By Kurt R. Karst –      

FDA’s recent approval of ANDA No. 090358 for an AB-rated generic version of IMITREX STATdose (sumatriptan succinate) Injection, approved under NDA No. 020080, puts some meat on the bones of the Agency’s July 2009 consolidated response to two citizen petitions (here and here) submitted by King Pharmaceuticals, Inc. (“King”) requesting that FDA decline to approve (or stay the approval of) ANDAs that reference a drug product containing an auto-injector device component – and in particular ANDAs for a generic version of IMITREX – unless the auto-injector component is “identical” to that of the Reference Listed Drug (“RLD”) in terms of performance, physical characteristics, and labeled instructions.  As we previously reported, FDA granted in part and denied in part the King petitions.

FDA’s consolidated petitions response, which is specific to combination products with an auto-injector component, provides some general guidance and insight into the Agency’s thinking on what “sameness” means with respect to auto-injector performance, physical characteristics, and labeling instructions.  For example, FDA commented that “when reviewing an ANDA for a combination product that includes an auto-injector constituent part, [the Agency] must evaluate the auto-injector constituent part of the combination product for which ANDA approval is sought to ensure that its performance characteristics and critical design attributes will result in a product that will perform the same as the RLD.”  FDA clarified, however, that “[t]his does not mean . . . that all design features of the auto-injector in the ANDA and its RLD must be exactly the same.  Some design differences may be acceptable as long as they do not significantly alter product performance or operating principles and do not result in impermissible differences in labeling.”

FDA also commented that “[f]or an ANDA for a product intended for emergency use by patients without professional supervision (such as a prefilled auto-injector indicated for emergency treatment of allergic reactions), it is particularly important to ensure that patients in an emergency situation can use the product safely and effectively in accordance with instructions provided for the RLD without additional physician intervention or retraining prior to use,” and that “[a] similar standard may be applied to certain products not intended for emergency use, if appropriate.”  Indeed, in the case of sumatriptan auto-injectors, FDA noted that “individuals experiencing migraines . . . may experience varying degrees of mental impairment, and this may affect the usability of an auto-injector, leading to possible errors or misadministration of the product,” and as such, “in reviewing an ANDA referencing [IMITREX], FDA will have to consider whether, given the characteristics of the proposed auto-injector constituent, the product can be safely substituted for the RLD without additional physician intervention or retraining prior to use.”

With respect to labeling and therapeutic equivalence issues, King had requested that “FDA require ANDA sponsors of drug products containing auto-injectors to use the same physical description of an auto-injector, the same operating instructions, and the same illustrations contained in the RLD labeling,” and that “the same standard should apply in assessing therapeutic equivalence. . . .”  FDA responded that although the auto-injector component in an ANDA for a combination product should be equivalent to that of the RLD product in terms of performance, operating principles, and critical design attributes. “labeling need not be identical.”  According to FDA:

Certain minor labeling changes may be acceptable to identify certain permissible differences between the ANDA and its RLD (e.g., to identify a change in materials to make the product lighter or to make it more robust or durable), as are minor differences (such as cosmetic appearance, color, shape) between the RLD and ANDA labeling when they do not interfere with operating conditions.  For products that require physician training before unsupervised patient use, differences in operation that require retraining prior to use are not expected to be acceptable in an ANDA. FDA will consider other proposed differences in labeling on a case-by-case basis.

That brings us to FDA’s decision to approve an ANDA for an AB-rated version of IMITREX STATdose.  A comparison of the FDA-approved labeling for IMITREX STATdose and its AB-rated generic version approved under ANDA No. 090358 posted on DailyMed – see here and here – while largely identical (as required by the FDC Act), includes different operating instructions under the “Patient Information – How To Use” sections of each set of labeling.  Consistent with FDA’s consolidated petitions response, however, the Agency apparently determined that these differences “do not interfere with operating conditions” and that the differences in operation do not require physician retraining. 

Whether FDA will apply the seemingly flexible approach the Agency apparently took in approving a generic version of IMITREX STATdose to other combination products that do not contain an auto-injector – such as Metered Dose Inhaler (“MDI”) and Dry Powder Inhaler (“DPI”) drug products – remains to be seen. 

