By Kurt R. Karst –      

Just days after FDA announced the release of three draft guidances on biosimilar product development (see our previous post here), and on the same day FDA officially noticed their availability in the Federal Register (here, here, and here) (as well as a proposed collection on § 351(k) biosimilar applications), FDA denied the outstanding requests in two citizen petitions submitted to the Agency in April 2003 (Docket No. FDA-2003-P-0003) and April 2004 (Docket No. FDA-2004-P-0214) by the Biotechnology Industry Organization (“BIO”) and Genentech, Inc. (“Genentech”), respectively.  Both petitions were submitted to FDA well before the March 2010 enactment of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which amended the Public Health Service Act (“PHS Act”) to, among other things, create an approval pathway for biosimilar and interchangeable versions of reference products (§ 351(k) biosimilar applications).  As such, the petitions primarily pertain to the submission and approval of 505(b)(2) applications under the FDC Act for “biotechnology-derived products” (i.e., therapeutic drug or biological products developed by biotechnology methods) or “follow-on therapeutic proteins” (i.e., polypeptide therapeutic products, including recombinant versions of therapeutic protein products, not submitted to FDA with a full complement of clinical data).

FDA had previously addressed most of the issues raised in the petitions in the Agency’s October 2003 and May 2006 petition responses (here and here); however, two outstanding requests remained:

(1) that FDA decline to publish a draft guidance regarding the “similarity” or “sameness” of a “biotechnology-derived product” or “therapeutic protein” that relies on confidential or trade secret information; and

(2) that FDA provide advance notice and a pre-deprivation hearing if FDA does decide to issue such a guidance using trade secret or confidential information.

Genentech broadly requested in its petition that FDA “refrain from publishing a draft guidance document setting forth standards for the ‘similarity’ or ‘sameness’ of biotechnology-derived products. . . that relies, directly or indirectly, on Genentech’s trade secret and confidential commercial data.”  FDA says in its 2012 petition response that Genentech “suggests that any guidance document FDA creates on this subject impermissibly will be infused with protected confidential and trade secret information.”  Any such argument must fail, however, says FDA, because the Agency’s “mandate is to protect the public health in the areas within its purview – including biotechnology-derived products – and it may, among other things, create guidance to industry regarding the laws it administers.”  With respect to the draft biosimilars guidances issued on February 9, 2012, FDA comments that they “do not violate any protections available to applicants by relying, either ‘directly or indirectly,’ on Genentech’s or any other entity’s confidential information. . . [,] do not disclose any trade secret or confidential information, and [that] FDA did not impermissibly use or rely upon any such information in developing them.”

BIO more specifically requested in its 2003 citizen petition that FDA “refrain from preparing, publishing, circulating, or issuing any new guidance for industry, whether in draft or final form, concerning follow-on applications for therapeutic proteins, particularly human growth hormone or insulin, under [FDC Act § 505(b)(2)] which was intended simply to codify FDA’s earlier ‘paper NDA’ policy.”  Insofar as BIO’s request is limited to guidace involving 505(b)(2) applications for therapeutic proteins, FDA comments in the Agency’s February 2012 response that FDA has general authority to issue guidance and notes that “if FDA deems such an exercise of its authority appropriate or necessary, the Agency may prepare, publish, circulate, or issue new draft or final guidance for industry concerning applications for therapeutic proteins (or any other subset of products) eligible for approval under [FDC Act § 505(b)(2)].”  Insofar as BIO’s petition more generally requests that FDA refrain from issuing guidance on class-specific biological products, FDA points to the text of the BPCIA, which permits the Agency to issue “specific” guidance “with respect to the licensure of a biological product under [PHS Act § 351(k)].”  Perhaps signaling future guidance, FDA comments that while the Agency “thus far has not published draft guidance on the subject of product class biological products, the [BPCIA] clearly contemplates that the Secretary may issue this type of guidance.”

Genentech specifically requested in its citizen petition that FDA provide advance notice and a pre-deprivation hearing if the Agency decides to issue guidance on biotechnology-derived product/therapeutic protein similarity/sameness issues using trade secret or confidential information.  In FDA’s February 2012 petition response, the Agency declined to address Genentech’s Constitutional and trade secret law arguments, and instead reasserted that that Agency “acts within its authority when it issues guidance documents in its areas of scientific expertise for purposes of executing its mandate as an agency.”  Moreover, says FDA, the draft biosimilars guidances “do not implicate, disclose, or rely upon Genentech’s (or any other company’s) confidential commercial or trade secret information.”

By Kurt R. Karst & David B. Clissold –   

Three House lawmakers (Reps. Henry Waxman(D-CA), Ed Markey (D-MA), and Diana DeGette (D-CO)) sent letters (here and here) to FDA Commissioner Dr. Margaret Hamburg and NIH Director Francis Collins earlier this week expressing their concern over a recent report published in the British Medical Journal (“BMJ”) documenting the underreporting of results of clinical studies on ClinicalTrials.gov.  According to the article published in the January 2012 issue of the BMJ, titled “Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study,” a database search of trials registered on ClinicalTrials.gov which completed in 2009 and that are covered by the 2007 FDA Amendments Act (“FDAAA”) showed that “[o]f the 738 trials that were classified as subject to mandatory reporting, 163 (22%) had reported results.  In comparison, 76/727 (10%) trials covered by the FDAAA but not subject to mandatory reporting had reported results . . . . ”

Section 801 of FDAAA amended PHS Act § 402 to expand the clinical trial registry data bank created by Section 113 of the Food and Drug Administration Modernization Act of 1997.  FDAAA § 801 expanded the clinical trial data bank (i.e., ClinicalTrials.gov) in two ways.  First, a broader range of “applicable” clinical trials must now be registered at ClinicalTrials.gov.  Second, certain results information from applicable clinical trials must now be submitted to the clinical trial registry data bank.

An “applicable drug clinical trial” is defined in PHS Act § 402(j)(1)(A)(iii) to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .”  An “applicable device clinical trial” is defined in PHS Act § 402(j)(1)(A)(ii) to mean “a prospective clinical study of health outcomes comparing an intervention with a device subject to section 510(k), 515, or 520(m) of the [FDC Act] against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and a pediatric postmarket surveillance as required under [FDC Act § 522].”  In March 2009, NIH posted a revised draft document on its website concerning FDAAA and clinical trial registration.  The document provides more detailed information on applicable clinical trials, including defining such trials to include certain in vivo bioequivalence studies used to support the approval of a generic drug under an ANDA (see our previous post here).

