By Kurt R. Karst –      

In what appears to be the first instance in which a court has considered the U.S. Supreme Court’s decision in PLIVA, Inc. v. Mensing in the context of a preemption defense in a state tort-law failure-to-warn case, Nevada State Court Judge Jerry Wiese II recently granted Plaintiff’s Motion for Partial Summary Judgment on Preemption Defense for Dear Doctor Liability in three propofol hepatitis infection cases – Carol Keck v. Endoscopy Center of Southern Nevada, L.L.C., et al., No. 08A575837, Megan T. Gasper, et al. v. Endoscopy Center of Southern Nevada, L.L.C., et al., No. 08A579660, Betty Hymas v. Endoscopy Center of Southern Nevada, L.L.C., et al., No. 08A582492, Nev. Dist., Clark Co.  In doing so, the court concluded that Mensing does not preempt the Plaintiffs’ claims that certain generic drug manufacturers could have sent a “Dear Doctor” or “Dear Healthcare Provider” letter warning against reuse of vials containing propofol (and that allegedly cause hepatitis infection).

In Mensing, the Court invoked the doctrine of impossibility preemption to hold that federal drug regulations applicable to generic drug manufacturers directly conflict with, and thus preempt, state tort-law claims based on drug manufacturers’ alleged failure to provide adequate warning labels for their products.  As part of its decision, the Court deferred to FDA’s position, articulated the Agency’s brief to the Court, that the Changes Being Effected (“CBE”) procedures are not available to generic drug sponsors to add or strengthen label warnings.  (As we recently reported, Public Citizen has submitted a citizen petition to FDA requesting that the Agency amend its regulations to permit ANDA sponsors to revise their labeling through the CBE and Prior Approval Supplement procedures.) 

With respect to “Dear Doctor” letters, FDA said in its brief to the U.S. Supreme Court that they qualify as labeling and, therefore, must be “consistent with and not contrary to [the drug’s] approved . . . labeling.”  Thus, the Supreme Court, again deferring to FDA, said that a “[a] Dear Doctor letter that contained substantial new warning information would not be consistent with the drug’s approved labeling,” and concluded that “federal law did not permit the Manufacturers to issue additional warnings through Dear Doctor letters.” 

In his decision, Judge Wiese writes that although “[t]his Court does not agree with the reasoning or the Supreme Court’s majority opinion in Mensing . . . . it is obligated to follow its decision.”  However, the Supreme Court did not, writes Judge Wiese,

indicate that “Dear Doctor” letters that were “consistent and not contrary” to the labeling, were preempted. . . .  While the FDA apparently believed that no liability may lie for failure to send such a letter unilaterally, the U.S. Supreme Court did not adopt this language, or set forth this holding as their own.  Consequently, it is not part of the Mensing ruling, and is not binding upon this Court. 

Continuing, Judge Wiese states that “[w]hile the U.S. Supreme Court may not have intended to leave this small argument available, the Court’s decision seems to indicate that a ‘Dear Doctor’ letter that is ‘consistent with and not contrary to the drug’s approved label,’ and which does not provide ‘substantially new’ or ‘additional’ warnings, would not be preempted under [Mensing].”  Judge Wiese is quick to note, however, that “[e]ven if the ability to send a ‘Dear Doctor’ letter is not precluded or preempted under Mensing, this Court is unclear with regard to the legal theory under which the Plaintiffs anticipate asserting a ‘duty’ to send a ‘Dear Doctor’ letter, since [Mensing] seems to hold that the state law failure to warn claim is preempted.”

It will be interesting to see whether this and other, let’s just call them “interesting,” arguments floating around out there will gain any traction in courts.

By Ricardo Carvajal –

FDA published a Federal Register notice asking for nominations of individuals to serve as voting members on the Tobacco Products Scientific Advisory Committee ("TPSAC").  The TPSAC has been ensnared in controversy due to allegations of bias and conflicts of interest among current and previous members.  As we noted in a prior blog posting, FDA's constitution of, and reliance on, the TPSAC is the subject of a lawsuit filed by Lorillard.  Doubtless FDA's selection of new voting members will be closely scrutinized.  Nominations are due by November 2.

By Kurt R. Karst –      

In a Report to Congress issued earlier this year and recently made public, FDA’s Rare Disease Group (“RDG”) and Neglected Tropical Disease Group (“NTDG”) report on their findings and recommendations to improve the current regulatory/scientific  armamentarium to facilitate the development of products for rare and neglected diseases.  As we previously reported, the report was required by Section 740 of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law No. 111-80), which also required FDA to establish the RDG and NTDG.  An attempt to build on Section 740 in appropriations legislation for Fiscal Year 2011 – see our previous posts here and here – was unsuccessful given all of the wrangling over the budget.  The findings and recommendations for both the RDG and NTDG are reported below.

RDG Report

Based on its review of FDA practices for regulating products for rare diseases, and comments and recommendations from a June 2010 public hearing (Docket No. FDA–2010–N–0218) (see our previous post here) and an October 2010 report from the Institute of Medicine, titled “Rare Diseases and Orphan Products: Accelerating Research and Development,” the RDG “identified both strengths and constraints in the current paradigm for drug and device regulation.”  According to FDA,

An evaluation of current agency practices revealed that extant regulations provide the flexibility needed for the review of medical products for the diagnosis, treatment, and prevention of rare diseases.  FDA recognizes that, for all serious and life-threatening diseases, greater drug safety risks may be justified when the potential benefits of the drug are seen in the essential aspects of the disease and outweigh these risks.  The approval standard for drugs and biologic medical products of “substantial evidence of effectiveness” and safety remains an appropriate one for rare diseases.  In devices, the approval standard for a humanitarian device exemption (HDE) of reasonable assurance of safety and probable benefit is also appropriate.  Current regulations allow for flexibility and scientific judgment9 when applying the standard in assessing the totality of the evidence. FDA has successfully applied this flexibility to approve therapeutics for rare genetic diseases (e.g., Huntington’s disease) and rare cancers, among others. . . .

In addition, FDA says that the Agency “makes best use of existing regulatory provisions to facilitate efficient drug development and availability of drugs to patients during the investigational period,” including use of the Fast Track and Accelerated Approval processes, Priority Review, and Expanded Access of patients to investigational products. 