Still awaiting a substantive response from FDA is a December 2009 citizen petition (Docket No. FDA-2009-P-0597) requesting “that specific legal and scientific requirements be upheld in the review of proposed generic copies of [MDI and DPI] products containing fluticasone propionate and/or salmeterol xinafoate” (i.e., SEREVENT DISKUS, FLOVENT DISKUS, FLOVENT HFA, ADVAIR DISKUS, and ADVAIR HFA).  For example, the petition requests that FDA not approve any ANDA referencing certain inhalation products unless the proposed generic version “conforms to the [RLD] in its patient instructions for use and handling. . . .”  “Different instructions for how to use an inhaler properly – including priming, dosing, cleaning, and storing – are simply too significant to possibly fit into the very limited zone of labeling differences that the law permits for generic drugs,” according to the petitioners.  Thus, the ultimate question for FDA seems to be this: To what extent must a proposed generic product be interchangeable in patient hands?  Wrapped up in this question are questions about similar external design (shape and size), number of doses, dose counter placement, and color scheme.    

By Kurt R. Karst –      

The latest battleground over the period of exclusivity that should apply to biological products is the Trans-Pacific Partnership (“TPP”) trade agreement.  As you might recall, earlier this year there was quite a hubbub over whether the 12-year reference product exclusivity period provided by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) is appropriately termed “marketing exclusivity” or “data exclusivity” (see our previous post here).  Then there was President Obama’s Fiscal Year 2012 Budget, which proposed slashing the BPCIA’s 12-year exclusivity period, such that “innovator brand biologic manufacturers would have 7 years of exclusivity and would be prohibited from receiving additional exclusivity by “evergreening” their products.” (See our previous post here.)   Cutting exclusivity, “would yield savings of $2,340,000,000 between 2012 and 2021,” according to the Obama Administration’s estimates.  Now there’s the TPP.

The TPP is an Asia-Pacific regional trade agreement being hammered out among the United States (specifically, the United States Trade Representative, Ron Kirk) and eight other partners (i.e., Australia, Brunei, Chile, Malaysia, New Zealand, Peru, Singapore, and Vietnam).  Currently, the TPP is composed of four members (Singapore, Brunei, New Zealand, and Chile) and endeavors to have full free trade between member countries by 2015.  The TPP would cover trade in goods and services and also includes a proposed chapter on intellectual property.  That proposed chapter is where the debate over biologics exclusivity is happening.

A July 27, 2011 letter signed by several members of Congress urges the Obama Administration to push for strong intellectual property rights in TPP negotiations, including consistency with U.S. biologics exclusivity under the BPCIA.  According to the letter:

Critical to increasing U.S. companies’ ability to export and contribute to U.S. GDP growth is ensuring that our government does all it can to help provide a level playing field for U.S. companies globally and advocate for intellectual property rights that provide certainty for America’s innovative companies in the biosciences and other sectors. . . . 

In the course of the TPP negotiations on intellectual property rights issues, we urge you to support current U.S. law on biologics, which provides for 12 years of protection.  The U.S.-led biopharmaceutical industry would be disadvantaged if the U.S. does not ensure consistency with U.S. law as part of the TPP, because foreign countries do not provide the same type of protection rules.  The current protections for biologic drugs were debated extensively and received strong bipartisan support in both the House and the Senate.  This provision is critical to keeping and expanding high-value U.S. jobs offered by America’s biotech sector and spurring the R&D investment needed to seize extraordinary opportunities for medical advances to combat our most costly and challenging diseases.

A rebuttal of sorts to the July 27th letter was sent to President Obama on August 4, 2011 and urges the President to refrain from negotiating exclusivity protections for biologic medicines.  According to that letter, also signed by several members of Congress:

[T]he consequences of [the BPCIA’s] mandated 12 years of biologics exclusivity are not yet known.  Additionally, the Food and Drug Administration has not yet promulgated any regulations to implement the biosimilars provisions of the new law, nor has the Agency approved any biosimilars in the United States. . . . 

Proposing 12 years of exclusivity in the context of TPP negotiations would also conflict with stated Administration policy, as reflected in the FY 2012 budget proposal, recommending that the exclusivity period for biologics be reduced to 7 years. . . .  Were the TPP ultimately to contain a 12 year biologics exclusivity provision, it would impede the ability of Congress to achieve the Administration’s proposed 7 year change without running afoul of U.S. trade obligations.  We see no reason for the United States to agree to such a provision, much less to propose it.

Another Member letter, dated August 2, 2011, and sent to Ambassador Kirk, raises several intellectual property issues regarding TPP talks.  Among other things, that letter raises concerns with proposals “that would undermine access to affordable medicines,” and specifically, one that would “propose expanding data exclusivity requirements . . . .”  The signatories to that letter “urge that any data exclusivity provisions, if included at all, be made voluntary, expire no later than a comparative period in the U.S., and include public health safeguards.” 