Under PHS Act § 402(j)(2)(C), the responsible party of an applicable clinical trial that is initiated after September 27, 2007, or that is ongoing on December 26, 2007, must submit to NIH certain required information for inclusion in the clinical trial data bank by December 26, 2007, or 21 days after the first patient is enrolled in the clinical trial, whichever is later.  The only exception to this rule is that if the clinical trial was ongoing on September 27, 2007 and was not for a serious or life-threatening disease or condition, the information must have been submitted by September 27, 2008. 

PHS Act § 402 also requires the submission of certain results information of applicable clinical trials to the clinical trial registry bank.  FDA, NIH, and the responsible parties for applicable clinical trials all have responsibilities under the law.  Among other things, NIH is responsible for maintaining the public database of trial results on ClinicalTrials.gov, and FDA is responsible for enforcing the statutory requirements.  (FDA and NIH were supposed to have, by September 27, 2010, expanded the results database by rulemaking to possibly include a summary of the clinical trial and its results, the full protocol, and other information.  That rulemaking has not yet been issued, but it might happen soon, according to the Fall 2011 DHHS Unified Agenda.)  Responsible parties for applicable clinical trials are responsible for, among other things, submitting certain results information to the basic results section of ClinicalTrials.gov. 

Subject to specified exceptions, the general rule is that as of September 27, 2008, the responsible party for an applicable clinical trial must submit the basic results information no later than 1 year “after the earlier of the estimated complete date of the trial . . . or the actual date of completion” (PHS Act § 402(j)(3)(E)).  One important exception is that if the trial is completed before the drug is approved or the device is cleared, the responsible party can delay submitting the results information until no later than 30 days after the drug or device is approved (PHS Act § 402(j)(3)(E)(iv)).  If the manufacturer of a drug or device or sponsor of an applicable clinical trial is seeking approval for a new use of the drug or device, the same information must be submitted on the earliest of 30 days after approval, 30 days after FDA issues a not approval letter or a not substantially equivalent letter, or 30 days after the application is withdrawn without resubmission for no less than 210 days (PHS Act § 402(j)(3)(E)(v)). 

The failure of a responsible party to submit the required clinical trial information under PHS Act § 402(j) is a prohibited act (FDC Act § 301(jj)) that could result in significant penalties of up to $10,000 per day (FDC Act § 303(f)(3)).  FDA has not, to our knowledge, taken any enforcement action with respect to PHS Act § 402(j). 

The February 14th letters from the trio of lawmakers to FDA and NIH raise both common concerns (e.g., “publication delays may allow ineffective or dangerous drugs to remain on the market, resulting in significant harm to patients and waste in the health care system”) and agency-specific concerns, such as “whether FDA is adequately enforcing the law requiring such reporting” and “whether NIH is adequately implementing the law requiring such reporting” (emphasis added).  The letters also contain requests specific to FDA and NIH to help the lawmakers better understand the issue.  FDA is asked to provide answers to the following questions:

1) Do the findings of the [study reported in the BMJ] correspond with FDA‘s internal data on compliance with the reporting requirements of Section 801 of the FDAAA?  Please summarize FDA‘s internal compliance data.

2) Has FDA issued any warning letters, imposed any fines, or otherwise initiated any enforcement actions related to these reporting requirements?

3) Does FDA have adequate resources and authority to enforce these reporting requirements?

4) Does FDA believe additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in Section 801 of the FDAAA?

NIH is asked to provide answers to the following questions:

1) Do the findings of the [study reported in the BMJ] correspond with NIH‘s internal data on compliance with the reporting requirements of Section 801 of the FDAAA?  Please summarize NIH‘s internal compliance data.

2) Does NIH have adequate resources and authority to implement these reporting requirements?

3) Does NIH believe additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in Section 801 of the FDAAA?

Depending on how FDA and NIH respond to the inquiries – particularly the queries regarding whether additional statutory changes are necessary – it is possible that we could see even more proposed legislation that might be taken up this year alongside the various user fee bills. 

An interesting finding of the BMJ paper was that the source of funding for the clinical trials greatly influenced the reporting of results.  Industry-funded studies were far more likely to report results (40%) than were studies “not solely industry funded“ (9%).  Of note, the latter category included studies funded solely by NIH and other government agencies.  This suggests that even NIH and FDA are not in compliance with their own reporting requirements, which would surely complicate enforcement and any attempted legislative correction.  Further, the “source of funding“ used by the BMJ authors does not necessarily reflect the “responsible party.”  As permitted under the statute (PHS Act § 402(j)(1)(A)(ix)), even industry-funded studies can designate “the principal investigator” as the party responsible for the submission of clinical trial information.  Before rushing to portray these findings as another example of “industry“ not in compliance with the law, it would seem prudent to know how many NIH employees designated as either the “sponsor“ or the “responsible party“ have failed to meet these reporting obligations.

By Jeffrey K. Shapiro –

This post is the second in an occasional series that will examine significant or interesting warning letters involving medical device companies. 

As a reminder, FDA issues warning letters to allege violations of the Federal Food, Drug, and Cosmetic Act and/or implementing regulations.  A warning letter is a statement of FDA’s enforcement position and a threat to pursue legal remedies if the target does not comply.  On occasion, FDA issues a warning letter that reveals a new or little known enforcement position.  This type of warning letter will be our critical focus.

On December 27, 2011, the Philadelphia district issued a warning letter focused on Medical Device Reporting ("MDR") issues. 

This warning letter has a fascinating comment about the presumption that a malfunction is likely to contribute to a serious injury or death if it were to recur.  Essentially, FDA criticizes the target company for following the agency’s own written guidance on this issue.

As background, under the MDR regulation, a malfunction is reportable if a recurrence would likely cause serious injury or death.  21 C.F.R. § 803.50(a).  The question is, if a malfunction actually causes a serious injury or death, must the manufacturer presume that subsequent occurrences of the malfunction are “likely” to do so as well?  In 1997 guidance, FDA said:

“FDA believes that once a malfunction has caused or contributed to a death or serious injury, a presumption that the malfunction is likely to cause or contribute to a death or serious injury has been established. This presumption will continue until the malfunction has caused or contributed to no further deaths or serious injuries for two years, or the manufacturer can show, through valid data, that the likelihood of another death or serious injury as a result of the malfunction is remote.”  (Emphasis added.)

