Professor Jordan Paradise of Seton Hall Law School Issues Paper on e-Cigarettes and the Law

Paper Warns Against ‘Nonexistent Safety Data’ and Charts a Course for FDA Oversight

Seton Hall Law Professor Jordan Paradise has released her newest paper, “No Sisyphean Task: How the FDA can Regulate Electronic Cigarettes,” scheduled to be published this Spring in Volume 13 of the Yale Journal of Health Policy, Law, and Ethics.

A report issued in February 2013 by the Centers for Disease Control and Prevention (CDC) estimates that as of 2011 “about one in five U.S. adult cigarette smokers have tried an electronic cigarette,” nearly twice as many as in 2010. CDC’s director, Tom Frieden, MD, MPH, remarked that “E-cigarette use is growing rapidly” but also noted that “there is still a lot we don’t know about these products….”

In “No Sisyphean Task: How the FDA can Regulate Electronic Cigarettes,” Professor Paradise investigates the rise of the e-cigarette phenomenon in the wake of the recently enacted Family Smoking Prevention and Tobacco Control Act of 2009 (TCA), the tumultuous history of attempts at tobacco regulation— through Congress, the FDA and the courts— and suggests a feasible approach to strengthening regulation of e-cigarettes under the existing statutory framework. These measures would facilitate oversight and the compilation of a safety profile for e-cigarettes; such a profile is conspicuously absent at present.

In the paper, Professor Paradise explains that because e-cigarettes contain nicotine, and are “derived from tobacco,” they have been found to fall under the designation of “tobacco products” under the TCA. Any product designated a Tobacco Product may not be considered a drug or medical device for FDA oversight purposes. Although e-cigarettes have been found to be a tobacco product, they are neither “cigarettes” nor “smokeless tobacco” under the statutory definitions.  This leaves their regulation unclear as neither drug-devices absent blatant health claims (which would subject them to rigorous preapproval clinical trials) nor cigarettes (subjecting them to flavor additive bans, advertising restrictions, and graphic warnings).  These perceived statutory gaps have thus far allowed the manufacturers, marketers and distributors of e-cigarettes  to sell their product to the public, largely unregulated and unsupervised.

Professor Paradise notes, “E-cigarettes are one of those products for which the technology has seemingly outpaced the law.  In fact, most of the core provisions of the TCA aimed at restricting youth access to smoking apply only to cigarettes and smokeless tobacco.  But there is sufficient foundation under the TCA for oversight of e-cigarettes, and that oversight can be used to inform consumers of the potential risks to health as well as any benefits.” She continued, “Although there seems to be a great many people who have benefitted from e-cigarettes to quit or drastically reduce their smoking, there is currently a dearth scientific testing, comparative data, manufacturing and quality controls, limits on nicotine levels, product standards, or labeling requirements.  This results in vials of the addictive drug nicotine being distributed for public consumption unchecked.  We don’t necessarily know what’s in e-cigarettes, we don’t know how much, nor do we know what e-cigarettes will ultimately do, health wise, to those who use them or those who are exposed to them second hand.”

As an example of potential for oversight of e-cigarettes under the existing statutory framework, Professor Paradise points out that the statute provides for heightened requirements for what are known as “modified risk tobacco products,” defined as “any tobacco product that is sold or distributed for use to reduce the harm or the risk of tobacco-related disease associated with commercially marketed tobacco products.”  The FDA has clarified the definition to say that what constitutes a “modified risk tobacco product” may be found through a product’s label, and it’s advertising—either explicit or implicit— and through any type of media.  Products which meet this definition are subject to satisfying the scientific data and comparative study requirements set out by the FDA.

In addition, Professor Paradise notes that “products which make ‘therapeutic claims,’ such as signaling that a product is intended for use as an aid in smoking cessation, reduction, or as a healthy alternative to smoking, will trigger the drug or medical device provisions under the Food Drug and Cosmetics Act as a threshold matter—bringing with it, again, the need for scientific data and comparative studies. The intent in ‘Intended use’ may be determined through explicit claims or ‘expressions’ by the original manufacturer or subsequent marketer or affiliates, or, according to the FDA, ‘be shown by the circumstances surrounding the distribution of the article.’”

A good look at the advertising for e-cigarettes and the circumstances surrounding their distribution is compelling, she said.”

Recommendations:

• Scrutinize claims and representations of e-cigarette manufacturers and distributors and identify those that trigger drug-medical device requirements.  These representations can be found on the labeling, packaging, advertising, and all printed promotional materials; television, internet, radio, and other communications; and statements in public documents, including patents and SEC filings.
• Examine the actual consumer use of e-cigarette products to support enforcement based on drug-device requirements because of the widespread intended use of the products for smoking cessation or reduction.
• Utilize the “new tobacco product” and “modified risk tobacco product” provisions contained in the TCA to implement heightened requirements for e-cigarettes.
• Provide clarity on the application of universal tobacco product requirements contained within the TCA and FDA regulations regarding manufacturer registration, disclosure to FDA of ingredients, and manufacturing practice requirements.
• Promulgate e-cigarette regulations and issue guidance documents for standardization, reporting, and labeling, including:

o   Product standards

o   Good manufacturing practices and quality control mechanisms

o   Uniform labeling and listing of ingredients on the label

o   Prominent and uniform display of nicotine levels

• Congressional amendment of the TCA to include e-cigarettes in the flavor additive ban, advertising and marketing restrictions, and other provisions to protect adolescents and youth.
• Proactive assessment by states and localities of the scope of laws covering access to tobacco products and public smoking bans.  Many are drafted in a manner that does not encompass e-cigarettes and “vaping”; states and localities should determine whether they should amend them to include e-cigarettes.

The paper, “No Sisyphean Task: How the FDA can Regulate Electronic Cigarettes,” may be found here on SSRN: http://papers.ssrn.com/sol3/papers.cfm?abstract_id=2118802;

Contact info may be found here.

 

The Seton Hall Law Center for Health & Pharmaceutical Law & Policy advances scholarship and recommendations for policy on the varied and complex issues that emerge within pharmaceutical and health law. Additionally, the Center is a leader in providing compliance training on the wide-ranging state, national and international mandates that apply to the safety, promotion and sale of drugs and devices. Seton Hall University School of Law, New Jersey’s only private law school and a leading law school in the New York metropolitan area, is dedicated to preparing students for the practice of law through excellence in scholarship and teaching with a strong focus on experiential learning. Founded in 1951, Seton Hall Law School is located in Newark and offers both day and evening degree programs. For more information visit law.shu.edu.