Notwithstanding the various FDA strengths identified in the report, FDA says that there are “clear areas for potential improvement,” which the Agency is trying to address through various ongoing activities, including “[e]xamining and evaluating policy and procedures for the regulation of medical products for rare diseases,” “[d]eveloping education and training programs for FDA rare disease reviewers and external stakeholders,” and “[i]ncreasing communication efforts involving rare diseases to stakeholders within the Federal government and outside FDA, as well as academia and the research community, industry, professional associations, and advocacy organizations.”  Given the significant increase in recent years to develop products for rare diseases (which is expected to continue for years to come), it is important that certain “impediments to progress” be addressed, including, according to FDA, “the often inadequate scientific foundation and core knowledge vital to support medical product development for rare diseases, limited regulatory precedents for most of the individual diseases and some of the most technologically innovative products in development, and suboptimal collaboration among relevant stakeholders.”  Some of the items listed under "Advancing Development of Drugs for Rare Diseases" in the proposed PDUFA V Reauthorization Performance Goals and Procedures (Fiscal Years 2013 through 2017) issued on August 31, 2011 appear to be directed to addressing some of these issues.

The RDG’s recommendations identify three key areas in need of additional efforts: (1) “increase the foundation of biomedical and regulatory science required to support development and regulatory assessment of medical products for rare diseases,” including conducting disease-specific natural history studies, identifying, developing, and qualifying novel biomarkers, and exploring the use of novel clinical trial designs and statistical methods; (2) “[i]ncrease collaboration among rare disease stakeholders both within and outside FDA;” and (3) “[g]ain a thorough understanding of the regulatory history of orphan drug products to help identify effective development approaches, particularly for addressing the uncertainties of biomedical knowledge along the product development pathway, so that patterns can be adapted to future development programs.”  This last key area includes performing “a detailed analysis of FDA’s 27-year history of Orphan drug approvals to identify factors and methods that have led to successful drug development and approval or have impeded development and identify areas for improvement,” and, in the case of medical devices, analyzing “the reasoning presented in device applications for requesting a [HDE] as well as why an application was successful or not with the goal of identifying areas for improvement” and undertaking an assessment of the barriers to and incentives for the development of medical devices for rare diseases.

NTDG Report

The NTDG report is less detailed than the RDG report, presumably given the more recent focus on tropical diseases product development, which the Tufts Center for the Study of Drug Development has tracked (see our previous report here).  (According to a World Health Organization report, neglected tropical diseases blight the lives of 1 billion people worldwide!)  The NTDG report is based on the group’s assessment of ongoing and planned activities and input and recommendations FDA received from a September 2010 public hearing (Docket No. FDA-2010-N-0364) on issues and concerns related to the development of neglected tropical disease products.  According to the NTDG,

appropriate regulatory paradigms are in place through FDA’s existing programs and activities related to FDA review of marketing applications for products for NTDs.  FDA has approved, licensed, or cleared a number of products for NTDs. . . .  FDA’s Office of International Programs has existing outreach activities related to NTD product development.  Nevertheless, the NTD group found that enhancing efforts, including those in Federal, academic, and other collaborative programs, could help strengthen certain basic and applied research areas (e.g., regulatory science), that form the foundation for medical product development and the basis of regulatory review and assessment.  The NTD group also found that enhancing the clinical trials infrastructure, through clinical trials consortia or other organizations, could facilitate the conduct of trials in countries of the developing world where NTDs mostly occur.

The NTDG makes four recommendations for improving the development of neglected  tropical disease products, including issuing guidance documents on neglected tropical disease drug product development (like the draft guidance FDA issued last week, titled “Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or Prevention"), revising CBER’s “General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases,” holding a CDRH Expert Panel meeting to discuss FDA’s regulation of diagnostic tests for pulmonary tuberculosis, and issuing guidance on the regulation of diagnostic tests for pulmonary tuberculosis.  The NTDG also notes that “[o]ne other consideration is to explore extending FDA’s Orphan Drug Grants Program to include grants for studies of diagnostic tests or other devices for NTDs.”

The NTDG report also says that “strengthening the scientific foundation that forms the basis of drug development and FDA’s regulatory process would greatly improve overall development process for NTD products.”  This includes basic and applied neglected tropical disease research by other Federal agencies (e.g., the National Institutes of Health), academia, or other consortia. 

We also note that FDC Act § 524, added to the statute by the 2007 FDA Amendments Act, created a new Priority review Voucher (“PRV”) program.  Under the PRV program, sponsors of certain new drugs and biologics for “tropical diseases” that have received priority review may receive a PRV entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock.  That program, as we recently reported, has not yet panned out, perhaps due, in part, to the high PRV redemption user fee FDA has set.  In Fiscal Year 2011 the PRV redemption fee was set at $4,582,000.  The Fiscal Year 2012 PRV redemption fee was just set by FDA at $5,280,000 – and that figure is in addition to the Fiscal Year 2012 full application fee of $1,841,500.  As we previously reported, legislation has been introduced to amend FDC Act § 524.

By Kurt R. Karst –      

On August 31, 2011, the Federal Trade Commission (“FTC”) announced the issuance of its final report, titled “Authorized Generic Drugs – Short-Term Effects and Long-Term Impact,” which has been in the works for years since it was requested in 2005 by several members of Congress.  The massive (270 pages in all) final report follows up on the FTC’s June 2009 interim report (“Authorized Generics: An Interim Report”). 

As we previously reported, the interim report presented the first set of results from the FTC’s study of authorized generics and focused on the effects of authorized generic introduction during the first, 180-day period of competition by a generic drug.  Not surprisingly, the FTC found in 2009 that drug retail and wholesale prices dropped, as well as an ANDA sponsor’s revenues (which sponsor was granted 180-day exclusivity) with the introduction of an authorized generic.  Those results were carried through to and modified in the FTC’s final report. 

The interim report also raised the FTC’s concern about the use of authorized generics in the context of patent settlement agreements and commented on how, according to the FTC, such agreements can harm consumers.  The final report includes additional data that the FTC says confirms its interim findings. 

The “authorized generic controversy,” as the FTC frames it, is as follows:

Brand-name companies that offer AGs contend that they are procompetitive – that they make valuable products available to consumers at lower prices than those of brand-name products and provide competition that leads to lower generic prices overall.  Some in the generic drug industry, in contrast, contend that AGs harm competition by drawing revenues away from generic firms during the 180-day exclusivity period provided for first-filers that challenge a brand-name company’s patents.  They caution that this reduces the potential reward available to generics that challenge patents, thereby discouraging patent challenges that facilitate earlier generic competition and reduce prices for consumers.  This, the AG critics argue, undermines long-run competition and the goals of the Hatch-Waxman Amendments.

The FTC’s final report, which includes a lot of nifty data, analysis, and commentary, to keep folks busy reading and thinking through the long Labor Day weekend (e.g., data on Paragraph IV certification filings and 180-day exclusivity), says that the bottom line is that although “authorized generics have a substantial effect on the revenues of competing, generic firms during the 180-day exclusivity period . . . the reduced revenue stemming from authorized generic competition during 180-day exclusivity has not affected the generic’s incentives in a way that has measurably reduced the number of patent challenges by generic firms;” however, “there is strong evidence that agreements not to compete with an authorized generic have become a way for brand-name companies to compensate generic competitors for delaying entry.”