The target of the warning letter apparently had incorporated the foregoing “two year presumption” in its warning letter procedure.  FDA did not approve.  The warning letter admonishes:

Also, your firm states in [redacted] that malfunctions causing or contributing to a death or serious injury will be reported to FDA until the malfunction has not caused or contributed to further deaths or serious injuries for two years. The guidance document “Medical Device Reporting for Manufacturers,” dated March, 1997, contains a discussion of malfunctions and reportability. The guidance advises that malfunctions should be reported until valid data shows that the likelihood of another death or serious injury occurring as a result of the malfunction is remote and references a two year period. The guidance is intended to assist industry with interpreting the requirements of the MDR regulation, 21 CFR Part 803. However we currently recommend that manufacturers who wish to stop reporting a malfunction contact the MDR Policy Branch for further discussion at 301-796-6670 or by email at MDRPolicy@fda.hhs.gov.

Stepping past the District's misleading characterization of the guidance document, the warning letter is troubling on two levels.  First, it appears that FDA is disavowing the “two year presumption.”   Apparently, FDA now wishes to adjudicate the expiration of the presumption on a case by case basis.  This policy change is unfortunate.  The two year presumption has been a rare “bright line” rule among a welter of MDR reporting elements that are mostly subjective and difficult to apply in the real world.  It has been in place for 16 years with no apparent ill effect.  The decision to now require case by case adjudication of the presumption will increase the cost and uncertainty of MDR reporting.  There does not seem to be an obvious benefit to doing so.

Second, many firms have relied upon FDA’s published guidance to incorporate the two year presumption in their MDR procedures.  To our knowledge, FDA has not publicly modified the guidance.  Therefore, it seems reasonable for firms to rely upon the guidance in formulating their MDR procedures.  Yet, the warning letter suggests that firms are no longer safe in doing so. 

It is arbitrary and capricious for an administrative agency to modify published guidance via individual warning letters.  This is the opposite of transparency.  If FDA wishes to alter the two year presumption, it should follow its own Good Guidance Practices.

The terminology of the warning letter creates even more confusion.  It couches the directive to consult the MDR Policy Branch as a “recommendation.”  So, is it now violative to have a two year presumption in an MDR procedure, or not?  Must firms proactively revise their procedures?  Or should they simply wait until an inspector criticizes the procedure or issues a Form 483 observation?  Perhaps this enforcement position is unique to the Philadelphia district?  It is hard to know.

What we do know is that this warning letter has taken the helpful certainty of the two year presumption and thrown it to the wind.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

Last week, Representative Bobby Rush (D-IL) announced the introduction of H.R. 3995, the Protecting Consumer Access to Generic Drugs Act of 2012.  The bill is the latest piece of legislation that attempts to stymie so-called pay-for-delay patent settlement agreements.  In January 2011, Senator Herb Kohl (D-WI) introduced S. 27, the Preserve Access to Affordable Generics Act (see our previous post here), and in November 2011, a group of bi-partisan Senators introduced S.1882, the Fair And Immediate Release of Generic Drugs Act, or the “FAIR GENERxICS Act” (see our previous post here), which also seeks to pull 180-day exclusivity into the mix by making some significant changes to the FDC Act’s exclusivity provisions.

The latest bill – H.R. 3995 – is different than the currently pending legislation, but harkens back to an older version of the Preserve Access to Affordable Generics Act introduced as S. 369 in February 2009, both in terms of substance and length.  Gone from new legislation is the controversial presumption that an agreement, if challenged by the Federal Trade Commission, is 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.  Instead, the Protecting Consumer Access to Generic Drugs Act of 2012 simply says that:

It shall be unlawful for any person to directly or indirectly be a party to any agreement resolving or settling a patent infringement claim in which – (1) an ANDA filer receives anything of value; and (2) the ANDA filer agrees not to research, develop, manufacture, market, or sell, for any period of time, the drug that is to be manufactured under the ANDA involved and is the subject of the patent infringement claim.

There are, of course, some exceptions.  For example, the bill would not prohibit agreements in which the value received by the ANDA sponsor includes no more than the right to market the drug product before the expiration of certain patents and non-patent marketing exclusivities.  The FTC may also promulgate regulations to further implement the exceptions included in H.R. 3995.

As in previous versions of legislation addressing patent settlement agreements, H.R. 3995 would amend the 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(V) (the so-called “Collusive Agreement Forfeiture Provision”) to make a violation of the Protecting Consumer Access to Generic Drugs Act of 2012 a forfeiture-triggering event. 

H.R. 3995 has been referred to the House Judiciary and Energy and Commerce Committees.  There, it will join a growing number of FDA-related bills that have recently been introduced in the current wave of FDA legislation as folks gear up for user fee creation and reauthorization – see our Legislation Tracker.  

By Nisha P. Shah –

On February 9, 2012, FDA released a new guidance document called, “Guidance For Sponsors, Investigators, and Institutional Review Boards – Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c).”  The guidance is intended to help small businesses understand the new informed consent requirements described in 21 C.F.R. § 50.25(c), which requires that informed consent documents and processes for “applicable clinical trials,” initiated on or after March 7, 2012, include a specific statement that clinical trial information will be entered into the clinical trial registry databank maintained by the National Institutes of Health/National Library of Medicine.  That statement is, “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

In the guidance, FDA clarifies that if an IRB has approved any informed consent documents for the applicable clinical trial before March 7, 2012, then the trial will be considered “initiated” prior to the compliance date, and the new statement will not be required in the informed consent documents.  Guidance, p. 4.  FDA also explains that any applicable clinical trial, including those conducted outside of the United States, must include the new statement in informed consent documents.  Regarding waiver of documentation of informed consents, the agency affirms that, “the trial participant still provides consent and the statement is required during the oral presentation of the research and/or in the written statement regarding the research, if required by the IRB under 21 CFR § 56.109(d).”  Guidance, p. 5.  Finally, according to the guidance, if an informed consent document fails to properly include the statement, then the IRB should be notified and a revised consent form containing the statement should be provided to the IRB for review and approval. 

