comments to the brief description, they cannot modify the brief description – which is “grabbed” by the widget from the page itself, and may be a “directed grab” of content through the website’s use of html tags. 

The website for Tasigna (nilotinib) capsules contained a Facebook Share widget, located on the right hand side, under efficacy claims, but above the Important Safety Information for the drug.  The brief description grabbed by the widget came from the upper portion of the page, and included the headline and a graphic.  DDMAC’s objection was that the grab contained no safety information, and in some cases, broadened the drug’s indication and made unsubstantiated superiority claims.  DDMAC did not cite the full website itself for any violations, only the grabs created by the Facebook Share widget.

Further, DDMAC cited Novartis for not submitting the Facebook Share grabs on Form 2253.

As industry anxiously awaits DDMAC’s Guidance on the use of the internet and social media (promised by the end of this year), in the interim, we can likely expect some “previews” of the Guidance through further Warning and Untitled Letters on the topic. 

Fortunately, FDLI is publishing in September a book on social media for FDA-regulated companies.  Order now, they make a great Labor Day gift!  (Full disclosure:  HPM co-blogger in chief, Jeff Wasserstein, wrote one of the chapters.)