 

FDA Warning Letters to Cosmetic Companies Leading to Consumer Fraud Litigation

This past September, the Food and Drug Administration (FDA) issued a Warning Letter against L’Oreal, the world’s largest cosmetics company.  The FDA cited claims gathered online from a subsidiary of L’Oreal, Lancôme, about its expensive Genifique, Absolue, and Renergie anti-aging creams and serums. Claims such as “[U]nique R.A.R.E. oligopeptide helps to re-bundle collagen” and “[B]oosts the activity of genes and stimulates the production of youth proteins” were deemed “intended to affect the structure or any function of the body,” thus rendering the claims to be drug-like under section 201(g)(1)(c) of the FDCA. Lancôme could either submit their cosmetics to the rigorous New Drug Approval process, in which safety and efficacy would be tested, or discontinue making such claims.  Lancôme chose the latter.

Although the FDA possesses the authority to regulate cosmetics companies, traditionally the agency has not enforced provisions of the FDCA against big name cosmetics corporations.  However, Lancôme has not been the only major cosmetics company to recently receive a Warning Letter for making drug-like claims. In October of 2012, the FDA sent a Warning Letter to Avon citing claims from their Anew product line.  The drug-like claims included, “The at-home answer to wrinkle filling injections.  Start rebuilding collagen in just 48 hours;” “[W]rinkles are a result of micro-injuries to the skin, so AVON studied how skin heals… ANEW’s Activinol Technology helps reactivate skin’s repair process to recreate fresh skin & help dramatically reverse visible wrinkles;” and, “In just 3 days, see tighter, firmer, more lifted skin.” As with Lancôme’s products, the FDA concluded that these products “are not generally recognized among qualified experts as safe and effective for the above referenced uses.”

The  ultimate impact of an FDA Warning Letter in terms of litigation remains unclear, but the legal industry has taken notice.  Attorneys at Venable LLP point out in their analysis of the FDA’s Warning Letter to Lancôme, “[F]ederal action has been shown to encourage consumer class action lawsuits.” Attorneys at Shook Hardy & Bacon LLP note, “Plaintiffs will allege that consumers were defrauded into purchasing the product because of illegal marketing claims and trumpet those same FDA warning letters as proof that the marketing claims were deceptive under state consumer fraud statutes.”

Those predictions turned out to be true.  Both Avon and L’Oreal and subsidiary Lancôme have been named defendants in multiple proposed class action suits for defrauding consumers. For cases naming L’Oreal and Lancôme as defendants, see Nino v. L’Oreal USA Inc., Case No. 1:12-cv-12362 (S.D. Fl.), Schwartz v. L’Oreal USA, Inc., Case No. 2:12-cv-5557 (N.D. Cal.), and Kallen v. L’Oreal USA, Inc., Case No. 12-9479 (C.D. Cal.).  For cases naming Avon as defendants, see Trujillo v. Avon Products, Inc., Case No. 12-9084, (C.D. Cal), Quinta v. Avon Products Inc., Case No. CV12-09629 (C.D. Cal.).

Attorneys at Morelli Ratner PC, who took part in filing Nino v. L’Oreal USA, Inc., write on their website: “The complaint alleges that the Defendants have advertised their “anti-aging” creams as having been scientifically tested, making claims and promising results to consumers that the Defendants know to be unfounded. Earlier this month, the Food and Drug Administration sent Lancôme a formal warning letter about the misleading advertising. The complaint alleges that L’Oreal has made millions of dollars by knowlingly  [sic] and willfully misleading consumers.” The complaint addresses that the lawsuit seeks restitution and disgorgement of profits, along with “benefits and other compensation obtained by Defendants from their wrongful conduct.”

All of the complaints for the proposed class actions cite to the Warning Letters issued against the companies.  The class actions against L’Oreal and Lancôme are to be centralized in the New Jersey District Court in the Newark Office with presiding Judge William J. Martini. In re L’Oreal Wrinkle Cream Mktg. & Sales Practices Litig., 2012 U.S. Dist. LEXIS 177694 (J.P.M.L. Dec. 12, 2012). With the potential rise in Warning Letters used in consumer fraud litigation against cosmetics companies, cosmetic companies, as Shook Hardy & Bacon LLP write, can no longer afford “to take a sit-back-and-wait approach.” It would seem that big name cosmetic companies have been put on notice: complying with FDA cosmetics regulations is now necessary for those who wish to maintain good public standing and to avoid costly litigation.

Canaries in a Coal Mine: Patient Complaints (Finally) Lead to Withdrawal of Generic Wellbutrin XL

Recently, the Food and Drug Administration announced that the manufacturer Impax Laboratories has asked the agency to withdraw its approval of a generic version of the antidepressant Wellbutrin XL 300 mg that is manufactured by Impax and marketed by Teva Pharmaceuticals.  A bioequivalence study sponsored by the FDA compared the Impax/Teva 300 mg generic to Wellbutrin XL 300 mg and found that the generic tablets failed to release the medication’s active ingredient into the blood “at the same rate and to the same extent” as the name brand.  While the results of the study only recently became available, the FDA acknowledges that it has been aware of concerns about the Impax/Teva 300 mg generic for over five years.

The Impax/Teva 300 mg generic was approved in 2006 on the basis of a study establishing that Impax’s 150 mg generic was bioequivalent to Wellbutrin XL 150 mg.  The FDA did not require that a bioequivalence study of the 300 mg generic be done, because the 300 mg dose of the drug poses a risk of seizures.  Soon after the Impax/Teva 300 mg generic was approved, the FDA began to receive “reports describing either adverse events or lack of an effect.”  As ABC News reports here, Joe Graedon of the consumer advocacy group the People’s Pharmacy was hearing the same things, and, in 2007, he asked Consumer Lab –according to its website, “the leading provider of independent test results and information to help consumers and healthcare professionals identify the best quality health and nutrition products”–to compare the Impax/Teva generic to its name brand counterpart.

Consumer Lab published an analysis demonstrating that “[i]n the first two hours of a dissolution test, we found [the generic] released 34 percent of the drug, while Wellbutrin released 8 percent” and that “[a]t four hours, the [Impax/]Teva product released nearly half of its ingredients, while original Wellbutrin released 25 percent.”  Consumer Lab’s president explained to ABC that the patent on the extended release technology used in Wellbutrin XL was still in effect when the Impax/Teva generic was approved.  As a result, the generic contained the same medication as the original but used a different (or perhaps no) extended release technology.