By Ricardo Carvajal –

In a decision sure to bring joy to the U.S. Department of Agriculture (“USDA”), the D.C. District Court granted the government’s motion for summary judgment in a lawsuit challenging a USDA regulation that requires domestically produced almonds to be treated for Salmonella.  The regulation was issued in the wake of Salmonella outbreaks associated with raw almonds, and it is credited with eliminating the domestic market for raw almonds.  The regulation was issued in part under the authority of the Agricultural Marketing Agreement Act of 1937 (“AMAA”).  The AMAA authorizes the issuance of marketing orders that dictate the “grade, size, or quality” of a commodity sold in a particular region of the U.S. 

Plaintiffs alleged that USDA had exceeded its authority because the regulation was a food safety measure, and not a quality measure.   The court noted that “quality” is not defined in the AMAA, and concluded that the term is ambiguous based in part on its dictionary definition (“[a]n attribute, property; a special feature or characteristic,” or “[a] particular class, kind, or grade of something, as determined by its character, esp[ecially] its excellence”).  The court further concluded that USDA’s interpretation of the AMAA as authorizing a food safety measure was reasonable, in that the AMAA “specifically contemplates interventions relating to ‘quality’” that are needed to “respond to both general market conditions and external threats, such as the Salmonella outbreaks…, which have the potential to cause significant market disruption.”

Curiously, in concluding that “quality” encompasses “safety,” the court did not delve into the definition of “safety” – and we won’t either.  However, we note that robust discussions of the distinction between safety and quality has taken place in other food-related contexts (see, e.g., the preamble to the dietary supplement GMP final rule). 

It’s not yet clear whether plaintiffs will appeal the court’s decision.  If so, they may also have to overcome the government’s argument that plaintiffs waived their claims by not raising them during the comment period preceding issuance of USDA’s final rule.  This potential hurdle highlights the importance of submitting timely comments during agency rulemaking.

By Jennifer D. Newberger –

On Wednesday, February 8, Representatives Mike Rogers (R-MI) and Ed Markey (D-MA) introduced H.R. 3975, The Pediatric Medical Device Safety and Improvement Reauthorization Act of 2012.  The bill would put into effect a rule previously withdrawn by FDA regarding the inclusion of pediatric information in certain medical device submissions to FDA, notwithstanding the requirements of the Administrative Procedure Act ("APA") to obtain and consider public input prior to implementing a final rule. 

A little background to the withdrawn rule is helpful in understanding the intent of this bill.  On April 1, 2010, FDA issued a proposed rule along with a direct final rule “that was intended to make noncontroversial amendments to existing regulations which would require the submission of readily available pediatric medical device information as a part of premarket approval applications, requests for humanitarian use device exemptions, and any product development protocols.”  Although the rule was intended to be noncontroversial, the agency received “significant adverse comment” and therefore withdrew the direct final rule on July 19, 2010. 

The withdrawal of the direct final rule due to receipt of significant adverse comment indicates that the APA worked precisely as intended—to allow for public participation in the rulemaking process.  This seems to be of no matter to the sponsors of this bill, which would have the withdrawn direct final rule take effect on January 1, 2013, notwithstanding the APA “and any other provision of law.” 

Certainly, just as Congress created the APA, it can create exceptions to the APA.  Before doing so, however, it should consider whether it truly wants to force upon the public a rule much of the public explicitly decried. 

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

Within moments of FDA’s (Dr. Janet Woodcock) announcement during the February 9th House Energy and Commerce hearing on generic drug and biosimilar user fees that the Agency would issue draft guidance on biosimilar product development later in the day, Twitter was, well . . . . all atwitter with the news.  Release of the draft guidances, which perhaps have been overpromised as “coming soon” since last summer, was officially announced by FDA just a couple of hours later. 

FDA issued three draft guidances, which provide the Agency’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to FDA pursuant to the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  The BPCIA amended the Public Health Service Act (“PHS Act”) to, among other things, create an approval pathway for biosimilar and interchangeable versions of reference products (so-called § 351(k) applications) and establish a 12-year exclusivity period for reference products licensed under PHS Act § 351(a).  FDA’s three draft guidances are pretty dense and take into consideration comments the Agency received in response to a November 2010 public hearing on BPCIA implementation, as well as FDA’s experience thus far in meeting with sponsors of biosimilar products.  (It was recently reported that FDA has held 21 Pre-IND sponsor meetings, has received 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products, and has received 9 INDs.)

Draft Guidance No. 1 – Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009:  This draft guidance document is intended to provide answers to common questions from sponsors interested in developing proposed biosimilar products.  The Q&As are grouped into three categories: (1) Biosimilarity or Interchangeability; (2) Provisions Related to Requirement to Submit a BLA for a “Biological Product;” and (3) Exclusivity (presumably carefully worded to avoid another tussle over “market” versus “data” exclusivity – see our previous post here). 

Many of the questions are drafted to elicit an initial proposed answer of “yes” or “no,” which is then futher explained and modified.  For example, FDA answers "yes" to each of the following burning questions:

• Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?
• Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar to the reference product?
• Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed?

Among other things, the draft guidance provides FDA’s interpretation of the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in PHS Act § 351(i)(1).  FDA defines the term “protein” to mean “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size,” and the term “chemically synthesized polypeptide” to mean “any alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.”  FDA goes on to note that the Agency considers “any polymer composed of 40 or fewer amino acids to be a peptide and not a protein.”  Therefore, says FDA, “unless a peptide otherwise meets the statutory definition of a 'biological product'“, it will be regulated as a “drug” under the FDC Act.

Draft Guidance No. 2 – Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:  This draft guidance – the longest of the three draft guidances – is where FDA lays out the Agency’s approach to determining biosimilarity.  “FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity, and recommends that sponsors use a stepwise approach in their development of biosimilar products” (italics in original) says FDA.  Under the risk-based, “totality of the evidence” approach, FDA will consider “the totality of the data and information submitted in the application, including structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and clinical safety and effectiveness data.”  Under the stepwise approach, biosimilar sponsors should evaluate at each step “the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty,” and should start with an “extensive structural and functional characterization of both the proposed product and the reference product.” 

Draft Guidance No. 3 – Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product:  The final draft guidance is intended to provide recommendations to biosimilar applicants on the scientific and technical information of the CMC section of a 351(k) application, and includes an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product.  FDA notes in the draft guidance that although it applies specifically to therapeutic protein products, “the general scientific principles may be informative for the development of other proteins, such as in vivo protein diagnostic products.” 