Outside of the TPP agreement talks, there is significant activity in the biologics/biosimilars space.  We understand that discussions about the structure of a user fee program for applications for biosimilar and interchangeable biological products are continuing.  FDA must submit its recommendations to Congress by January 15, 2012.  (See our previous post here.)  And last week, several FDA officials co-authored an article that appeared in the New England Journal of Medicine, titled “Developing the Nation’s Biosimilars Program.”  That brief article notes that FDA’s “totality of the evidence” approach, under which the Agency  integrates various kinds of evidence in making regulatory decisions, “along with the FDA’s experience with fingerprint-like characterization of complex products, will be essential in designing a U.S. biosimilars policy that encourages development of biosimilars, emphasizing the use of innovative technologies.”

By Cassandra A Soltis –

In a decision that could have implications in the United States, the U.K.’s Advertising Standards Authority (“ASA”), which describes itself as “the UK’s independent watchdog” that regulates advertising, found both a Lancôme and a Maybelline advertisement misleading because the images of the models, which were digitally retouched, were not accurate representations of the results that the products could achieve. 

The Lancôme advertisement for “Teint Miracle,” a foundation, included claims that the product “recreates the aura of perfect skin.  Instantly complexion appears naturally bare, beautifully flawless and luminous, as if lit from within.”  The ASA stated that the advertisement was misleading because, although “the product was capable of improving skin’s appearance,” the evidence did not show “that the ad image accurately illustrated what effect the product could achieve, and that the image had not been exaggerated by digital post production techniques.” 

The ASA came to a similar conclusion regarding Maybelline’s “The Eraser” foundation advertisement, which included claims such as “covers” fine lines and “conceals” crow’s feet as well as a disclaimer that the image of the model was an “Illustrated effect.”  The ASA noted that “the area around the model’s left eye had been digitally re-touched and . . . the text had drawn particular attention to the product’s effect in this area.”  The ASA stated that the ad was misleading and “must not appear again in its current form,” even though the advertiser had consumer testing results showing the public “agreed with the claims.” 

On this side of the pond, the National Advertising Division of the Better Business Bureau (“NAD”), which is a similar self-regulatory body in the United States, reviewed an advertisement for one of Maybelline’s “Eraser” line of cosmetics and came to a slightly different conclusion.  NAD Case #5241, Maybelline New York Inc., Instant Age Rewind Eraser Treatment Makeup (Nov. 10, 2010).  The “Instant Age Rewind Eraser Treatment Makeup” advertisement included claims such as “Erase fine lines” and “crow’s feet,” along with a close-up shot of a model’s face that was digitally altered.  The ad qualified the claims with a statement that the product “[d]oesn’t just cover; after 8 weeks of use reduces imperfections without makeup on.”  In addition, the disclosure “visual is a dramatization of actual product results” appeared at the bottom of the ad.

The NAD was concerned that, despite the disclosure that the visual was a dramatization, the digitally altered image showed the complete elimination of age-related imperfections.  However, because the ad qualified the “Erase fine lines” and similar claims with the text “reduces imperfections,” and the advertiser’s consumer survey showed that 68% of the respondents thought that this was the ad’s message, the NAD concluded that the photograph could still be used in future ads but recommended that the “visual dramatization” disclosure be removed and replaced with “a disclaimer clarifying the results which consumers can expect to achieve.” 

Given the publicity that the ASA’s Lancôme and Maybelline rulings have had here in the United States (for example, see here and here), and the increased concern about the digital manipulation of ads generally, it will be interesting to see whether the NAD will take a different approach in reviewing digitally manipulated ads.

By Cassandra A. Soltis –

The Food and Drug Administration (“FDA”) has reopened the comment period for its proposed rule on “gluten-free” labeling of food to announce the availability of, and seek comments on, its report titled “Health Hazard Assessment for Gluten Exposure in Individuals with Celiac Disease:  Determination of Tolerable Daily Intake Levels and Levels of Concern for Gluten,” which discusses FDA’s gluten safety assessment.  FDA also requests comments on a number of related issues, including whether and how this safety assessment should affect the proposed “gluten-free” definition in the final rule and on FDA’s tentative conclusion to adopt the proposed rule’s analytical methods-based approach to define the term “gluten-free.”

If you recall, FDA proposed to define “gluten-free” for voluntary use in food labeling as a food that does not contain any of the following:  (1) an ingredient that is any species of wheat, rye, barley, or a crossbred hybrid of these grains; (2) an ingredient derived from one of these grains and that has not been processed to remove gluten; (3) an ingredient derived from one of these grains and has been processed to remove gluten if the use of that ingredient results in the presence of 20 ppm or more gluten in the food (i.e., 20 micrograms or more gluten per gram of food); (4) 20 ppm or more gluten.  72 Fed. Reg. 2795 (Jan. 23, 2007). 