The FDA was made aware of Consumer Lab’s results, but declined to act on them.  The agency believed that differences in rate of release were unlikely to be clinically significant because “[t]he antidepressant effect of this drug does not appear for several weeks after initiation of treatment, and the effect is, in large part, related to long-acting metabolites.”  The FDA concluded that “[t]he recurrent nature of [major depressive disorder] offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product.”

As the FDA explains in a Questions and Answers document posted to its website, despite its conclusion that the Impax/Teva generic was clinically equivalent to the name brand, in November 2007 the agency “asked Impax/Teva to conduct a study directly on its 300 mg extended-release product to compare its bioequivalence to Wellbutrin XL 300 mg … [in]patients who had reported lack of efficacy after switching from Wellbutrin XL 300 mg to [the Impax/Teva product].”  That study was terminated in late 2011 because “Impax/Teva was unable to recruit a significant number of affected patients to generate the necessary data.”  It was not until 2010 that the FDA decided to sponsor its own bioequivalence study.  That study, of 24 healthy adult volunteers, was not completed until August of this year, because the agency had to “get funding for the study, design[] the study, obtain[] approval from the Institutional Review Board for Protection of Human Subjects, recruit[] and enroll[] healthy volunteers, conduct[] the study, develop[] an analytical method of analyzing the data, and complete[] its analysis of the study data.”

As a result of its experience with the Impax/Teva 300 mg generic, the FDA reports that it “is revising its guidance to industry for how to conduct premarket bioequivalence studies in generic [Wellbutrin] products.”  It will no longer be possible for a company to extrapolate the results of bioequivalence studies done on 150 mg tablets to 300 mg tablets.

One wonders whether there might be other lessons to be learned from the Impax/Teva 300 mg generic experience.  For one, I wonder if the FDA could have–and, if so, if it should have–acted more quickly.  The agency does seem to have taken patients’ complaints about the Impax/Teva tablets seriously.  At the same time, it took six years to withdraw a generic drug that patients complained about immediately upon its approval.   Delays of this sort have the potential to undermine trust in generics generally.

Another potential lesson to be learned from the Impax/Teva 300 mg generic experience is specific to antidepressants.  As Michelle Hottinger and Bryan A. Liang note in their article Deficiencies of the FDA in Evaluating Generic Formulations: Addressing Narrow Therapeutic Index Drugs, which is forthcoming in the American Journal of Law and Medicine, much about antidepressants’ mechanism of action is still not understood, which “may leave some uncertainty as to [their] pharmacokinetics.”  Even where an antidepressant meets the FDA’s bioequivalence standards, Hottinger and Liang write, “therapeutic equivalence is not guaranteed.”  Given this, the FDA might be well-advised to pay heightened attention to adverse event reports about generic antidepressants.

The Treatment of Neonates in Pending Legislation Permanently Reauthorizing the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act

Last week, the United States Senate took up debate of The Food and Drug Innovation and Safety Act, S 3187.  A similar bill, HR 5651, was voted out of the House Energy and Commerce committee earlier this month. In addition to re-authorizing user fees for drug and devices and newly authorizing user fees for biologics and generic drugs, the bills include provisions reauthorizing and making permanent both the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). As reported here, S 3187 and HR 5651 are expected to pass the House and Senate in the coming weeks and to go to a conference committee in June. Lawmakers hope to present the final version of the legislation to President Obama before the Fourth of July.

The BPCA and the PREA are often described as taking a carrot and stick approach.  The BPCA is the “carrot,” providing a drug’s manufacturer with six additional months of protection from generic competition in return for studying the drug in children.  The PREA is the “stick,” requiring, as I explained here, “that, as a condition of FDA approval of a new drug application or supplemental drug application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration, drugs be studied in children. Applicants must submit a ‘pediatric assessment’ which evaluates the drug’s safety and effectiveness for use in children and ‘supports dosing and administration’ for any pediatric sub-populations for which the drug is found to be safe and effective.  The PREA also requires applicants to request approval of the formulations appropriate for those sub-populations for which the drug is found to be safe and effective.”

While not without their flaws, the BPCA and the PREA have increased our knowledge of the safety and effectiveness of drugs when used in children.  As Daniel Frattarelli of the American Academy of Pediatrics testified before Congress earlier this year, as a “direct result of BPCA and PREA[,]” “we have gone from a situation where about eighty percent of time, the drugs we were using in children did not have FDA-approved pediatric labeling to today where that number is down to about fifty percent.”

In addition to reauthorizing permanently the BPCA and PREA, both S 3187 and HR 5651 make minor changes to the laws, addressing some but not all of the concerns raised in the Institute of Medicine’s February 2012 report, Safe and Effective Medicines for Children: Pediatric Studies Conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. For example, the IOM suggested that “[m]ore timely planning, initiation, and completion of pediatric studies would benefit children[,]” and both bills require that companies submit the pediatric research plans required under PREA earlier in the process than they currently do.  The bills also include provisions designed to, in the words of one of the sponsors of HR 5651, “increase[] transparency on the status of pediatric clinical trials required under PREA” and to provide FDA the necessary enforcement tools to ensure that trials are completed on time.

One problem that the IOM discussed in its report that is only partially addressed in the draft legislation is the need for more studies of drugs in neonates, that is, infants up to four weeks old.  Per the IOM, “[f]rom 1998 through 2010, only 23 of the more than 350 labeling changes resulting from [studies conducted pursuant to the BPCA and the PREA] included information from studies with neonates.”  There were also “five products [that] had been studied in neonates and companies had received exclusivity, but no information from the neonatal studies was added to the labeling.”

The draft legislation incorporates the following provisions relating to neonates:

• Both the House and the Senate bills provide that if the FDA issues a request pursuant to the BPCA and “does not request studies in neonates, such request shall include a statement describing the rationale for not requesting studies in neonates.”

• Both the House and the Senate bills require that the reports that the FDA will be required to make to Congress every five years include a discussion of “the efforts made by the Secretary to increase the number of studies conducted in the neonatal population (including efforts made to encourage the conduct of appropriate studies in neonates by companies with products that have sufficient safety and other information to make the conduct of the studies ethical and safe)[.]“

• The House bill includes a provision that would ensure that the Pediatric Review Committee (PeRC), which is responsible for carrying out the BPCA and PREA, has as a member an agency employee with expertise in neonatology.