Under the PHS Act, as amended by the BPCIA, the terms “biosimilar” or “biosimilarity” mean that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (emphasis added).  FDA’s draft guidance provides a list and discussion of various factors to consider when assessing whether products are, in fact, highly similar.

We’re likely to see quite a bit of commentary submitted to FDA on the draft guidances in the coming weeks and months.  We’ve also heard that FDA might be scheduling a public hearing to elicit further comments on and discussion of the draft documents and the Agency’s approach to biosimilarity laid out therein.   

By Kurt R. Karst –      

In music, “coda” is a term used primarily to designate a passage that brings a piece (or a movement, which may be part of a symphony – an extended musical composition) to an end – the “fine.”  A coda can be as simple as a few measures, or as complex as an entire section.  These musical terms serve as a nice metaphor for The Medicines Company’s (“MDCO’s”) decade-long battle (multi-movement symphony) to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin). 

As most folks know by now, FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000 under NDA No. 020873, and MDCO submitted its PTE application to the U.S. Patent and Trademark Office (“PTO”) on February 14, 2001 – 62 days after NDA approval, including the December 15, 2000 date of approval.  Under 35 U.S.C. § 156(d)(1), the submission of a PTE application must occur “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use.”  (For additional background, see our previous post here.) 

In August 2010, Judge Hilton of the U.S. District Court for the Eastern District of Virginia (Alexandria Division) granted MDCO’s Motion for Summary Judgment and ordered the PTO to consider timely filed MDCO’s PTE application for the ‘404 patent under a next business day interpretation of the PTE statute, making December 18, 2000 the operative date for beginning the 60-day period instead of December 15, 2000.  The government decided not to appeal the decision, and the PTO proceeded to request that FDA determine the regulatory review period with respect to MDCO’s PTE application for the ‘404 patent.  FDA issued a notice in December 2010 with its determination. 

ANDA sponsor APP Pharmaceuticals, LLC (“APP”) attempted to intervene in the PTE litigation before Judge Hilton; however, APP’s Motion to Intervene was denied.  APP appealed the decision to the Federal Circuit challenging not only the district court’s intervention decision, but also the underlying merits decision.  

In the meantime, Congress passed the Leahy-Smith America Invents Act (“AIA”) (Pub. Law No. 112-029).  Section 37 of the AIA, titled “Calculation of 60-Day Period for Application of Patent Term Extension” and referred to by some as “The Dog Ate My Homework Act” or the “Medco fix,” amended the PTE statute at 35 U.S.C. § 156(d), and was intended to legislatively resolve MDCO’s PTE battle.  (There were several failed attempts in Congress to pass “The Dog Ate My Homework Act” going back to 2006.)  There was a post-AIA attempt in Congress to effectively nullify Section 37, but that effort failed – see here.

Shortly after the enactment of the AIA, MDCO sent a letter to the Federal Circuit notifying the Court of the enactment of Section 37 and asserting that it resolves the merits of the ongoing ‘404 patent PTE litigation with APP.  APP vigorously disagreed that Section 37 resolved the case, however, and argued that Section 37 cannot constitutionally be applied and that Section 37 does not take effect for one year after the AIA‘s enactment (i.e., September 16, 2012).  The parties brief the issues and oral argument was held on November 15, 2011 – see our previous post here. 

Before the Federal Circuit could issue its decision on AIA Section 37, MDCO and APP entered into a settlement agreement that includes APP’s agreement to dismiss its appeal of Judge Hilton’s August 2010 decision, as well as another Hatch-Waxman patent infringement lawsuit brought in the U.S. District Court for the District of Delaware over  two other Orange Book-listed patents for ANGIOMAX – see our previous post here.  The Federal Circuit dismissed the case on January 24, 2012.

Exiting the last movement of the ANGIOMAX Symphony and moving on to the coda, the PTO issued a Notice of Final Determination on January 31, 2012 saying that the ‘404 patent is entitled to a PTE of 1,728 days that expires on December 15, 2014 – 14 years to the clendar day that FDA approved NDA No. 020873, but three days earlier than the December 18, 2000 next business day date MDCO was determined to have received notification of the approval.  Although not necessary, MDCO promptly notified the PTO on February 3, 2012 of its acceptance of the 1,728-day PTE.  While the ‘404 PTE battle has taken numerous twists and turns throughout the years and has touched all three brances of government, we expect the coda here to be short.  All that seems to be left now is for the PTO to issue a Certificate of Extension (which will look something like this) and publish the information on the Official Gazette – fine!  Adieu ANGIOMAX PTE battle.

By Kurt R. Karst –      

It’s about that time of year again when we do some number crunching and take stock of the year that was in orphan drug designations and approvals.  And what a year it was!  FDA not only approved a record 26 marketing applications for products for orphan (i.e., rare) diseases and conditions, but FDA’s Office of Orphan Products Development (“OOPD”) granted a record 199 orphan drug designation requests.   OOPD also received 306 orphan drug designation requests in 2011, which is only second to the record of 323 designation requests set in 2010 (see our previous post here).  Of the 3,659 orphan drug designation requests submitted to FDA since the enactment of the Orphan Drug Act in 1983, OOPD has granted 2,507 of them, or about 68.5%. 

The tables below show OOPD’s designation and FDA’s orphan drug approval track record.  (Additional historical information on the year-by-year designation/approval numbers since the enactment of the Orphan Drug Act in 1983 is available here.) 

 
In addition to the record numbers of orphan drug designations and approvals, 2011 also saw a change in OOPD leadership with the installment of Gayatri Rao, M.D., J.D. as Acting Director (see our previous post here), and the first U.S. Conference on Rare Diseases and Orphan Products.  At the conference, Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski announced the release of a landmark report he authored on the flexibility in FDA’s review of potential treatments for patients with rare diseases (see our previous post here).  Shortly thereafter, FDA issued a proposed rule intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since the Agency promulgated its orphan drug regulations in December 1992 (see our previous post here).  FDA also issued a report to Congress with findings and recommendations to improve the current regulatory/scientific armamentarium to facilitate the development of products for rare and neglected diseases (see our previous post here). 