In the Federal Register notice announcing the reopening of the comment period, FDA states that it has “tentatively concluded” that it will “use both the ELISA R5-Mendez Method and the Morinaga method” to “assess compliance with [the] gluten threshold level for foods bearing ‘gluten-free’ labeling claims,” and that these methodologies will be included in the codified language of the final rule.  76 Fed. Reg. 46671, 46672-73 (Aug. 3, 2011).  However, because there are no currently available validated methods to assess the gluten content of certain foods, such as fermented or hydrolyzed foods, “FDA is considering whether to require manufacturers of such foods to have a scientifically valid method that will reliably and consistently detect gluten at 20 ppm or less before including a ‘gluten-free’ claim in the labeling of” these foods.  Id. at 46673 (footnote omitted).  

Because the proposed rule’s definition of “gluten-free” would permit foods not completely free of gluten to bear the claim, FDA seeks comments on whether it would be necessary for a “gluten-free” claim to be qualified with a statement such as “does not contain 20 ppm or more gluten.”  Id. at 46675.  In addition, in light of FDA’s safety assessment, which suggests that a level below 20 ppm for a “gluten-free” claim might be more protective for the most sensitive individuals with celiac disease, FDA invites comments on whether a gluten threshold level lower than < 20 ppm should be adopted and, if so, what impact this might have on both manufacturers of foods with “gluten-free” claims and on consumers of these foods.  Id.  FDA also requests comments on whether a “low-gluten” claim should be defined, and if so, what threshold level should be used.  Id. at 46676.

Comments on the proposed rule and the other issues highlighted by FDA are due October 3, 2011. 

In his recent article appearing in FDLI Update, Hyman, Phelps & McNamara, P.C.’s Douglas B. Farquhar discusses the recent and highly publicized directed verdict for Lauren Stevens, the former in-house lawyer at GlaxoSmithKline, who was on trial for charges that she, basically, lied to the federal government in response to a subpoena demanding documents.  (See our previous post here.)  United States District Court Judge Roger W. Titus’ ruling, writes Mr. Farquhar, “should be a clarion call that prosecutors need to be mindful stewards of the enormous power that they have to decimate people’s lives.”

The American Conference Institute will be holding its 12th annual “Maximizing Pharmaceutical Patent Life Cycles” conference in New York City from October 3-5, 2011.  A copy of the conference program is available here.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be presenting at the conference in a session titled “REMS Studies and Generic Entry: Exploring the Latest Regulatory Conundrum Affecting Pharmaceutical Patent Life Cycle Strategies.”  (We’ve previously posted on this topic here.)

The conference will include presentations from key representatives from the PTO (invited), FTC and FDA (invited), an update on biosimilars, in-depth discussions on life-cycle management developments including, analyses of recent critical cases affecting patent life cycle planning, and much more.

FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $200 discount off the current price tier (which expires this Friday).  The discount code is: FLB 200.  We look forward to seeing you at the conference.

By Ricardo Carvajal –

The Federal Trade Commission ("FTC") issued the latest in a series of reports on sales, advertising, and promotion of cigarettes and smokeless tobacco.  The reports are based on data submitted to FTC by industry.  The cigarette report states that the “total number of cigarettes reported sold or given away decreased by 7.7 billion cigarettes (2.2 percent) from 2006 to 2007, and then by another 20.2 billion units (4.5 percent) from 2007 to 2008,” such that the total number of cigarettes sold or given away in 2008 was 322.6 billion.  For purposes of reference, that figure was reported as 402.2 billion in 2001.  There was also a decline in advertising and promotional expenditures, from $12.49 billion in 2006 to $9.94 billion in 2008 – the lowest figure reported since 2000.

The smokeless tobacco report states that “the total amount of smokeless tobacco sold by manufacturers to wholesalers and retailers increased from 115.82 million pounds in 2006 to 118.23 million pounds in 2007. Sales rose again in 2008 to 119.92 million pounds.”  That figure was reported as 112.2 million pounds in 2001.  The report also presents data on the number of units of smokeless tobacco given away, by package size.  Advertising and promotional expenditures increased from $354.1 million in 2006 to $547.9 million in 2008 – more than twice what was reported in 2000. 

FDA regulations issued under the authority of the Family Smoking Prevention and Tobacco Control Act curtail the distribution of free samples of cigarettes and smokeless tobacco, and FDA recently published a final rule that will require more prominent and graphic health warnings on cigarette labeling and advertising – assuming it survives a court challenge.  It will be interesting to see whether advertising expenditures are influenced by FDA’s implementation of the new law.