• The House bill also includes a provision requiring that the staff of the Office of Pediatric Therapeutics, which is “responsible for coordination and facilitation of all activities of the Food and Drug Administration that may have any effect on a pediatric population or the practice of pediatrics or may in any other way involve pediatric issues, including increasing pediatric access to medical devices[,]” 21 U.S.C. § 393a, include “one or more additional individuals with expertise in neonatology[.]“

Ensuring that individuals with expertise in neonatology serve on the Pediatric Review Committee and staff the Office of Pediatric Therapeutics will not guarantee that studies in neonates are conducted where appropriate.  The IOM concluded in its report that it did not have enough information to know whether additional expertise would have made a difference in the quality of the FDA’s review of studies in neonates.  It also wrote, however, that it “had some concerns about whether sufficient expertise in neonatology and neonatal pharmacology was brought to bear on some requests, for example, those for bacterial conjunctivitis and GERD.”   Common sense suggests that expertise in neonatology is a necessary but not sufficient condition for high quality review; the bill that comes out of conference committee should incorporate the two provisions from the House bill.

As the IOM emphasizes, industry-funded research conducted pursuant to the BPCA and the PREA will never be enough to build an adequate evidence base for drug treatment of neonates, because the BPCA and the PREA only apply to relatively new drugs.  This has a disproportionate effect, because, as the IOM explains, “[m]any drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group.”  The IOM discusses an ongoing study of caffeine citrate, which is used to treat apnea of prematurity, which is following children treated with the drug through the age of twelve.  As the IOM notes, “[t]he study, which was funded by the Canadian Institute for Health Research, illustrates the importance of long-term studies of the benefits and risks of neonatal therapies and the importance of public funding for such studies, particularly for long-marketed drugs.”

Recommended Reading: The FDA on Its Post-2007 Safety Ramp-Up and Barbara Evans on the Ethics of FDA-Mandated Postmarketing Studies

The FDA has released a report — Advances in FDA’s Safety Program for Marketed Drugs — in which the agency declares that, as a result of reforms implemented following the passage of the Food and Drug Administration Amendments Act (FDAAA) in 2007, it “now oversees the safety of both innovator and generic marketed drugs with the same rigor and focus as for premarket drug review.”  The FDA is likely engaging in a bit of hyperbole, given the vast disparity in resources allocated to pre- and postmarket review and its previous representation to Congress that “postmarket surveillance will ultimately require a level of staffing and organizational structure similar to that used for premarket review.”  As Professor Barbara Evans points out in her most recent article, The Ethics of Postmarketing Observational Studies of Drug Safety under Section 505(o)(3) of the Food, Drug, and Cosmetic Act (forthcoming in the American Journal of Law & Medicine), the FDA spends upwards of $500 million a year on pre-market review while Congress authorized expenditures of just $25 million a year for the years 2008 to 2012 to implement FDAAA’s various provisions related to post-market safety.

Still, the FDA does marshal some impressive facts and figures in its report.  Among the changes the FDA highlights, the Office of Surveillance and Epidemiology, which is “primarily responsible for monitoring postmarket drug safety data[,]” grew in size from 123 employees in 2007 to 245 employees today.  New safety positions have also been established within each of the 18 divisions of the Office of New Drugs, to ensure that “postmarket safety issues that arise related to the drugs approved in their division are handled effectively[,]” and within the Office of Generic Drugs’ Division of Clinical Review, to “evaluate[] and track[] reports of potential inferior generic product quality, adverse events, and reports of different therapeutic effect compared to the relevant reference listed drug.”   In addition, the FDA now has “a team of biostatisticians dedicated exclusively to postmarket safety evaluation.”

Since 2008, the FDA has used its new powers under FDAAA to require manufacturers (1) to conduct more than 385 postmarket drug safety studies, (2) to adopt “new safety labeling 65 times … generally for whole classes of drugs,” and (3) to implement 64 risk evaluation and mitigation strategies (REMS).  The agency receives many more adverse event reports today than in the past — the number more than doubled between 2005 and 2010, from 323,384 to 673,259 reports — and it has developed new data mining algorithms to identify patterns that might indicate new or increased drug safety risks.  The FDA has also “carried through on its commitment to communicate early and often about new drug safety issues[,]” issuing 68 Drug Safety Communications (DSCs) in 2011, up from 39 DSCs in 2010.  The FDA notes that “[t]he DSC webpage has now become one of the most visited pages on the FDA’s website, receiving more than 8  million page views in 2011.”

On top of all of the above-described activity, the FDA has been working to develop the  FDAAA-authorized Sentinel System, which will be “a national electronic system for securely accessing health care data [such as insurance claims and clinical records] to monitor the safety of drugs and other FDA-regulated medical products.”  The FDA explains in its report that it has developed a “Mini-Sentinel” pilot program that provides the agency with access to the “electronic health information of more than 125 million patients, provided by 17 data partners nationwide.”  The agency has therefore met the target set in FDAAA that it have access to the information of 100 million patients by July 2012.

In her interesting and important article, Professor Evans addresses a potential intersection between the Sentinel System and the observational studies that FDAAA authorizes FDA to require manufacturers to conduct.  A key concern about these studies is that personal health information that is disclosed to a drug or device company that is unrelated to one of that company’s products “may be subject to no federal regulatory protections whatsoever: not HIPAA, not the Common Rule, and arguably not even FDA’s human subject protections.”  As a result, institutional review boards “understandably may conclude that privacy risks are not minimal and refuse to approve [a HIPAA] waiver” allowing the data to be disclosed.  If this data access problem is not solved, the FDA could be forced to order companies to conduct randomized controlled trials “to answer questions that could have been answered using observational approaches[,]” which “is troubling since, by their nature, postmarketing [randomized controlled trials] of drug safety are ethically dubious affairs that pose special risks for human subjects.”  Based on a careful analysis of the language of FDAAA, Professor Evans concludes that the data access problem is not insolvable, because the FDA can enter into collaborative agreements pursuant to which manufacturers cover the cost of performing studies using the Sentinel System.  She cautions, though, that protecting patient interests will require, in addition to “a strong set of contractual provisions[,]” “an open, transparent public process for deciding the content of those provisions and for ensuring their careful, ongoing enforcement.”

Introducing Xiao Ma (马潇)

This semester, Health Reform Watch will be hosting a series of blog posts on Chinese regulation of pharmaceuticals by Xiao Ma. Xiao is an LL.M. student at Seton Hall Law who has worked in both the medical and legal systems in China. Xiao graduated from SiChuan University in 2009 with a Medical Science and a Law degree.