The final report contains four main findings:

• Competition from authorized generics during the 180-day marketing exclusivity period has led to lower retail and wholesale drug prices.  During this time, competition by an authorized generic is associated with retail prices that are four-to-eight percent lower, and wholesale prices that are 7 to 14 percent lower, than those without an authorized generic.

• Authorized generics have a substantial effect on the revenues of competing generic firms.  During the 180-day exclusivity period, the presence of an authorized generic competitor on average reduces the first-filing generic’s revenues by 40 to 52 percent. In addition, revenues of the first-filing generic are between 53 and 62 percent lower during the first 30 months after the exclusivity period ends, if it is facing authorized generic competition. Introduction of an authorized generic can mean hundred of millions of dollars in lost revenue for the first generic competitor to enter the market.

• Lower expected profits could affect a generic company’s decision to challenge patents on products with low sales.  However, the reduced revenues resulting from authorized generic competition during the 180-day exclusivity period have not substantially reduced the number of challenges to branded drug patents by generic firms. Despite the presence of authorized generic competition, generic companies have continued to challenge patents, even on brand-name drugs in small markets.

• There is strong evidence that agreements not to compete using authorized generics have become a way that some branded firms compensate generic firms for delaying entry to the market.

It is the last finding that the FTC will almost certainly use to further its agenda (read crusade) both on Capitol Hill and elsewhere to put an end to patent settlement agreements, or what opponents call “pay-for-delay” or “reverse payment” agreements.  Retiring Senator Herb Kohl’s (D-WI) bill to restrict such agreements, the Preserve Access to Affordable Generics Act (S. 27), was reported out of the Senate Judiciary Committee in July.  The FTC’s final report could add some steam to the bill.  (For an interesting twist on how the FTC handled a recent case, see WLF’s The Legal Pulse recent post “FTC Injects Its Crusade Against “Reverse Payment” Drug Patent Suit Settlements into Merger Consent Order.”)

What is less clear is how the FTC’s final report might pan out for Sen. John Rockefeller’s (D-WV) pending bill, the Fair Prescription Drug Competition Act (S. 373), and the related bill introduced in the House of Representatives by Rep. Jo Ann Emerson (R-MO), H.R. 741.  (See our previous post here.)  Both bills would amend the FDC Act to prohibit the manufacture, marketing, sale, or distribution of an authorized generic version of an NDA-approved drug until any period of 180-day exclusivity associated with an ANDA for a generic version of that NDA-approved drug has expired or has been forfeited.  The FTC’s final report could take any wind out of the sails of those bills.

ADDITIONAL READING:

• Waxman/Rockefeller Statements

• GPhA Statement

By Anne Marie Murphy –

This week FDA announced the publication of a draft guidance titled, “Oversight of Clinical Investigations: A Risk Based Approach to Monitoring.”  This is the first time since 1988 that the agency issued a specific guidance document on how a study sponsor may meet its obligation to monitor or oversee the conduct of a clinical study. 

For purposes of the guidance, “monitoring” refers to the methods that sponsors and contract research organizations (“CROs”) use to oversee the conduct of and reporting of data from clinical studies.  FDA indicates that the primary focus of study monitoring should be protecting study subjects, ensuring the integrity of study data, and ensuring that clinical investigators comply with applicable regulations. 

Sponsors have always been free to adopt monitoring practices and procedures as they saw fit.  Historically, however, FDA notes that industry sponsors have relied heavily on frequent on-site visits to clinical sites to verify data and ensure compliance.  FDA also notes a misconception on the part of industry that FDA expects 100% verification of study data.  

In addition to on-site monitoring, the draft guidance encourages the use of centralized monitoring, i.e., remote evaluation of study data at a location other than the site where the study is being conducted.  The extent to which remote or centralized monitoring is used should depend on the complexity of the study and the electronic accessibility of study data.  According to the guidance, centralized monitoring should:

• include activities that can be done as well or better remotely (e.g., standard checks for consistency and completeness of data);
• target on-site monitoring by identifying higher risk clinical sites;
• perform monitoring activities that can only be done in a centralized manner (e.g., statistical analyses to identify data trends);
• identify missing or inconsistent data and potential protocol violations;
• verify source data remotely, where both source data and CRFs can be accessed remotely;
• analyze site characteristics (e.g., high screen failure or protocol violation rates and delays in reporting data);
• complete administrative tasks such as collecting regulatory documents.

For each clinical trial, FDA recommends that the sponsor develop a monitoring plan that describes:

• the monitoring approaches and procedures to be used;
• communicating monitoring results;
• managing noncompliance, including developing specific processes for investigating suspected data falsification;
• training and study-specific information, including training monitors and study site staff.

FDA intends to evaluate processes through which sponsors may voluntarily submit monitoring plans to the appropriate FDA review division and request feedback. 

The guidance also addresses a sponsor’s ability to transfer of monitoring obligations to a CRO.  It notes that any such transfer must be in writing, and that the sponsor retains responsibility to oversee the CRO’s activities. 

Comments on the draft guidance should be submitted by November 28, 2011.

By Ricardo Carvajal –

In June, we reported that the DC Circuit Court of Appeals decided it lacked exclusive jurisdiction over a Natural Resources Defense Council (“NRDC”) citizen petition seeking FDA action against BPA.  Undeterred, NRDC has now filed its complaint in district court.  The complaint catalogues numerous risks allegedly posed by BPA, contends that food is the principal rout of exposure for most people, and contends that FDA underestimates BPA exposure resulting from consumption of canned food.  The complaint further alleges that "consumers trying to protect themselves and their families from BPA exposure are unable to do so because food packaging and containers made with the chemical are rarely so labeled" – an allegation that appears to take no notice of the healthy market for products bearing "BPA-free" claims.  The complaint asks the court to compel FDA to issue a substantive respond to NRDC's petition by a fixed date.

By Kurt R. Karst –      

On August 29, 2011, Public Citizen announced that it submitted a citizen petition to FDA requesting that the Agency amend its regulations to permit ANDA sponsors to revise their labeling through the Changes Being Effected (“CBE”) and Prior Approval Supplement (“PAS”) procedures.  The petition is in response to the U.S. Supreme Court’s June 23, 2011, 5-4 landmark consolidated decision in PLIVA Inc. v. Mensing (Docket No. 09-993), Actavis Elizabeth, L.L.C. v. Mensing (Docket No.  09-1039), and Actavis, Inc. v. Demahy (Docket No. 09-1501) (and for which rehearing was requested and recently denied), in which the Court invoked the doctrine of impossibility preemption to hold that federal drug regulations applicable to generic drug manufacturers directly conflict with, and thus preempt, state tort-law claims based on drug manufacturers’ alleged failure to provide adequate warning labels for their products (see our previous post here), and in response to FDA’s position (pages 16-17) that the CBE and PAS procedures are not available to ANDA sponsors to add or strengthen label warnings.  (Public Citizen submitted an amicus brief in the Mensing case in support of Respondents.)