The Institute of Food Technologists (“IFT”) is requesting proposals for its March 28-29, 2012 annual Wellness Conference, which will explore new trends and examine recent scientific, technological, and business information in the health and wellness sector of the food industry.  The conference will cover a variety of topics related to consumer lifestyles and demographics, health issues, and weight management.  Submission Guidelines and topical priorities can be viewed here.  The deadline for submissions is August 18, 2011.  Hyman, Phelps & McNamara, P.C.’s Cassandra Soltis, a Wellness 2012 Advisory Panel Member, will moderate some of the sessions. 

By Cassandra A. Soltis & Anne Marie Murphy –

The Department of Health and Human Services, Office of the Secretary, along with the Office of Science and Technology Policy, has issued an advance notice of proposed rulemaking (“ANPRM”) requesting comments on how to update current regulations on the protection of human subjects who participate in research. 

Existing regulations on human research have been in place for decades with little significant change.  Thus some have dubbed the current initiative “historic.”  The impetus to modernize the regulations is in part a result of the way human research has evolved over the years.  Changes in the way human research is conducted include an increase in multi-site clinical trials and observational studies; research in the social and behavioral sciences; research using databases, the Internet, and biological specimen repositories; and perhaps most significantly the use of advanced technologies, such as genomics.  Other factors motivating change include criticism of the existing regulatory scheme by government bodies (e.g., Government Accountability Office) and academics.  A recent Executive Order also charges Federal agencies to review and update existing significant regulations to ensure that objectives are being met in the most efficient manner.  Improving Regulation and Regulatory Review, January 18, 2001. 

The ANPRM addresses a host of concerns over the “Common Rule,” which is codified at 45 C.F.R. part 46, subpart A, and has been adopted by about 15 Federal departments and agencies.  The Common Rule generally requires that Federally funded investigators obtain and document the informed consent of research subjects and describes, among other things, the requirements for membership, function, operations, research review, and recordkeeping of institutional review boards (“IRBs”).  Regulations to protect human subjects involved in FDA-regulated research include the provisions set forth at 21 C.F.R. parts 50 (informed consent), 56 (IRBs), 312 (investigational drugs), and 812 (investigational medical devices).  FDA’s regulations on informed consent and IRBs are separate from, but largely track, the provisions of the Common Rule.  The proposed rulemaking notes that other regulatory schemes, such as FDA regulations and the HIPAA Privacy Rule, will be affected and “will need to be harmonized.”

Seven primary categories of concern are highlighted in the ANPRM:
 
(1) Ensuring that the rules relate to the magnitude of risk to study subjects.  For example, IRBs have been criticized for spending too much time reviewing studies that involve minimal risk or overestimating foreseeable risks to subjects, particularly in the context of social and behavioral research.

(2) Streamlining IRB review of multi-site studies. 

(3) Improving informed consent.  Particularly in biomedical research where risks can be significant, there is value in ensuring that the consent process conveys the information needed for a potential subject to make an informed decision in a manner that the subject can understand.  At the same time, a rigid requirement to obtain written informed consent for certain types of research, e.g., surveys or interviews, has been questioned. 

(4) Strengthening data protections to minimize information risks.  For example, where genetic information is collected and stored, study subjects incur the risk of accidental or unauthorized disclosure of personal information.  HIPAA requirements address such risks in part, but apply only to covered entities. 

(5) Collecting information that would better allow evaluation of the system and how well human subjects are protected.

(6) Extending the scope of the Common Rule to include research studies conducted at institutions that receive any Federal funding, even if not specific to the study at issue.  This responds in part to those who have called for legislation to expand the Common Rule to cover all human subjects research conducted in the United States, regardless of the source of funding.

(7) Clarifying and harmonizing regulatory requirements and guidance across Federal agencies.

The ANPRM requests public comment on these issues and asks for responses to more than 70 specific related questions.  Barring an extension, comments must be submitted by 5 p.m. on September 26, 2011.

By Ricardo Carvajal –

FDA announced fee rates for reinspections of domestic and foreign facilities, importer reinspections, and noncompliance with a recall order – all authorized by the Food Safety Modernization Act ("FSMA").  The fees kick in on October 1, 2011.  The hourly fee rate is $224 ($335 if foreign travel is required).  FDA can be expected to collect fees under the following circumstances:

• Reinspection after a previous inspection that was classified as Official Action Indicated (meaning that significant objectionable conditions or practices were found and regulatory action is warranted to address non-compliance), and where non-compliance was materially related to food safety requirements (meaning the food is adulterated under FDC Act § 402 or misbranded under § 403(w)).  For domestic facilities, fees will be collected from the responsible party (the person who submitted the food facility registration required under § 415).  For foreign facilities, fees will be collected from the U.S. agent.  The fee will be based on the number of hours FDA spends on the reinspection.  Those hours could add up quickly, given that FDA can include time spent on physical surveillance, travel, preparation of reports, and sample analysis.