Xiao has served as Associate Counsel at Si Chuan Yuanda Shuyang Pharmaceutical Co. He was an Intern Official at Chengdu Wuhou District Center for Disease Control and Prevention, and an Intern Physician at Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital. He brings a unique set of skills and perspectives on ongoing legal developments in clinical trials, drug research and development, and international trade. Having taught Xiao in my seminar on Health Information, Privacy, and Innovation, I’m very glad he’ll be sharing his perspectives on Health Reform Watch.

FDA Drafts Guidance on Mobile Medical Apps

In an effort to keep up with advancing technology, the Food and Drug Administration (FDA) has proposed new regulations to monitor medical smartphone applications (apps). The draft proposal states that any mobile app that is intended for use in performing a medical device function meets the definition of a medical device under the Federal Food, Drug, and Cosmetic Act. Specifically, these mobile medical apps must be either used as an accessory to a regulated medical device, or transform a mobile platform into a regulated medical device.

To further clarify what apps will be regulated, the document notes that a mobile app is a device “when the intended use of a mobile app is for the diagnosis of disease or other conditions, or the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or any function of the body of man.” The guidance document explains how the intended use of mobile apps can be shown by labeling claims, advertising materials, or oral or written statements by manufacturers or their representatives.

The goal of the regulations is to protect patient safety, though to date there have been no adverse events reported to the FDA. The proposal seems to be forward looking in creating a framework for mobile app manufacturers. According to the Associated Press, there are already more than 17,000 medical applications currently available.

Physicians can use mobile phones to calculate prescription dosages, review disease treatment guidelines, and explain diagnoses and procedures to patients. The FDA expects that by 2015, 500 million smartphone users will rely on health care apps.

Two medical apps have already received FDA approval for use by physicians. The first is a prenatal care app called AirStrip OB. Cleared in 2009, the app allows obstetricians to use their phones to remotely access real-time data for mothers and babies. The second app, approved earlier this year, is Mobile MIM. This app allows hospitals and doctors offices to send images to physicians’ mobile devices. The FDA noted that the software should not be used to replace radiology workstations as the primary way to view medical images, but is useful when a physician has limited access.

Opinions from within the industry vary on the new guidelines. Some feel that the regulation is both necessary and welcome. By regulating the medical app industry, the FDA is offering market players clear guidelines for continued development. Others argue that the regulations may be too far reaching. For example, medical apps to calculate prescription dosages for patients are not new and are based on accepted formulas. Smartphone apps that achieve the same goal increase efficiency and do not put patients at risk, and therefore do not merit differential treatment.

The proposed regulations raise two main concerns for patients and physicians. The first is a privacy concern, similar to the drawbacks considered for other forms of Electronic Health Records. Transferring data between hospital systems and physician smartphones will increase confidentiality and security concerns. Once patient data is accessed on a smartphone, privacy may be easily breached should the phone be used by another person, lost or stolen. The second concern is that these proposed rules could increase the purchase price for medical apps. App developers will likely have increased costs for filing applications and seeking legal counsel, and those costs will be passed to end users.

The draft proposal is currently in an open comment period, and the FDA will amend the regulations after the comment period closes.

The Ban on Off-Label Promotion after Sorrell v. IMS Health

In the wake of Sorrell v. IMS Health, in which the Supreme Court invalidated on First Amendment grounds a Vermont law barring drug companies from using physician-specific prescribing data to craft physician-specific sales pitches, lawyers on both sides of the case have weighed in on the opinion’s implications for the Food & Drug Administration’s ban on off-label promotion.  In doing so, they build upon an exchange between the dissent and the majority in Sorrell.  Writing in dissent, Justice Breyer argued that the fact that the Vermont ban is “speaker-based” (i.e., that it only applies to drug companies) should not mean that it is subject to heightened scrutiny, because in the regulatory context it is not unusual for rules to apply only to regulated entities.  By way of example, Justice Breyer cites the ban on off-label promotion, which limits what manufacturers but not others can say to doctors about unapproved uses.  In response, the majority suggests that the government “might defend” the ban on the ground that it “will prevent false or misleading speech.”  The majority then reiterates that Vermont’s interest in banning data mining “instead turns on nothing more than a difference of opinion” between the state and the companies about the truthful marketing messages to which doctors should be exposed.

In an article for BNA’s Pharmaceutical Law & Industry Report, Lisa Blatt and colleagues (who represented PhRMA, one of the respondents in the case) contend that: “Sorrell builds on prior Supreme Court precedent in establishing a strong foundation to argue that a pharmaceutical company’s truthful, non-misleading information about its products cannot be subjected to content-based and speaker-based restrictions.”  And they predict (correctly) that “[t]he implications of Sorrell for the FDA’s off-label promotion regulatory regime may be tested in litigation, as well as in new regulations, in the months ahead.”  On July 14, 2011, as reported here, the Second Circuit ordered supplemental briefing on the implications of Sorrell for its pending decision in United States v. Caronia, a criminal case in which a sales representative was convicted of conspiring to misbrand the sleep aid Xyrem by promoting it for a number of off-label uses.  On the regulatory front, on July 5, 2011, seven leading pharmaceutical companies filed a citizen petition asking “the Commissioner of Food and Drugs to clarify FDA regulations and policies with respect to manufacturer dissemination of information relating to new uses of marketed drugs and medical devices.”

In a very provocative blog post at The Incidental Economist, Kevin Outterson (who wrote an amicus brief on the side of the petitioner in Sorrell on behalf of, among others, the New England Journal of Medicine) appears to concur with Blatt that “[i]n the wake of Sorrell … we can expect the FDA to relax rules against off-label promotion.”  Professor Outterson characterizes the Supreme Court’s decision as a radical adjustment of the regulatory balance between the FDA and the companies it regulates.  Under our current system, data on the safety and efficacy of drugs is largely generated privately, as a condition of marketing approval.  The ban on off-label promotion is a key component of the system, because it provides manufacturers with a powerful push to continue to study their products after they are initially approved for sale.  Without it (or, even more radically, without any requirement that a manufacturer establish that a drug is efficacious before marketing it), we’ll either need to find other ways to incentivize private sector research or spend more public money on the study of drugs, both easier said than done.  Professor Outterson suggests a third way, that: “the US could simply free ride off the studies produced to satisfy Europe’s Phase III approval process.”  As he points out, however, “[t]hat would work only so long as the EU didn’t make the same changes.”

Perhaps naively, I am hopeful that the ban on off-label promotion will survive the coming wave of legal challenges largely intact.  In addition to its role in incentivizing research (a neutral function which distinguishes it from the data mining law at issue in Sorrell), I think that the ban serves as an important prophylactic against false and misleading product promotion.  (I elaborate on this argument here.)  This preventive role further distinguishes the ban on off-label promotion from the law invalidated in Sorrell.