The Public Citizen petition makes three requests:

(1)  That FDA amend, through notice and comment rulemaking, its PAS and CBE regulations at 21 C.F.R. § 314.70(a) to specify that subsections (b) and (c) apply to ANDA sponsors.  Such an amendment, says Public Citizen “might also make exceptions to reflect situations in which the agency believes that particular ANDA holders lack an adequate basis to make labeling changes, such as, perhaps, during the first few months after the first ANDA holder enters the market or for an ANDA holder that sells very few prescriptions of a drug (for example, under 1,000 prescriptions per year);”

(2) That FDA amend its regulation at 21 C.F.R. § 314.150(b)(10) (permtting ANDA approval to be withdrawn if a generic drug’s approved labeling differs from that of the RLD) “to specify that this regulation does not apply to ANDA holders permitted to supplement labeling through CBE or PAS procedures;” and

(3) That FDA clarify in its regulations (and specifically 21 C.F.R. § 201.57(c)(6)(i)(A)) “that all ANDA holders are required to report safety concerns to the FDA as soon as they become aware of a clinically significant hazard.”  

Public Citizen’s petition is premised on the contention that despite significant changes in the generic drug market since the 1984 enactment of the Hatch-Waxman Amendments, “FDA regulation of generic labeling has remained substantially unchanged.”  “The regulatory revisions requested here would bring postmarket regulation in line with the realities of the pharmaceutical market and help to ensure that drug labeling provides adequate warnings to patients based on information that comes to light after the drug is approved for marketing,” says the petition.  Moreover, according to Public Citizen, “FDA’s position on the inapplicability of 21 C.F.R. § 314.70 to ANDA holders, and the Supreme Court’s recent decision in PLIVA, which turns on the limitations of the regulatory scheme, threaten the safety of prescription drugs, and accordingly, pose unnecessary risks to patients.”  Amending FDA’s regulations to make the PAS and CBE procedures applicable to ANDA sponsors in response to new risk information would undo the impossibility that the Supreme Court found in Mensing, says Public Citizen.  “In that event, common law could once again complement the FDA’s mandate to monitor drug safety across the full range of drugs, rather than just the decreasing portion occupied by brand-name drugs.” 

Interestingly, Public Citizen contends that its proposed regulatory changes “would not impose an obligation beyond the capacity of generic manufacturers.”  “It is our understanding,” says Public Citizen, “that under current regulations, a generic manufacturer is designated by the FDA to maintain the label of a drug when the name-brand manufacturer of that drug withdraws from the market.  This procedure manifests the FDA’s confidence in the ability of generic manufacturers to perform ongoing pharmacovigilance duties – which makes sense, given their substantial scientific and financial resources, as well as the effort they must already invest to comply with post-approval safety regulations.”  This is presumably a reference to FDA’s practice of unilaterally designating an ANDA as the sole RLD for a multi-source generic drug product where the brand-name drug has been discontinued and is listed in the Discontinued Drug Product List of the Orange Book.  In such cases, FDA has stated time and time again that when an NDA designated as the RLD is discontinued for reasons other than safety or effectiveness “[a]pproved ANDAs that refer to the NDAs . . . are unaffected by the discontinued marketing of the products subject to those NDAs. . . .  If FDA determines that labeling for these drug products should be revised to meet current standards, the agency will advise ANDA applicants to submit such labeling.”  FDA, Notice, Determination That MOTRIN (Ibuprofen) Tablets and Four Other Drug Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness, 75 Fed. Reg. 48,352, 48,353 (Aug. 10, 2010) (emphasis added).

By William T. Koustas & John R. Fleder –

Google, Inc. (“Google”) and the Department of Justice (“DOJ”) (acting in concert with FDA’s Office of Criminal Investigations) have settled the government’s criminal investigation into Google’s AdWords program, which displayed advertisements on websites for online Canadian pharmacies.  The government contends that these advertisements resulted in the unlawful importation of controlled and non-controlled prescription drugs into the United States.  Google has agreed to pay $500 million as a civil forfeiture in order to resolve this matter.

The government claims that, since 2003, Google was aware that online Canadian pharmacies were using Google’s AdWords program to place advertisements on websites to illegally sell prescription products to U.S. consumers.  In the just released Non-Prosecution Agreement (“the Agreement”), the government acknowledges that in 2009, Google took steps to prevent pharmacies outside the U.S. from advertising on AdWords.  However, the government contends that for six prior years Google failed to take the same actions to prevent Canadian pharmacies from placing advertisements on Google in order to sell drugs to U.S. consumers.  Indeed, the government claims that Google actively assisted some online Canadian pharmacies to target their advertisements to U.S. consumers.  The government claims that the “shipment of prescription drugs from pharmacies outside the United States to customers in the U.S. typically violates the Federal Food, Drug, and Cosmetic Act and in the case of controlled prescription drugs, the Controlled Substances Act.”

The Agreement also states that once Google became aware of the government’s investigation in 2009, Google required online pharmacies to engage the National Association of Boards of Pharmacy to certify that online pharmacies seeking to advertise on AdWords were accredited through its Verified Internet Pharmacy Practice Sites (“VIPPS”) program.  According to the Agreement, the VIPPS program conducts site visits as part of the its certification process, has “stringent standards” against the issuance of prescriptions based on online consultations, and does not certify Canadian online pharmacies.  Google also hired a third-party company to detect pharmacy advertisers’ attempts to exploit flaws in the AdWords screening system designed to prevent foreign online pharmacies from advertising to U.S. customers without Google’s knowledge.  In fact, Google has sued online pharmacy advertisers that have violated Google’s terms of use for advertisers.

In addition to paying $500 million, Google has agreed to take a number of remedial steps that are outlined in the Agreement.  These steps are intended to prevent online foreign pharmacies from using AdWords to advertise to U.S. customers.

The government agreed to release Google from any further civil, administrative or equitable claims relating to this issue; however, it is fair to ask: why would Google enter into this Agreement and what did it really get from it?

The first tangible benefit to Google is that it has avoided a likely criminal prosecution.  It is quite clear that the DOJ was conducting a criminal investigation of Google.  What is not clear is the charges that DOJ was considering.  The Agreement does mention that Google’s supposed illegal conduct violated both the Federal Food, Drug, and Cosmetic Act and the Controlled Substances Act.  DOJ may well have threatened Google with other charges such as criminal conspiracy and/or RICO violations.  One cannot tell what DOJ threatened from the public documents.  However, one can certainly see that Google agreed to pay an amount that seems on its face to be quite large even for a company the size of Google.  Indeed, the money Google has agreed to forfeit represents far more than the money Google realized in profits, or even than the gross amount it received in revenue from the Canadian pharmacies.  It appears that Google has agreed to forfeit an amount that also includes the revenue that the Canadian pharmacies derived from sales to U.S. consumers even though Google presumably received only a small fraction of that amount in revenue.