The 2011 orphan drug designation and approval numbers may be difficult marks to beat; however, FDA appears to be off to a decent start in 2012 with 8 designations and 2 approvals in January.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

On February 7, 2012, Judge Amy Berman Jackson of the U.S. District Court for the District of Columbia issued her decision in the long-running dispute concerning FDA’s July 23, 2010 approval of Sandoz Inc.’s (“Sandoz’s”) ANDA No. 077857 for a generic version of Sanofi-aventis U.S. L.L.C.’s (“Sanofi’s”) anti-coagulant drug LOVENOX (enoxaparin sodium injection).  Concluding that FDA’s (1) “request for immunogenicity data in Sandoz’s ANDA was both lawful and reasonable;” (2) “approval of the drug did not constitute an arbitrary departure from agency precedent;” and (3) “determination of active ingredient sameness was [reasonable],” Judge Jackson granted Motions for Summary Judgment filed by FDA and intervenor Sandoz (here and here) and denied Sanofi’s Cross-Motion for Summary Judgment.  The 33-page decision may have important implications on future lawsuits involving the approval of generic versions of complex drug products, and perhaps even biosimilars. 

As folks might recall, Sanofi initially filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction late on July 26, 2010 requesting that the  court issue a declaratory judgment that FDA acted unlawfully in approving ANDA No. 077857, as well as a temporary restraining order and preliminary injunction directing FDA to immediately suspend and withdraw approval of the Sandoz ANDA, and a permanent injunction under the same terms (see our previous post here).  On the same day that FDA approved Sandoz’s ANDA, the Agency responded to a February 2003 Sanofi citizen petition in which the Agency outlined five criteria (i.e., standards for identity) that an ANDA applicant needs to demonstrate sameness of its active ingredient as compared to LOVENOX (see our previous post here).  (FDA has subsequently indicated that the Agency might be considering applying similar criteria to another complex drug product, as well as biosimilars.) 

Judge Emmet G. Sullivan, who was originally assigned the case, denied Sanofi’s motion in an opinion handed down on August 25, 2010 (see our previous post here).  Several months later, Sanofi filed its Motion for Summary Judgment (see our previous post here) arguing three points:

(1) FDA exceeded its authority under the FDC Act (specifically FDC Act § 505(j)(2)(A)) by requiring Sandoz to submit studies beyond what is permitted for ANDAs (i.e., immunogenicity studies that, according to Sanofi, are studies intended “to demonstrate safety and effectiveness,” rather than, as FDA argued, chemistry, manufacturing, and control information);

(2) FDA departed from Agency precedent by approving ANDA No. 077857 when the product has not yet been fully characterized; and

(3) FDA approved ANDA No. 077857 without sufficient evidence that the drug product has the “same” active ingredient as LOVENOX (as required by FDC Act § 505(j)(2)(A)).

Judge Jackson ruled that each issue can be decided on summary judgment as a pure question of statutory interpretation or a pure question of law. 

Did FDA exceed its authority under the FDC Act by requiring Sandoz to submit immunogenicity data as part of its ANDA?  Analyzing this issue under the familiar two-step Chevron analysis, the court ultimately agreed with FDA that the Agency has the authority to interpret the “full description” requirement of FDC Act § 505(b)(1)(D) to encompass the information FDA requires to make the findings required by FDC Act § 505(j)(4)(A) specific to ANDAs, such as immunogenicity data, stating:

Through the ANDA pathway’s specific embrace of the NDA requirements, and the imposition of the clear demands in [FDC Act § 505(j)(4)(A)], Congress rendered the ANDA requirements to be ambiguous and open to agency interpretation, and not as restrictive as the plaintiffs describe them to be.  By specifically incorporating [FDC Act § 505(b)(1)(D)] into the ANDA requirements, Congress gave FDA the authority to utilize its expertise to determine what information it needs to make the assessment it is required to make under [FDC Act § 505(j)(4)(A)].

Citing D.C. Circuit precedent, Judge Jackson noted that the Court’s observations in Serono Labs., Inc. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998), “express a clear view that [FDC Act § 505(j)(2)(A)] does not limit the agency’s freedom to determine what kinds of information will be needed to fulfill the listed ANDA requirements.”  Moreover, writes Judge Jackson, an analysis of the statutory text both in light of the entire statutory scheme and the statute’s purpose suggest that FDC Act § 505(b)(1)(D) applicable to NDAs and included by reference in FDC Act § 505(j)(2)(A) applicable to ANDAs is ambiguous, and therefore, cannot be decided at Chevron Step I.

Moving on to Chevron Step II, the court agreed with the determination Judge Sullivan made in connection with his August 25, 2010 decision that FDA’s interpretation of the statute to include immunogenicity testing was reasonable.

According FDA the deference required under Serono to make its own determination about the information it might need, the Court finds that FDA’s interpretation of the ANDA approval regime was reasonable, and that it was reasonable for the agency to conclude that immunogenicity studies are encompassed by the “full description” described in [FDC Act § 505(b)(1)(D)].  The potential for the generic drug to elicit a different adverse response than the parent could be the result of impurities, which in turn result from the methods, facilities, and controls used to manufacture, process, and pack a drug.  By revealing what impurities remain at the end of that process, the studies shed light on, or indirectly “describe,” those methods and controls.

Did FDA depart from Agency precedent by approving a generic drug that is not fully characterized?  Giving short schrift to this argument, Judge Jackson specifically incorporates Judge Sullivan’s analysis of this issue from his August 25, 2010 decision, and writes that “[i]n making its decision to approve Sandoz’s drug before it was fully characterized, FDA ‘provided ‘legitimate reason[s]’ for deciding that enoxaparin should be treated differently than the drugs cited by Sanofi’ [(i.e., Premarin, Hyaluronidase, and Omnitrope)] and therefore satisfied the minimal standard of rationality required.”  Judge Jackson also expresses some skepticism that the Premarin, Hyaluronidase, and Omnitrope precedents in which FDA would not accept an ANDA “rise to the sort of precedent from which a departure needs to be justified,” but she further notes that the court “does not reach that question since the decision and the manner in which [FDA] diverged from previous decisions were adequately explained in this instance.”

Did FDA sufficiently prove that Sandoz’s generic enoxaparin has the same active ingredient as Lovenox?  Here, arguments focused on the five criteria FDA laid out in the Agency’s citizen petition response that an ANDA applicant needs to demonstrate sameness of its active ingredient as compared to LOVENOX: (1) equivalence of physicochemical properties; (2) equivalence of heparin source material and mode of depolyierization; (3) equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) equivalence in biological and biochemical assays; and (5) equivalence of in vivo pharacodynamic profile. 