FDA Taking Baby Steps Towards Regulating Nanotechnology

FDA Taking Baby Steps towards Regulating Nanotechnology

Jordan Paradise, J.D.[1]

[Ed. Note: HRW is pleased to welcome Seton Hall Law Professor Jordan Paradise, who researches and publishes on the legal, ethical, and societal implications of emerging science and technologies such as genetics and nanotechnology. She teaches Food & Drug Law, Administrative Law and Advanced Seminars in the field of Health & Technology. Professor Paradise has an article forthcoming in Volume 56 of St. Louis University Law Journal on the topic of FDA regulation of nanotechnology entitled Reassessing 'Safety' for Nanotechnology Combination Products: What Do 'Biosimilars' Add to Regulatory Challenges for the FDA? Her research and publications, including her forthcoming article, can be found at SSRN -- http://ssrn.com/author=512260]

On June 9, 2011, the Food and Drug Administration (FDA) released draft guidance for industry laying out the agency’s “current thinking on whether FDA-regulated products contain nanomaterials or otherwise involve the application of nanotechnology.”[2] The guidance urges that the document does not establish legally enforceable obligations, but should be viewed only as recommendations for industry.  It “does not establish regulatory definitions” or “address the regulatory status of products,” but does state that future additional guidance may be issued for specific product or classes of products.  Published concurrently with an announcement on policy principles for nanotechnology regulation from the Office of Science and Technology Policy,[3] the draft guidance exemplifies the ongoing battle by federal administrative agencies to quantify, categorize, and regulate nanotechnology.

Framed as two general “Points to Consider” applicable to both new products and any manufacturing changes to FDA-approved and cleared products, the draft guidance provides both a dimensional aspect — “whether an engineered material or end product has at least one dimension in the nanoscale range (approximately 1nm to 100 nm)” — and a behavioral aspect — “whether an engineered material or end product exhibits properties or phenomena, including psychical or chemical properties or biological effects, that are attributable to its dimensions, even if these dimensions fall outside the nanoscale range, up to one micrometer.”  Notably, the second point expands the first dimensional aspect beyond the 100 nm range if the properties exhibited are tied directly to its dimensions up to one micrometer (also called a micron).  (One nanometer is equal to 10^-9 meters (a sheet of paper is about 100,000 nanometers thick)); one micrometer/micron is equal to 10^-6 meters.)

Supporting its two points, the guidance also provides the agency’s “Rationale for Elements within the Points to Consider.”  These largely recite the current state of knowledge of nanoscale properties and phenomena as the underpinnings of the two points.   Specifically, the FDA distinguishes the “deliberate manipulation and control of particle size” of an engineered material or end product from the natural functioning at the nanoscale, identifies the traditional bounds of the nanoscale encompassing 1nm to 100nm as serving merely as “a first dimensional reference point” for industry, highlights the relationship between size and physical and chemical properties as important for questions of safety and efficacy, and explains the broadening of dimensions of “nanoscale” up to one micrometer as linking to the use of agglomerates and aggregates that may coat or functionalize a product.

While couched as a “first step” by the FDA, the draft guidance reflects an incremental and coordinated effort among various FDA Centers, including the Center for Drug Evaluation and Research (CDER), the Center for Biologics Research and Evaluation, the Center for Devices and Radiological Health, and the Center for Food Safety and Nutrition on issues with nanotechnology products.  Nearly four years ago, the FDA’s multi-center Nanotechnology Task Force[4] published a report[5] acknowledging that future advancements in nanotechnology may pose challenges for the existing FDA oversight structure.  Rapidly developing nanoscale[6] applications were identified as integrating mechanical, chemical, electrical, and optical properties in novel and dynamic ways:

The very nature of nanoscale materials — their dynamic quality as the size of nanoscale features change, for example, and their potential for diverse applications — may permit the development of highly integrated combinations of drugs, biological products, and/or devices, having multiple types of uses, such as combined diagnostic and therapeutic intended uses.  As a consequence, the adequacy of the current paradigm for selecting regulatory pathways for “combination products” may need to be assessed to ensure predictable determinations of the most appropriate pathway for such highly integrated combination products.[7]

Infused with public and private investments, nanotechnology-based research and development is now burgeoning.  The cumulative federal investment in nanoscale science and engineering research and development through the National Nanotechnology Initiative (NNI) over the last decade has reached nearly $14 billion;[8] the 2011 NNI budget provides $1.76 billion spread across 15 federal agencies.[9] The unique and far-ranging properties of nanostructures and nanotechnology have particularly facilitated breakthroughs in the pharmaceutical and medical device realms.  The interface of nanotechnology and biotechnology have increased bioavailability, introduced more targeted drug delivery and release, decreased adverse side effects, and enabled cutting-edge cancer treatments.  Current projections place the “nanomedicine” market at $53 billion in 2011.[10]

Following its 2007 report, the FDA has taken a number of internal steps aimed at nanotechnology in addition to the recent guidance.  FDA’s CDER and the Research Office of Pharmaceutical Science issued an internal Manual of Policies and Procedures (MaPP) in May 2010 that instructs drug reviewers to capture “relevant information about nanomaterial-containing drugs” that will be entered into a nanotechnology database.[11] The MaPP states that “in order to develop guidance for industry, CDER needs to organize all the data submitted in support of nanotechnology-based drug applications,”[12] gather all “relevant information about nanomaterial-containing drugs” and enter them into a nanotechnology database maintained by the agency.[13] While imposing no additional requirements on drug applicants, it signals recognition from the FDA of the nascent state of understanding of the complex scientific implications in human drugs.