Thus, it is a fair assumption that Google agreed to this settlement because the DOJ threatened a criminal prosecution against Google, and possibly even some of its executives, that if brought would have caused Google harm that was worth far more than the $500 million the company forfeited to the government.

This settlement also raises the important question of whether this Agreement will be used as a precedent against other companies.  Will the government pursue other organizations that do not themselves sell FDA-regulated products but which do publish advertisements for companies that sell products to U.S. consumers?  Will the government generally take the view that it will seek a monetary judgment that exceeds the revenue derived by the company with which the government settles?  Is the government’s pursuit of this case due solely to the megasize of Google?  Will the government pursue other entities this way even if those entities are not involved in the sales of pharmaceutical products through foreign online marketing to the U.S.?  Unfortunately, there is nothing in the public filings that provides clear answers to these questions.

By Riëtte van Laack –

Under the law, a manufacturer of a new dietary ingredient ("NDI") or a dietary supplement containing an NDI must notify FDA of the basis for the manufacturer’s conclusion that its product “will reasonably be expected to be safe.”  FDA’s regulation, 21 C.F.R. § 190.6, specifies what information an NDI notification ("NDIN") must contain.

In a June 3, 2011 notice, FDA announced that, based on experience from the last three years, it estimated the annual reporting burden of NDINs to be 1100 hours, i.e., 50 NDINs with an average burden of 20 hrs per NDIN.

Although FDA received several comments that its estimate was too low, it submitted its original estimate to the Office of Management and Budget.   FDA maintained that the preparation of an NDIN imposes a minimal burden because FDA requires “only that information that the manufacturer or distributor should already have developed as the basis for its conclusion that a dietary supplement containing an NDI will reasonably be expected to be safe.”  The 20 hrs is “for extracting and summarizing the relevant information from the company’s files” and presenting it as required by FDA and does not include time for generating and collecting the information.

FDA’s estimate also does not include the burden resulting from the recently issued draft NDI guidance in which the Agency indicates that dietary supplement manufacturers must submit NDINs for virtually all their dietary supplements containing an NDI – see our previous post here.  Apparently, the burden associated with this guidance is a separate issue to be considered in the future.

By Ricardo Carvajal –

Del Monte Fresh Produce N.A., Inc. ("Del Monte Fresh") sued to invalidate an FDA import alert on cantaloupe from Productos Agricolas de Oriente, S.A. ("PAO"), a Guatemalan producer that is one of Del Monte Fresh’s principal suppliers.  FDA imposed the import alert as the result of a multi-state outbreak of Salmonella Panama that FDA attributed to PAO cantaloupes.  The complaint alleges that FDA’s conclusion regarding the likely source of the outbreak “was not rationally supported by the evidence available to FDA,” and that “FDA also did not take into account evidence that did not support that conclusion.”  In specific, the complaint alleges that all tests of PAO cantaloupes for Salmonella or other pathogens have been negative, that FDA inspections and other audits of PAO have been satisfactory, and that some evidence suggests that the outbreak may have been caused by cantaloupes from other sources or foods other than cantaloupe.  Thus, if the case proceeds, it will likely focus on the sufficiency of the epidemiological evidence relied on by FDA.  Given the increasing sophistication of (and reliance on) epidemiological investigations in responding to outbreaks of foodborne illness, that makes this a case to watch.

It’s that time of year again when we at FDA Law Blog turn to our loyal readers and say:  “Our fellow Blogerians, Ask not what your blog can do for you – ask what you can do for your blog.”  Yes, the American Bar Association (“ABA”) announced that it is now accepting 2011 nominations for the Blawg 100 (the top 100 legal blogs – or “blawgs” – in the blogosphere).  With your help we made the top 100 list the past two years.  This year, with your help once again, we are hoping to add another championship ring (ok, it’s really a badge for posting on the blog) and join the list of winning teams with three-peat occurrences.

We ask that FDA Law Blog readers use the ABA’s Blawg 100 Amici Form and nominate FDA Law Blog!  Although it’s called a “friend-of-the-blawg brief,” filling out the form will take only a couple of minutes.  In fact, you only have 500 characters to say why you’re a fan of the blog.  Remember, when you complete the nomination form, our URL is www.fdalawblog.net.  (There are other blawgs out there with – gasp! – curiously similar URLs and/or names to FDA Law Blog.  But, hey, imitation is the best form of flattery, right?)  Friend-of-the-blawg briefs are due no later than Friday, September 9th.

ABA editors make the final decisions about what’s included in the Blawg 100.  We hope they’ll be impressed with what our readers have to say about us.  Thank you!

By Kurt R. Karst –      

Recently we reported on the “other battle” going on concerning patents listed in the Orange Book for The Medicines Company’s (“MDCO’s”) ANGIOMAX (bivalirudin) Injection.  With patent reform reportedly high on President Obama’s agenda, and with the fast approaching September 6th return of House and Senate Members from recess, when, according to Senate Majority Leader Harry Reid (D-NV), the House-passed patent reform bill – the America Invents Act (H.R. 1249) – will be the first item taken up for consideration in the Senate, we thought an update was in order on where things stand with MDCO’s efforts to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX. 

Section 37 of H.R. 1249, titled “Calculation of 60-day period for application of patent term extension,” would amend the PTE law at 35 U.S.C. § 156(d)(1) to provide that the 60-day period “beginning on the date the product received permission . . . for commercial marketing or use” would begin on the next business day “if such permission is transmitted after 4:30 P.M., Eastern Time, on a business day, or is transmitted on a day that is not a business day.”  This provision would effectively codify Judge Claude M. Hilton’s August 3, 2010 decision in The Medicines Company v. Kappos, 731 F. Supp. 2d 470 (E.D. Va. 2010), in which Judge Hilton ordered the Patent and Trademark Office (“PTO”) to consider timely filed MDCO’s PTE application for the ‘404 patent.  (We note that FDA recently informed the PTO that the 180-day period for filing a due diligence petition for a determination of whether the PTE applicant acted with due diligence during the regulatory review period passed without the filing of such a petition.)  Senator Reid recently filed cloture on a motion to proceed with H.R. 1249.  Barring any amendments added to the bill in the Senate, the House would not need to further consider the legislation.  