Instead of focusing on any one criterion, Judge Jackson focused on whether all five, overlapping criteria, when considered together, provided “a reasonable way for FDA to determine active ingredient sameness.”  “Not only did FDA support its approach in a thorough, well-reasoned response to Sanofi’s citizen petition, but it also carefully considered both sides of the argument internally – to settle the internal dispute over the validity of the five-pronged test – before doing so. . . .  While fully characterizing enoxaparin would have been another reasonable, or perhaps even more reasonable, way to determine active ingredient sameness, the Court is satisfied that the five-pronged approach FDA used was reasonable,” concludes Judge Jackson. 

By Jennifer D. Newberger –

On Thursday, February 2, Senators Bob Casey (D-PA) and John McCain (R-AZ) introduced S. 2067, titled the “Safe, Efficient, and Transparent Medical Device Approval Act” or the “SET Device Act.”  The bill would require FDA to reclassify preamendment Class III devices or require them to go through the premarket approval (“PMA”) process, and would streamline the de novo process.

In the Safe Medical Devices Act of 1990, Congress amended Section 515 of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to require FDA to reclassify preamendment Class III devices to a lower class or require them to go through the PMA process.  The deadline to do so was December 1, 1995, but FDA still has over 20 preamendment Class III devices to reclassify.  The SET Act would require FDA to issue a final regulation for each device it determines should remain in Class III, or special controls for devices it reclassifies into Class II, within 18 months of enactment of the bill. 

This would not be the first time FDA has been encouraged to comply with the statutory requirements to classify the remaining Class III preamendment devices.  In January 2009, the Government Accountability Office (“GAO”) issued a report recommending that FDA “expeditiously take steps to issue regulations for class III device types currently allowed to enter the market via the 510(k) process by requiring PMAs or reclassifying them to a lower class.”  In response to the GAO report, FDA stated that it was committed to complete the classifications “as expeditiously as possible.”  In the three years since then, FDA has only issued final rules classifying four devices.  Given FDA’s disregard for the timeframe in the current statutory requirement, and its failure to follow through after the GAO report, there is no reason to believe that FDA will comply with the 18 month deadline put forth in this proposal.

Like two bills proposed in Congress in 2011 on which we previously commented (here and here), this bill also proposes to streamline the de novo process.  The current statutory language requires a sponsor to submit a 510(k) notification to FDA even if believes there is no appropriate predicate device.  The sponsor must then wait to receive a not substantially equivalent determination from FDA before it submits a de novo reclassification petition to reclassify the device into Class I or II.  Under the proposal in the SET Act, a sponsor may follow a process similar to that under current law, or may submit an initial petition for reclassification after determining that no predicate exists without the need to submit a 510(k) and wait for a not substantially equivalent determination. 

This proposed change will benefit both industry and FDA.  It will save FDA time and resources by consolidating the 510(k) review and de novo classification processes into one step.  It will also allow sponsors to more quickly bring new, innovative, low- to moderate-risk devices to market because they can submit a reclassification petition without having to wait for a not substantially equivalent decision.  Despite these positive procedural steps, the question remains whether FDA would be willing to review devices through the de novo process rather than requiring devices without a predicate go through the PMA process.  One of the reasons FDA may be hesitant to utilize the de novo process is the burden of creating special controls.  Perhaps if, in addition to remedying the procedural hurdles, creating special controls could be optional, FDA may be more likely to clear products through the de novo process.  Nevertheless, this bill is a step in the right direction.  As we stated in our prior blog posts on this topic, FDA and industry both would like to see improvements in the de novo process, and this bill should receive much support and little resistance.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Alan M. Kirschenbaum & Michelle L. Butler - 

A long anticipated proposed revision to CMS regulations governing the Medicaid Drug Rebate Program ("MDRP") appeared in the Federal Register on Thursday, February 2, 2012.  As expected, the proposal implements amendments to the MDRP that were enacted in the Patient Protection and Affordable Care Act ("ACA") (see our previous post here).  However, the regulation would also make a number of important changes to the MDRP and Medicaid drug payment that were not mandated by the ACA.  Among other notable provisions, the proposed regulation would:

• Require states to convert to an actual acquisition cost basis for Medicaid prescription drug payment 
• Expand the MDRP to the U.S. territories
• Apply a statutory alternative rebate for line extensions of oral solid dosage form innovator drugs, not only to new formulations, but new indications, combination products, and products marketed by companies independent of the company marketing the original drug
• Limit wholesaler sales included in AMP to those that can be documented as being subsequently sold to retail community pharmacies
• Require manufacturers of unapproved drugs to submit to CMS evidence that the product meets the definition of a covered outpatient drug
• Provide for penalties of $10,000 per day per drug for tardy AMP reports

Hyman, Phelps & McNamara, P.C. has prepared a memorandum summarizing the most important provisions of the proposed regulation.  The memorandum is available here.

By Kurt R. Karst –      
 
Earlier this week, Representatives John Carney (D-DE) and Larry Bucshon (R-IN) introduced H.R.3839, the “Drug Shortage Prevention Act,” which, according to its sponsors, is intended to bring “more efficiency to the manufacturing and distribution processes” and to require “FDA to take action to prevent drug shortage problems before they begin impacting patients.”  The bill is the latest action plan to address the increasing problem of drug shortages.  Last year saw the introduction of the “Preserving Access to Life-Saving Medications Act of 2011” (S. 296, H.R. 2245), an Executive Order from President Obama (see our previous post here), and an interim final rule from FDA to make better use of its existing shortage-related authority under the FDC Act among other things (see our previous post here).  The topic of drug shortages is expected to be raised next week at the House Energy and Commerce Committee hearing on generic drug and biosimilar user fees.

H.R.3839 would amend the FDC Act to add § 506D to require FDA to develop and make publicly available two lists of products: (1) a National Critical Drug List; and (2) a National Critical Drug Shortage List.  The bill does not actually define the terms “critical drug” or “critical drug shortage.”  Rather, FDA would be required to solicit stakeholder input through a public hearing or public docket to define the terms.  The bill does state what information should be included in each list, such as (for the shortage list) an indication of the severity of the shortage, the reason for the shortage, and identification of alternative therapies.