• Import reinspection/reexamination after a refusal under § 801(a) (including refusal pursuant to an import alert for detention without physical examination) that is materially related to food safety requirements.  Fees will be collected from the importer.  The fee will be based on the time spent on the activity in question (e.g., evaluation of a request for, and supervision of, reconditioning; review of evidence regarding admissibility, under some circumstances; evaluation of a request for removal from import alert, under some circumstances). 

• Recall activities performed by FDA as the result of noncompliance with a recall order.  The fee will be collected from the person who received the recall order, which would be the responsible party (in the case of domestic facilities) or the importer.  Again, the hours could add up quickly, considering the time spent on audit checks, inspections, and monitoring of disposition, among other things.

For the first year, there will be no formal mechanism for fee reductions for small business because FSMA requires notice and comment rulemaking to implement such fee adjustments.  In the interim, to help develop proposed guidelines, FDA published a separate notice requesting comment on the burdens imposed by the fees on small business, and whether FDA should alleviate those burdens.  FDA will also “consider waiving in limited cases some or all of an invoice fee based on a severe economic hardship, the nature and extent of the underlying violation, and other relevant factors.”

By Kurt R. Karst –     

Each year around this time, some of us at our firm participate in a version of The Price Is Right Showcase Showdown in which folks “bid” on what they think the PDUFA application user fee rate will be set at for the next Fiscal Year (“FY”).  (There’s always that one person who goes a dollar over the previous highest bid.)  Bids are placed based, in part, on previous FY application user fee rate increases and other historical information.  For example, for FY 2011, FDA set the full application fee at $1,542,000, a 9.7% (or $136,500) increase over the FY 2010 fee of $1,405,500.  This year, nobody anticipated that FDA would increase the application fee as high as it did – by a dollar amount higher than any and previous increase in the history of PDUFA, and at a rate higher than any fifth year of a PDUFA cycle. 

In a Federal Register notice scheduled for publication on August 1st, FDA will announce the Prescription Drug User Fee Act (“PDUFA”) user fee rates for Fiscal Year (“FY”) 2012.  (In separate notices, FDA will announce the FY 2012 user fee rates for animal drugs, animal generic drugs, medical devices, and fees under the Food Safety Modernization Act domestic for foreign facility reinspections, recall, and importer reinspection.)  The FY 2012 PDUFA application user fee rates is set at $1,841,500 for an application requiring “clinical data,” and one-half of a full application fee ($920,750) for an application not requiring “clinical data” and a supplement requiring “clinical data.”  (The term “clinical data” for PDUFA user fee purposes is explained in an FDA guidance document available here.)  Annual establishment and product fees have been set at $520,100 and $98,970, respectively.  The FY 2012 fees go into effect on October 1, 2011.

The first table below shows the percent increase since the previous FY for each of the five FYs under PDUFA IV (for each fee type), and should be used with the table from our previous post, which tracks PDUFA user fees rates since the inception of PDUFA.  The next three tables show the historical trend for each PDUFA user fee.

 
  
 
When it was enacted in 1992, PDUFA was hailed by some as an unprecedented accord among FDA, the pharmaceutical industry, and Congress.  In exchange for the promise of a speedier drug review system, the industry agreed to pay user fees.  Over the years, the cost to the industry for FDA’s promise of improved performance has increased considerably (as shown in the above tables). 

So, is industry getting what it is paying for?  Some, would say no.  At a recent Senate hearing on PDUFA V, Senator Richard Burr (R-NC) criticized FDA for delays in approval decisions.  According to FDA Commissioner Hamburg, who testified at the Senate hearing, except for FY 2008-09, “FDA has maintained strong performance in meeting the PDUFA application review goals.”  Dr. Hamburg’s testimony included the following table on application review performance metrics.

By Jennifer D. Newberger –

On July 29, 2011, the Institute of Medicine ("IOM") released its long-awaited report, “Medical Devices and the Public’s Health, The FDA 510(k) Clearance Process at 35 Years.”  Both industry and FDA were likely surprised by the IOM’s recommendation: do away with the 510(k) process as quickly as possible, and put in its place “an integrated premarket and postmarket regulatory framework that effectively provides a reasonable assurance of safety and effectiveness throughout the device life cycle.” 