Interest in (read lobbying for and against) the inclusion of Section 37 in what might become the enacted version of the America Invents Act has been running high.  A few weeks back, we reported on two instances in which PTE applicants for patents covering BEYAZ (drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium) Tablets and SYMBICORT (budesonide; formoterol fumarate dihydrate) Inhalation Aerosol notified the PTO that, pursuant to The Medicines Company decision, their PTE applications should be considered timely filed because of after business hours NDA approvals.  Since that post, we have become aware of a third instance in which The Medicines Company decision has been raised in a petition to the PTO. 

Specifically, AstraZeneca AB (“Astra”) contends in a recent Request for Reconsideration of Final Agency Action submitted to the PTO that its PTE application for U.S. Patent No. 5,817,338 (“the ‘338 patent”) covering PRILOSEC OTC (omeprazole magnesium) Delayed-Release Tablets was timely submitted.  As we previously reported, the PTO determined in December 2008 that the 60-day period for submitting a PTE application for the ‘338 patent began on June 20, 2003, when FDA approved NDA No. 021229, and ended on August 18, 2003, making Astra’s August 19, 2003 PTE application untimely.  According to Astra, however, FDA approved NDA No. 021229 at 4:47 PM on June 20th.  Therefore, Astra states:

in accordance with [sic] district court’s decision in The Medicines Company, Applicant’s period to file the PTE Application did not begin to run until the first business day following the FDA’s after-hours transmission.  The next business day was Monday, June 23, 2003.  If the first day of the 60 day period set forth in 35 U.S.C. § 156(d)(1) was June 23, 2003, then [sic] 60 day period ended on August 21, 2003, thus rendering the submission of the PTE Application on August 19, 2003, timely within the meaning of § 156(d)(1).

After business hours approvals have provided fodder for MDCO to lobby on Capitol Hill for the inclusion of Section 37 in the America Invents Act, portraying Section 37 as a law of general applicability rather than as single company legislation.  One lobbying piece that is supposedly circulating on Capitol Hill includes a table identifying several instances in which PTE applications were allegedly filed late under the PTO’s pre-The Medicines Company counting method in which the day of approval counted as day 1.  “[T]o the extent transmission of FDA approval for these drugs occurred after normal business hours, Section 37 could also benefit these additional innovators – who also were caught in a procedural trap by the PTO,” says the two-page lobbying piece. 

Advocacy letters have also been submitted to Members of Congress.  A letter from Massachusetts General Hospital to Sens. Herb Kohl (D-WI) and Michael Lee (R-UT) extends the hospital’s support for the inclusion of Section 37 in H.R. 1429.  Another letter signed by 25 doctors from across the country and sent to U.S. Senate leaders says that the passage of Section 37 “is critically important to medicine and patients,” that “[b]y clarifying the rules on patent restoration, the provision will help all companies – both now and in the future – by providing the certainty necessary to encourage them to invest the money and effort needed to bring innovative new drugs to the market,” and that “[t]he provision will also ensure that government officials interpret the rules in a consistent manner.” 

Meanwhile, the Generic Pharmaceutical Association (“GPhA”) has been lobbying against inclusion of Section 37 in the America Invents Act.  In June, GPhA lamented over the House’s “failure to correct a fatal flaw in the bill.”  According to FDA Week (subscription required), GPhA is currently focusing its patent reform lobbying efforts on stripping Section 37 from the America Invents Act. 

By Cassandra A. Soltis –

In response to the Food and Drug Administration’s (“FDA’s”) proposed rule on nutrition labeling of standard menu items in restaurants and similar retail food establishments, members of the U.S. Senate and House of Representatives have requested that FDA exclude grocery stores from the menu labeling requirements.  The proposed rule (see our previous post here) would require menu labeling at retail food establishments if they sell restaurant or restaurant-type food and if their primary business activity is the “sale of food” (i.e., including packaged foods) to consumers.  76 Fed. Reg. 19,192, 19,196 (Apr. 6, 2011).  FDA indicated that it would generally expect grocery stores, such as those that prepare and sell restaurant-type food on the premises, to be subject to the menu labeling regulation.  Id. at 19,198. 

However, letters (here and here) from both the Senate and House of Representatives request FDA to follow “Congressional intent” and adopt FDA’s alternative definition of “restaurant or similar retail food establishment,” which would essentially exclude grocery stores from menu labeling.  Under the alternative definition, “restaurant or similar retail food establishment” would mean a retail establishment “where the sale of restaurant or restaurant-type food – as opposed to food in general – is the primary business activity of that establishment.”  Id. 

The letter from Senate members explained that “the plain language of the statute” indicates that grocery stores were not intended to be covered by the menu labeling law.  In addition, the letter stated that requiring such information on foods served in grocery stores “would place a disproportionate cost on grocery store chains . . . because grocery store chains lack the menu standardization of restaurant chains.”  The Senate members also cited to FDA budget constraints and costs passed on to consumers as reasons for adopting the alternative definition. 

The House members noted that “[h]istorically, labeling regulations, such as for nutrition panels, food safety, ingredient, and country-of-origin labeling have been applied differently between supermarkets and restaurants” and that “[t]hese are key reasons why none of the states or municipalities that have enacted menu labeling laws have applied them to supermarkets.”  The House members “urge[d] FDA to adopt the agency’s own alternative to limit restaurant menu labeling regulations to establishments that primarily sell restaurant foods.” 

By Kurt R. Karst –      

Earlier this week, a group of five tobacco companies (R.J. Reynolds Tobacco Company, Lorillard Tobacco Company, Commonwealth Brands,  Inc., Liggett Group LLC, and Santa Fe Natural Tobacco Company, Inc.) filed a four-count Complaint against FDA in the U.S. District Court for the District of Columbia challenging the Agency’s June 22, 2011 final rule, promulgated pursuant to the Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), requiring the display of certain health warnings and graphics on cigarette packages and in cigarette advertisements.  As we noted back in November 2010 when FDA issued its proposed rule, a court challenge seemed inevitable. 

Under the Tobacco Control Act, each cigarette package and advertisement must bear one of nine new textual warning statements.  FDA is required to issue regulations requiring accompanying color graphics that depict the negative health consequences of smoking.  FDA’s final rule specifies the nine color graphic images (see here) that must accompany each of the nine new textual warning statements, and that the Plaintiffs in their August 16th Complaint say “are designed to shock, disgust, and frighten adult consumers of cigarettes.”  The Tobacco Control Act states that the new textual and graphic warnings, among other requirements, will become effective “15 months after the issuance of” a final rule.  FDA says in its final rule that the regulations  will take effect on September 22, 2012, when cigarettes for sale or distribution in the U.S. may longer be manufactured or advertised without the new health warnings, and on October 22, 2012, when cigarette manufacturers will no longer be allowed to distribute cigarettes for sale in the U.S. unless they display the new health warnings.