FDA has also held several public meetings to gather nano-specific information: in October 2006 to aid  the Task Force Report;[14] in September 2008 to assist the agency in implementing recommendations  laid out in the Task Force Report;[15] and in September 2010 to solicit data and information on biocompatibility assessment of diagnostics and devices that include nanomaterials.[16] The FDA also maintains materials for the public on its webpage regarding nanotechnology.[17]

FDA is also partnering with the National Cancer Institute’s Nanotechnology Characterization Laboratory and the National Institute of Standards and Technology to conduct “preclinical efficacy and toxicity testing of nanoparticles” in an effort to identify appropriate standards for molecular-sized cancer drugs.[18] The FDA has identified risk characterization based on physical and chemical properties, in vitro and in vivo models to assist in predictions of human response to exposure, quantification methods, measures of adsorption and transport, and relationships between nanomaterial properties and the human body in terms of uptake via the skin, lungs, and gastrointestinal tract as specific areas of interest.[19]

Although moving slowly, the FDA is moving forward on issues of nanotechnology.  Stay tuned…

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[1] Prof. Paradise has an article forthcoming in Volume 56 of St. Louis University Law Journal on the topic of FDA regulation of nanotechnology entitled Reassessing ‘Safety’ for Nanotechnology Combination Products: What Do ‘Biosimilars’ Add to Regulatory Challenges for the FDA? Her research and publications, including her forthcoming article, can be found at SSRN — http://ssrn.com/author=512260

[2] FDA Draft Guidance for Industry, Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology, June 9, 2011, available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm For more information, see also FDA Draft Guidance Questions and Answers, June 9, 2011, available at http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm258391.htm; Jeffrey Ventura, FDA Press Release, FDA takes ‘first step’ toward greater regulatory certainty around nanotechnology, June 9, 2011, available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258377.htm

[3] Office of Science and Technology Policy, Office of Management and Budget, and the United States Trade Representative, Policy Principles for the U.S. Decision-making Concerning Regulation and Oversight of Applications of Nanotechnology and Nanomaterials, June 9, 2011, available at http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/nanotechnology-regulation-and-oversight-principles.pdf

[4] Press Release, Food and Drug Administration, FDA Forms Internal Nanotechnology Task Force (Aug. 9, 2006), available at http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4241B1-02-33-FDA-Nano%20FDA%20News%20release.pdf.

[5] Food and Drug Administration Nanotechnology Task Force, Nanotechnology: A Report of the U.S. Food and Drug Administration Nanotechnology Task Force (2007), p. 20-21, available at http://www.fda.gov/nanotechnology/taskforce/report2007.pdf.

[6] The nanoscale is traditionally measured as under 100nm (or 10^-9m, or one billionth of a meter).   The National Nanotechnology Initiative (NNI) defines “nanotechnology” as involving three inter-related (and inseparable) aspects: “1) [r]esearch and technology development at the atomic, molecular or macromolecular levels, in the length scale of approximately 1-100 nanometer range; 2) creating and using structures, devices and systems that have novel properties and functions because of their small and/ or intermediate size; and 3) ability to control or manipulate at the atomic scale.”  Environmental Protection Agency, Nanotechnology: An EPA Research Perspective (June 2007), http://nepis.epa.gov/Adobe/PDF/P1003H7X.PDF

[7] Id.

[8] Office of Science and Technology Policy, NNI Strategic Plan 2010; Request for Information, 75 Fed. Reg. 38,850-53, 38,850 (2010).

[9] National Nanotechnology Initiative, About the NNI — Funding, http://www.nano.gov/initiatives

[10] Raj Bawa & Summer Johnson, The Ethical Dimensions of Nanomedicine, 91 Med. Clinics N. Am. 881-87, 882 (2007), citing Nanotechnology in Healthcare (Cleveland: Freedonia Group 2007).

[11] Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, MaPP 5015.9 Reporting Format for Nanotechnology-Related Information in CMC Review (effective date June 3, 2010), available at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM214304.pdf.

[12] Id. at 2.

[13] Id.

[14] Planning of Public Meeting, Regulated Products Containing Nanotechnology Materials, 71 Fed. Reg. 155, 46,232-33 (Aug. 11, 2006).

[15] Public Meeting, Consideration of FDA-Regulated Products That May Contain Nanoscale Materials, 73 Fed. Reg. 153, 46,022-24 (Aug. 7, 2008).

[16] Public Workshop on Medical Devices and Nanotechnology: Manufacturing, Characterization, and Biocompatibility Considerations, 75 Fed. Reg. 162 (Aug. 23, 2010).

[17] Food and Drug Administration, Nanotechnology, http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/default.htm

[18] See National Cancer Institute, Nanotechnology Characterization Lab, http://ncl.cancer.gov/

[19] Food and Drug Administration, 2010 FDA Research Project Categories, http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm196697.htm

Functional Foods: What Happens When Advertising Misleads Consumers?

An article recently published in the New York Times focuses on the complexities of modern-day food labeling. It seems that almost every product in the grocery store touts a label boasting of some health benefits, from supporting heart health to lowering cholesterol levels. These items are referred to as functional foods or nutraceuticals, and they are foods that claim to provide health benefits beyond the traditional nutrients they contain. Functional foods are one of the fastest growing areas in the food industry.

While companies cannot claim that functional foods actually prevent or cure diseases, they can market foods with having health-promoting or wellness-maintaining properties. The article explains how economists refer to items like functional foods as credence goods. For these foods, most consumers are unable to assess the utility of health claims and therefore rely on advertisements to be true. Misleading marketing and advertising can leave consumers confused about what they are buying and about just how helpful some products are in maintaining overall health.

The Federal Trade Commission (FTC) oversees food advertising and has filed recent complaints of deceptive marketing against Kellogg and Dannon. Frosted Mini-Wheats can no longer claim that they are clinically shown to improve children’s attentiveness by nearly 20 percent, and boxes of Rice Krispies are no longer emblazoned with a claim that they support children’s immunity. Dannon was forced to remove claims that its Activia yogurt improves intestinal transit time, as the FTC found no scientific proof for such a claim.

The Food and Drug Administration (FDA), which oversees food labeling, has also noted the problems with false or misleading claims on functional foods. Commissioner Margaret Hamburg wrote an open letter to the industry urging them to examine product labels to avoid violating established labeling standards. But the issue seems too complicated for an open letter to solve. As the FDA’s deputy commissioner for foods Michael Taylor wrote last year,

“Going after [misleading marketers] one-by-one with the legal and resource restraints we work under is a little like playing Whac-a-Mole, with one hand tied behind your back.”

The Deputy Commissioner appears to be right, and not all food companies are willing to give up false or misleading claims or labeling without a fight. In 2010, the FDA found that the makers of POM Wonderful pomegranate juice had violated the Federal Food, Drug, and Cosmetic Act by making therapeutic claims that “establish that the product is a drug because it is intended for use in the cure, mitigation, treatment, or prevention of disease.” When POM did not retract its claims, the FTC filed a complaint against the maker for deceptive advertising based on unsubstantiated scientific claims. POM was initially defiant (calling the FTC complaint unwarranted), but eventually settled and changed their advertising.

The company did, however, file a federal lawsuit against the FTC for acting outside its authority and violating the right to free commercial speech. As NYU Professor Marion Nestle pointed out in an article, POM’s suit is being brought “not because they are claiming they have science on their side, but because they think their health claims, believable or not, are protected by the First Amendment.”