FDA would be required to expedite its review of NDAs and ANDAs seeking approval of a “critical drug” and any request by the sponsor of a critical drug to approve a change to the manufacturing process, manufacturing facility, or to add an alternate active pharmaceutical ingredient supplier.  “In expediting the review of applications and requests . . . [FDA] shall not unnecessarily delay the review of applications and requests for drugs and biological products that are not critical drugs.”  In addition, the bill would require the HHS Secretary to conduct a study on the feasibility of creating a national contingency plan to address critical drug shortages, including the possible creation of a Federal stockpile of critical drugs or the expansion of an existing Federal stockpile of drugs to include critical drugs for such purpose.

The Drug Shortage Prevention Act also requires FDA to notify the DEA of any critical drug on the critical drug shortage list that is a controlled substance, and permits the Attorney General to allow for the determination of whether or not it is appropriate to increase a controlled substance quota to address the shortage.

By Jennifer D. Newberger –

On January 31, 2012, Rep. Edward Markey (D-MA) introduced H.R. 3847, the “Safety of Untested and New Devices Act of 2012,” also known as the “SOUND Devices Act of 2012.”  The bill attempts to limit the body of devices that may be available for use as predicates.  The key provisions include:

• Submitters of 510(k) notifications would be required to include information about the history of corrections and removals of the predicate device and the predicates of that predicate; 
• FDA may reject a claim of substantial equivalence if the predicate device or its predicates were corrected or removed, or if FDA is in the process of taking regulatory action against the predicate or its predicates, due to an “intrinsic flaw in technology or design that adversely affects safety”;
• FDA may reject a claim of substantial equivalence if the predicate was corrected or removed and the manufacturer failed to report such correction or removal; and
• When a device is corrected or removed because of an intrinsic flaw in technology or design that adverse affects safety, FDA may order manufacturers of devices “in the same lineage” to submit a report stating whether their device shares the same intrinsic flaw, and if not, why not.

The underlying assumption reflected in the bill seems to be that sponsors are rampantly foisting badly designed devices on the public, that they refuse to improve their devices to correct known problems, and that FDA does not now have sufficient statutory authority to prevent the proliferation of badly designed devices. 

This assumption is not based in reality.  If one thinks back to the commonly used medical devices in use 20 years ago, or even 10 years ago, there has been continuous and sometimes dramatic improvement in quality of the design and technology of a wide range of devices.  Furthermore, FDA has ample authority to ensure the quality of the devices cleared through the 510(k) process, and it frequently exercises it.  Hence, the title of this blog post – this bill is truly a solution in search of a problem.

Turning to the provisions of the bill, certain of these proposals would be nearly impossible for sponsors to meet, while others would give FDA authority to prohibit a large number of devices from serving as predicate devices, limiting the use of the 510(k) program as a viable option for marketing devices.  As noted, all of this drama would be inflicted on the device industry for very little gain in patient health or safety.

Submission of Predicate Information.  The bill would require sponsors to provide information to FDA in a 510(k) submission on the “market status” of each predicate device and “each device in the full device lineage.”  The information to be provided includes information about whether the device has been corrected or removed from the market, the basis for such correction or removal, “including whether such correction or removal was because of an intrinsic flaw in technology or design that adversely affects safety,” and why the proposed device does not share “any such intrinsic flaw.”  Of course, all of these concepts are highly subjective and likely to engender years of disputes between FDA and industry. 

Also, the question of whether the device has been corrected or removed is not time-limited.  A strict reading of the bill language indicates that the question is whether the predicate (or its predicate) was ever corrected or removed.  Note also that this is not limited to reportable corrections or removals, e.g., Class I or Class II recalls, meaning that a sponsor would need to submit information related to Class III recalls, even though that information is generally not required to be reported to FDA.  It is not explained how the sponsor will be able to gather information that is not publicly available.

A “device in the full device lineage” is a “device for which a substantial equivalence determination was made leading to a substantial equivalence determination for a predicate device” used in a new submission.  So this means that a sponsor needs to provide market information not only on the predicate device, but on any device that served as a predicate to the predicate.  In the case of a device that cites multiple predicates, the sponsor presumably will need to provide a complete family tree for each of the predicates.

“Intrinsic flaw in technology or design that adversely affects safety.”  Currently, the Federal Food, Drug, and Cosmetic Act ("FDC Act") prohibits a finding of substantial equivalence to a predicate that was removed from the market at the initiative of FDA or was determined to be misbranded or adulterated by a judicial order.  (Both FDA-mandated recalls and judicial orders of this nature are exceedingly rare.)  In addition to these criteria, the bill would permit FDA to reject a claim of substantial equivalence to any predicate (or predicate’s predicate) corrected or removed from the market at the initiative of the sponsor and the correction or removal “is due, in whole or in part, to an intrinsic flaw in technology or design that adversely affects safety.”  The bill fails to address the obvious point that a correction or removal is typically conducted in order to modify a device to address a problem in design or manufacturing.  So, if the predicate device was, in fact, modified to address a design problem, what is the impact of the modification on the requirements of this bill?  If the modification was cleared through the 510(k) process, presumably the sponsor can simply claim substantial equivalence to the post recall 510(k) clearance and avoid this bill altogether.

FDA may also reject a claim of substantial equivalence to a predicate if FDA is undertaking any regulatory action (e.g., trying to rescind clearance, issuing a recall order) to remove the predicate, or the predicate’s predicate, from the market “because of an intrinsic flaw in technology or design that adversely affects safety.”  This means that, without considering whether the proposed device introduces modified technology or design that could remedy the problems associated with the predicate, FDA may reject a claim of substantial equivalence based solely on the safety issues of the predicate. 

Failure of predicate manufacturer to submit required report of correction or removal.  The most broad-reaching of the new authorities would permit FDA to reject a claim of substantial equivalence to a predicate “if the predicate device has been corrected or removed from the market and the manufacturer or importer of the predicate failed to submit” the required notice of such correction or removal.  Under this provision, the sins of the father would indeed be visited upon the sons.

Shared intrinsic flaw.  When a device is corrected or removed from the market because of an intrinsic flaw in technology or design that adversely affects safety, the bill would allow FDA to order a manufacturer or importer of a marketed “device in the same lineage” to submit a report stating whether the marketed device shared any intrinsic flaw, and, if not, to explain why the device does not share the flaw.

Congress, industry, and FDA should all consider how to best assure that marketed devices are as safe as they possibly can be.  This bill, however, does nothing to further that goal, and it should not be taken seriously.