The Plaintiffs allege in their Complaint that FDA’s final rule “violates the First Amendment under any standard of review.”  Not only are the warnings imposed by the final rule “not purely factual and uncontroversial commercial disclosures aimed at preventing deception of consumers,” but they “do not further any compelling governmental purpose,” and “are not the least restrictive means available to accomplish any governmental purpose,” says the Complaint.  Moreover, “[t]he warnings imposed by the Rule are unjustified because they would have few if any benefits.”  (Another lawsuit, filed in the U.S. District Court for the Western District of Kentucky in 2009 and decided in January 2010, challenged the constitutionality of other Tobacco Control Act provisions.  In that case, the district court held invalid the Tobacco Control Act’s ban on color and imagery in tobacco advertising and upheld several other provisions of the law.  That decision has been appealed U.S. Court of Appeals for the Sixth Circuit.) 

FDA’s final rule also allegedly “contravenes core requirements” of the Administrative Procedure Act (“APA”).  “In promulgating the Rule, FDA acted arbitrarily and capriciously by attempting to justify the Rule (and its rejection of alternatives to the Rule) on grounds that were illogical, contradictory, and without support in the regulatory record, and by employing different standards of analysis to comments supporting the Rule than to comments opposing the Rule.”  Moreover, “FDA failed to provide Plaintiffs with meaningful notice as required under 5 U.S.C. § 553(b)(3), by failing to disclose key technical data, methodologies, and assumptions underlying the Rule,” according to Plaintiffs.

Noting the Tobacco Control Act’s 15-month effective date for the new textual and graphic warnings (among other requirements), Plaintiffs contend that:

Congress’s use of a single implementation date for the new textual and graphic warnings and the Related Requirements demonstrates an intent that manufacturers not be subjected to multiple, costly overhauls of their packaging and advertising.  In light of this intent, the Act must be read to tie the effective dates of all cigarette packaging and advertising changes to the “issuance” of regulations by FDA that are constitutionally and procedurally valid.  Any contrary reading would frustrate the congressional intent reflected in the Act and create the anomaly that an invalid Rule would have substantial and detrimental legal effect.

Thus, the Plaintiffs seek both declaratory and injunctive relief that the new textual and graphic warnings will become effective, and that FDA will not enforce the requirements, until 15 months after FDA issues regulations “that are permissible under the United States Constitution and federal law.”

By Jennifer D. Newberger –

On August 15, 2011, FDA released two Draft Guidances:  “Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review” and “Design Considerations for Pivotal Clinical Investigations for Medical Devices.”  Each is discussed in turn below.

Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review

This Draft Guidance appears to be the first time FDA has articulated, in a formal manner, the factors that, theoretically, FDA considers in balancing the risks and benefits of a medical device, and how, ideally, that balance should affect the clearance or approval of a device. 

The guidance states that it applies to devices subject to premarket approval (PMA), and, “in limited cases,” devices subject to premarket notification (510(k)) requirements.  As noted in the Draft Guidance, under section 513(a) of the Federal Food, Drug and Cosmetic Act (FDC Act), FDA determines whether PMA applications provide a “reasonable assurance of safety and effectiveness” by “weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use.”  FDA may also utilize a similar analysis in the review of 510(k) devices when there are differences between the proposed device and the predicate device that may affect the safety and/or effectiveness of the proposed device.

The Draft Guidance splits the factors FDA may consider into three categories:  effectiveness, safety, and other.  For effectiveness, the consideration is the extent of the probable benefit(s), measured by taking into account the following factors:

• Type of benefit
• Magnitude of the benefit
• Probability of the patient experiencing a benefit
• Duration of the effect(s)

The safety considerations that help FDA determine the extent of the probable risk(s) and/or harm(s) include:

• Number, severity, and types of harmful events associated with use of the device: Device-related serious adverse events, Device-related non-serious adverse events, and Procedure-related or indirect harms
• Probability of a harmful event
• Duration of harmful events
• Risk from false-positive or false-negative for diagnostics
• Number of different types of harmful events that can potentially result from using the device and the severity of their aggregated effect.

The additional factors FDA may consider when weighing probable benefits and risks include:

• Uncertainty as to the benefits and risks.  This may be due to a poorly designed clinical trial, or the generalizability of the trial results to the intended treatment and user population.
• Characterization of the disease.  How does the disease affect patients?  What is its natural history and progression?
• Patient tolerance for risk.  In determining patient tolerance for risk, FDA may consider disease severity, disease chronicity, and the availability of alternative treatment/diagnostic options.
• Availability of alternative treatments or diagnostics.  The Draft Guidance indicates that in considering alternative treatment options, FDA may even consider off-label uses of marketed products if there are no approved or cleared products for the intended condition and patient population.  The Draft Guidance states:  “[I]f a new device has a very small benefit and there is significant uncertainty about that benefit, we may still approve the product if there are no available alternative treatments or diagnostics and the risk profile is acceptable.”
• Risk mitigation, such as the inclusion of warnings in the labeling or restricting the indication to a more limited use. 
• Novelty of technology.  FDA recognizes that new technologies carry with them more uncertainty than established technologies, but also may offer previously unavailable advantages.  As a result, FDA states that it “may approve a device with less benefit or more risk than would be generally tolerated for more established technologies, particularly where providers and patients have limited alternatives available, to facilitate patient access and encourage innovation.”

The factors put forth in this Draft Guidance are likely familiar to sponsors of premarket device submissions, although presented in a more systematic fashion.  As always, of course, the question is less about what the Draft Guidance states, and more about how it will be implemented, e.g., how, exactly, the competing factors are weighed.  In light of the ongoing debate over FDA’s impact on innovation, it is interesting that FDA explicitly considers novelty as a factor in favor of approval, in part to “encourage innovation.”  While this Draft Guidance may helps sponsors better understand what information they may need to balance, for instance, uncertainty generated by a small clinical trial, it will perhaps never be possible to determine precisely what FDA will consider sufficient to outweigh the possible risks of a device.  Hopefully this Draft Guidance is a reasonable starting point in analyzing the factors that should be assessed.

Design Considerations for Pivotal Clinical Investigations for Medical Devices

The most important lesson from this Draft Guidance does not appear to be the descriptions of the different types of clinical study designs, or even FDA’s assessment of the value of those designs, but rather a conclusion that is reached from reading between the lines:  the concept of least burdensome is no more, and if a sponsor decides not to conduct a randomized, double-masked (blinded), controlled, parallel group clinical study, it better have a good reason for not doing so.  Not only must it have a good reason, it must provide that reason to FDA:  the Draft Guidance states that an IDE application “should include the details of the proposed study design and a rationale for the study design chosen, including an explanation of the alternate study designs considered and why those study designs were dismissed as inappropriate, impractical, or not possible.”  This is at odds with the Guidance FDA issued in 2002 regarding the “least burdensome provisions,” in which FDA specifically stated:  “If clinical data are needed, FDA and industry should consider alternatives to randomized, controlled clinical trials when potential bias associated with alternative controls can be addressed.”  It is also at odds with the Draft Guidance on Benefit-Risk Determinations discussed above, which states that clinical testing may include not only randomized clinical trials, but “partially controlled studies, studies without matched controls, well-documented case histories conducted by qualified experts, reports of significant human experience, and testing on clinically derived human specimens.”