The IOM reached this decision based on a consideration of two questions posed to it by FDA:

1. Does the current 510(k) clearance process optimally protect patients and promote innovation in support of public health?
2. If not, what legislative, regulatory, or administrative changes are recommended to optimally achieve the goals of the 510(k) clearance process?

The IOM stated that it was difficult to answer those questions, since it found that the 510(k) process was not intended to determine whether a new device provides a reasonable assurance of safety and effectiveness or whether it promotes innovation.  Rather, according to the IOM, it was intended only to determine whether the new device is substantially equivalent to an already marketed (predicate) device, and there was therefore an inherent conflict between the legislative framework of the 510(k) program and the FDA’s stated goals.

On first glance, this might look good for industry.  If FDA does not have the statutory authority to request information about safety and effectiveness (except to support the safety and effectiveness of technological changes), then the report could have concluded that FDA should just stick to its statutory mandate to determine whether a new medical device is substantially equivalent to a predicate.  In fact, the first conclusion of the committee is that the 510(k) process “cannot be transformed into a premarket evaluation of safety and effectiveness as long as the standard for clearance is substantial equivalence to any previously cleared device.”  But, rather than simply telling FDA that it is going beyond its statutory mandate in trying to use the 510(k) process as a premarket evaluation of safety and effectiveness, and rather than proposing ways to “fix” the 510(k) process, the IOM stated that it “does not believe that further investment in the 510(k) process is a wise use of the FDA’s scarce resources and is not recommending specific changes in the 510(k) clearance process itself.  Instead, it believes that the FDA’s resources would be put to better use in obtaining information needed to develop a new regulatory framework for Class II medical devices and addressing problems with other components of the medical device regulatory framework.”

The IOM did not, however, propose how FDA might use its “scarce resources” to obtain the information necessary to completely overhaul the entire medical device premarket approval program.  The report repeatedly noted that the 510(k) clearance process is “not a stand-alone program, but a component of the larger medical device regulatory framework.”  If FDA were to adopt the IOM’s recommendation to scrap the 510(k) program altogether (which is extremely unlikely), this raises the obvious question of whether changes would be made not only to the premarket pathway for Class II devices, but for Class and I and Class III as well.

Although it did not describe a specific regulatory framework, the report does provide what the IOM committee considers to be an “ideal regulatory framework”:

• The process should be based on sound science.
• The process should be clear, predictable, straightforward, and fair.
• The process should be self-sustaining and self-improving.
• The process should facilitate innovation that improves public health by making medical devices available in a timely manner and ensuring their safety and effectiveness throughout their lifecycle.
• The process should apply relevant and appropriate regulatory authorities and standards throughout the life cycle of devices to ensure safety and effectiveness.
• The process should be risk-based.

These elements are broad and far-reaching, and not very controversial.  However, they do not appear to provide FDA with any solid ground upon which to move forward with the IOM recommendation to conjure an entirely new pathway for medical device premarket review (which would, of course, need to be enacted by Congress).  But perhaps that won’t matter, since FDA has already stated in response to the report that it “believes that the 510(k) process should not be eliminated,” but that it is “open to additional proposals and approaches for continued improvement of our device review programs.”  

The committee also declined to comment specifically on whether the 510(k) process has an effect, for better or worse, on medical device innovation over the years.  It  concluded that “[i]nformation that would allow an understanding of the extent to which the 510(k) clearance process either facilitates or inhibits innovation does not exist.”  It further noted:  “The 510(k) process does not require a moderate-risk device to be innovative, nor does it reward innovation. However, the 510(k) process can facilitate innovation by making new devices available to consumers in a timely manner. It is unclear—and the committee concludes that it is indeterminable, given current information—whether the 510(k) process over the last 35 years has had a positive or negative effect on innovation. To answer this question, the FDA should commission an assessment to determine this effect.”  Perhaps that is what FDA thought it was doing when it commissioned the IOM to address this issue, but apparently it was mistaken. 

One subject on which the report does provide some detailed discussion is that of improving FDA’s postmarket surveillance system.  The report states that FDA should give priority to postmarket surveillance as an “invaluable investment” in both short- and long-term oversight of medical device safety and assessment of device effectiveness.  It also notes that although FDA stated that its postmarket authorities have “important limitations,” the committee did not seem convinced that such limitations exist, and the report encourages FDA to identify and address any such limitations.

One area that both industry and FDA are interested in improving is the de novo review process, an area on which the committee was to provide suggestions.  Rather than specifically describing how the de novo process itself may be improved, however, the report states a “pilot program of a modified de novo process would allow the FDA to determine its feasibility as a replacement for the 510(k) clearance process.”  The report does not indicate what that “modified” de novo process would look like, apart from expediting development of special controls, developing guidances, and adopting standards for devices.

So where does all this leave us?  Though hard to say, there a couple conclusions that seem reasonable.  First, the IOM committee specifically states that it “is not suggesting that all, many, or even any medical devices cleared through the 510(k) process and currently on the market are unsafe or ineffective. The continual use of many of these devices in clinical practice provides reason for a level of confidence in their safety and effectiveness.”  Perhaps this will provide more confidence that most devices on the market are safe and effective for their intended uses, even if cleared through the 510(k) process.  Second, FDA has already stated it does not think the 510(k) program needs to be completely scrapped and an entirely new medical device review program put in place.  It wants to work within the framework that already exists.  While IOM’s recommendation to get rid of the 510(k) process certainly gives FDA the ammunition to do just that if it wants to, the likelihood of that happening is low.  Perhaps this means that industry need not worry about sweeping overhauls taking place any time soon, at least based on recommendations from the IOM.

FDA has already stated that it will be opening a public docket to receive comments on the report.  Given the sheer breadth of the report, there may be many areas that will attract comments.  So, for better or worse, perhaps the most reasonable conclusion is simply that nothing is bound to change for a good, long while, and it is no more clear today than prior to release of the report what those changes are likely to be.

By Ricardo Carvajal –

A federal district court dismissed with prejudice a claim that Bayer’s labeling of gummy vitamins violated the Arkansas Deceptive Trade Practices Act.  Plaintiff alleged that the brand name “ONE A DAY” is misleading because the daily serving size for the vitamins is two gummies.  Acknowledging that plaintiff’s claim “carries a logical appeal” and “is not silly,” the court nonetheless ruled that no reasonable consumer would be deceived when the label is considered as a whole.  The label stated the dosage three times, as well as the number of servings in the container.  Further, plaintiff failed to allege that he was deceived. 

By Susan J. Matthees –

FDA recently denied a 2006 citizen petition submitted by Wyeth Consumer Healthcare (“Wyeth”) requesting that FDA withdraw a 2005 Notice of Proposed Rulemaking (“NPRM”) that would reclassify phenylpropanolamine (“PPA”) from Category I (generally recognized as safe and effective) to Category II (not generally recognized as safe and effective).  Wyeth alleged that FDA’s proposal to reclassify PPA was based on one flawed study of PPA and that the NPRM incorrectly described the safety status of PPA.  FDA disagreed, stating that the weight of evidence indicates that PPA’s safety has not been demonstrated. 

PPA has a relatively long history of use in the United States.  The ingredient was synthesized in the early 1900s and by the early 1940s was used in OTC nasal decongestant products.  Beginning in the 1970s, PPA was marketed as an appetite suppressant in OTC weight control drug products.  According to FDA, a 1991 review of adverse event reports from 1977 to 1991 and published studies on PPA suggested that PPA might be associated with an increased risk for hemorrhagic stroke.  In 2000, FDA’s Nonprescription Drugs Advisory Committee evaluated data on PPA and concluded that PPA should not be generally recognized as safe.  That same year, FDA conducted its own analysis of PPA data and requested that manufacturers voluntarily discontinue marketing products containing PPA.  In 2005, FDA proposed the reclassification of the ingredient from Category I to Category II. 

Wyeth objected to the proposed reclassification, alleging that FDA based its proposal to reclassify PPA on the findings of one flawed study, the Yale Hemorrhagic Stroke Project (“HSP”).  According to Wyeth, the HSP study is not a reliable study because the findings were based on a small number of cases and that there were a number of errors in the study, including errors in determining subject eligibility and classification and confounding factors that could undermine the validity of the results. 

FDA disagreed that the HSP study was fatally flawed, saying that Wyeth failed “to present convincing evidence that the HSP study is irreparably compromised.”  FDA also explained that the Agency’s proposal to reclassify PPA was based on all available data for the drug and the totality of the evidence suggested that the drug’s safety has not been demonstrated.  FDA reviewed 20 years of adverse event reports for PPA and the published results of a Korean study that was similar to the HSP.  Although Wyeth had criticized the Korean study, FDA concluded that the study provides “additional supportive evidence.”  FDA also stated that the adverse event reports for PPA are consistent with known biological effects of PPA on blood pressure. 

On July 26, 2011, Hyman, Phelps & McNamara, P.C. filed a request for a one-year comment period to allow affected businesses adequate time to respond to a lengthy and controversial draft guidance on New Dietary Ingredient ("NDI") notifications that FDA issued earlier this month.  Our previous post on the draft NDI guidance is available here.