For those readers not familiar with the concept of the least burdensome provisions, here is a little background.  There are two provisions in the FDC Act known as the “least burdensome provisions.”  One of these provisions, section 513(a)(3)(D)(ii), generally applies to PMAs, and states that “[a]ny clinical data, including one or more well-controlled investigations, specified in writing by [FDA] for demonstrating a reasonable assurance of device effectiveness shall be specified as a result of a determination by [FDA] that such data are necessary to establish device effectiveness.”  The second least burdensome provision, generally applicable to 510(k) submissions, states that, in requesting information to demonstrate that devices with different technological characteristics are substantially equivalent, FDA “shall only request information that is necessary to making substantial equivalent determinations.  In making such a request, [FDA] shall consider the least burdensome means of demonstrating substantial equivalence and request information accordingly.”

Each of these provisions implies that a requirement to provide clinical data to demonstrate a reasonable assurance of safety and effectiveness, or substantial equivalence, must be based on a determination that such data are necessary to make the showing.  In other words, if a showing of reasonable assurance or substantial equivalence may be made without clinical data, FDA should—or perhaps, must—permit the sponsor to provide other than clinical data to support its applications. 

While there may be room for debate as to whether a showing of substantial equivalence between two products with different technological characteristics always requires clinical data, requiring clinical data for PMAs is not new or even particularly controversial.  The type of study, however, has generally been determined based on the type of device and the endpoints desired.  This Draft Guidance, while describing many different types of clinical study designs, doesn’t explicitly reject any particular design, but makes very clear that well-controlled, randomized, masked studies are the clear favorite, and plants a seed of doubt as to whether other studies will really ever be acceptable to FDA.  The text of the document belies the assurance in the Draft Guidance stating that “the principles of study design discussed in this guidance are consistent with the principles discussed in the Least Burdensome Guidance, but expand upon them by discussing the considerations that may affect the level of evidence necessary to meet the standard for premarket approval or clearance.”

The specific clinical design study factors discussed in the Draft Guidance are not, in and of themselves, anything particularly surprising.  The Draft Guidance breaks clinical studies into two broad categories:  clinical outcome studies, for therapeutic and aesthetic devices, and diagnostic clinical performance studies, for diagnostic devices.  For both types of studies, the Draft Guidance addresses some general principles in designing a clinical study:  avoiding bias and variability in device performance; clear statement of study objectives; subject selection that adequately reflects the target population for the device; and selection of enrollment sites appropriate for the intended use of the device.

The Draft Guidance identifies the below elements in designing a clinical outcome study:

• Selection of appropriate endpoints.  These should be pre-specified at the design stage of the pivotal clinical study, and should provide sufficient evidence to fully characterize the clinical effect of the device for the desired intended use.
• Randomization.  The Draft Guidance recommends randomization of subjects so the groups are comparable at baseline prior to the intervention, and states that the inability to randomize may subject the study to “bias of unknown size and direction” which can in turn adversely impact the level of evidence provided by the study. At the same time, the Draft Guidance recognizes that there are situations in which randomization is impossible, difficult, or potentially inappropriate.  In such a situation, the Draft Guidance recommends sponsors contact FDA to discuss concerns with randomization and determine an appropriate study design.
• Masking (blinding).  The Draft Guidance notes that masking is important to reduce bias, because knowledge of treatment may affect the behavior of subjects or interpretation of clinical outcomes by investigators.  The Draft Guidance suggests certain steps a sponsor may take to minimize bias where masking is not possible, such as masking subjects until after the procedure and drafting a script for clinical staff to use to standardize the follow-up questions asked of study participants.
• Controls in comparative clinical trials.  The Draft Guidance discusses active intervention control, placebo control, no intervention control, subject as own control, and subject-level data on a parallel group (historical control), making clear that historical control is the least desirable, which has long been FDA’s policy.
• Placebo effect and other phenomenon.  Because placebo devices may appear to demonstrate effectiveness, the Draft Guidance recommends use of a placebo to compare the investigational device to a therapy that is ineffective.  If superiority to the placebo can be demonstrated, it can be inferred that that investigational device is effective.
• Non-comparative clinical outcome studies.  The Draft Guidance states that study designs that do not use concurrent (or historical) controls are not well-controlled studies.  These studies may include single-group study with objective performance criterion; single-group study with performance goals; observational studies or registries; meta-analysis; and literature summaries.

The Draft Guidance addressed the following with regard to diagnostic clinical performance studies:

• Consideration of intended use.  The pivotal diagnostic clinical performance study must support the intended use of the diagnostic device, by evaluating what the device measures or detects; what the device reports; cell, tissue, organ, part, or system examined; specimen source(s), specimen type(s), and specimen matrix(-ces); how the device is used; when the device is used; by whom the device is used; for what; and on whom device is used.
• True status of the target condition.  There generally must be an assessment of the true status of the target condition.  If no gold standard exists to make this determination, an alternative type of assessment may be used.
• Study population for evaluation of diagnostic performance.  Sites selected for investigational use should be representative of the types of sites where the device is intended to be used, and study subjects should represent the target condition spectrum.
• Study planning, subject selection, and specimen collection.  For a prospective study, specify inclusion/exclusion criteria, method of subject recruitment and selection, testing protocol, and analysis methods to be used.  Retrospective selection of previously archived specimens may introduce issues of bias, such as non-representation of the target population.  Sponsors should consult with FDA to determine if available specimens or subject data are appropriate to support a diagnostic device’s intended use.
• Diagnostic clinical performance comparison studies.  Comparative studies comparing the investigational device with an established device is only possible when a clinical reference standard is used, and sponsors designing such studies should consult with the appropriate review division at the design stage.
• Masking in diagnostic performance studies.  Diagnostic device clinical studies may involve multiple evaluations and users/readers.  The user of the investigational diagnostic device should not be aware of the result from the clinical reference standard or other diagnostic evaluation, and vice versa.
• Skill and behavior of persons interacting with the device.  Protocols should account for variability in the performance of persons interacting with the device, because use of a diagnostic device may require certain levels or types of skills or knowledge.

This Draft Guidance may in fact help sponsors design their clinical studies because they now have additional insight into what FDA likes and dislikes, and how FDA suggests adjusting for bias or other complicating factors.  Nevertheless, the unspoken conclusion of the Draft Guidance is clear—FDA will be requesting, or perhaps requiring, increasingly demanding study designs.