There are other ways to confront misleading ‘healthy’ claims before they are printed on products and sold to consumers. The article notes the approach of the European Food Safety Authority, an independent panel of experts to whom food makers submit applications of scientific evidence backing their desired claims. The panel reviews each case and issues an opinion on the evidence, and will create a list of approved health claims for companies to use in the future.

The FDA’s approach is focused on the other end of the product line, and encourages consumers to learn to read nutrition labels and make wise purchasing decisions. This includes updating the Nutrition Facts Panel printed on the back of food packages, adding calorie counts to restaurant menus, and pushing the Let’s Move initiative to combat childhood obesity. A smarter consumer is an admirable and essential goal, but with the amount of money put into advertising on a global scale, the FDA must issue stricter guidelines for food companies. Hopefully, the outcome of the POM lawsuit will help empower the FDA to do just that.

…After the Horse Has Already Left the Barn: FDA Continues to Postpone Conflicts Review Until Studies Are Complete

On Tuesday, the Food and Drug Administration released a draft guidance on financial disclosure by clinical investigators, targeted at the investigators themselves, at drug and device companies and others who sponsor clinical trials, and at the agency staff who review the disclosures.  In the draft guidance, which updates an earlier one, the FDA briefly reviews the financial disclosure regulations, which have not changed, and then provides heavily revised and expanded answers to frequently asked questions.

The draft guidance is a response to a January 2009 report by the Department of Health and Human Services’ Office of the Inspector General (OIG) which recommended that the FDA (1) “ensure that sponsors submit complete financial information for all clinical investigators[,]” (2) “ensure that reviewers consistently review financial information and take action in response to disclosed financial interests[,]” and (3) “require that sponsors submit financial information for clinical investigators as part of the pretrial application process.”  The draft guidance addresses the first two recommendations but, unfortunately, FDA has still not taken action on the third.

The draft guidance responds to the OIG’s first recommendation in a number of ways, including in its response to the question “What does the FDA mean by due diligence?” which has grown from three sentences in the earlier guidance to four paragraphs in this one.  The draft guidance sets forth in detail what those applying for marketing approval must do to obtain financial information from every investigator who worked on every clinical trial submitted in support of the application.  For example, when an applicant is missing an investigator’s financial information because it cannot find him or her, it must try to locate the investigator by making at least two phone calls, sending at least two certified letters, and requesting new contact information from the investigator’s previous institutions.  From there, the search might progress to contacting professional associations and conducting internet searches.  The draft guidance’s recommendations, if followed, should drastically reduce the number of applications that rely on the due diligence exemption to excuse missing financial information.

With regard to the OIG’s second recommendation, the draft guidance adds and answers the following question: “What will FDA’s reviewers consider when evaluating the financial disclosure information?”  In its answer, the FDA explains that “outcome payments (that is, payment that is dependent on the outcome of the study) elicit the highest concern, followed by proprietary interests (such as patents, royalties, etc.); but these are rarely seen.”  More typical are equity interests and significant payments of other sorts, in which case the agency takes into consideration the amount and nature of the payment as well as other factors such as the total number of investigators and subjects in the study, whether and how the study is blinded, controlled, and randomized, and whether the study endpoints were objective or subjective.  While the agency elsewhere rejects the idea that the financial disclosure requirements be waived for “efficacy studies that include large numbers of investigators and multiple sites[,]” it would appear to agree that the likelihood of a single investigator biasing such a study’s results is low.

The FDA has not taken action on the OIG’s third recommendation, that investigators’ financial information be submitted to the agency as part of the investigational new drug applications (IND) and investigational device exemptions (IDE) applications that are filed before studies in humans are initiated.  The draft guidance does exhort sponsors to consult the FDA early and often to minimize potential bias.  The draft guidance explains that “[b]y collecting the information prior to the study start, the sponsor will be aware of any potential problems, can consult with the agency early on, and can take steps to minimize any possibility for bias.”

When sponsors do choose “to consult the FDA early”, the draft guidance provides that agency staff should “focus on the protection of research subjects and the minimization of bias from all sources.”  The suggestion that agency staff play a role in protecting research subjects is interesting.  It is not mentioned in the regulations or anywhere else in the draft guidance and it is only possible where sponsors voluntarily seek the FDA’s input.  By the time an applicant is required to turn over investigators’ financial information, as part of an application for marketing approval, the horse has left the barn.  The clinical trials are complete and it is too late to protect participant’s rights and interests.  Bias, by contrast, can sometimes be addressed retroactively.  The draft guidance notes that the FDA’s “[r]eviewers might … compare results from more than one investigator, re-analyze the data excluding the investigator’s results, analyz[e] the data in multiple ways, and/or determin[e] if results can be replicated over multiple studies.”  Even bias is better dealt with prospectively, though, not least because agency staff are aware of and sensitive to the expense associated with conducting clinical trials and are likely to be highly reluctant to disregard a trial’s results.

Because prospective review of investigators’ financial information would allow the FDA to “focus on the protection of research subjects and the minimization of bias” across the universe of studies, not just those in which the sponsor chooses “to consult the FDA early,” the financial disclosure regulations should be revised per the OIG’s recommendations to require that financial information be submitted as part of the pretrial application process.

Comments on the draft guidance are due by July 25, 2011.

Ag-Gag: A Black-Boxed Food Supply

I recently discussed the OIRA’s contribution to some terrible incidents in egg safety. Denis Sterns has written a challenging article on the bigger picture, explaining “Why Food in the United States May Never be Safe:”

This article . . . interrogates the idea of food safety by opening the question of whether a rational economic actor in a free market for food can reasonably be expected to invest in improving the safety of the food products he makes and sells. It is precisely the lack of (cr)edibility in the market – i.e., the absence of reliable quality signals, the lack of traceability, the high degree of anonymity, and the destruction of trust – that creates the structural impediments and powerful disincentive for improving the quality and safety of food. . . . Recall the huge public uproar, and swift policy changes, that followed the release of video of “downer” cattle being abused at a California meat plant. To obtain the video, the Humane Society had to sneak someone inside the plant to secretly record the offending conduct.

The secrecy of some food suppliers is very troubling. Stearns proposes constant surveillance of their actions: “With video cameras always in place . . . one can only expect that most of the shocking conditions that are found after the fact of an outbreak would be less likely to occur in the first place.” Stearns also criticizes FDA’s “wholly voluntary and largely ineffective” traceback regulations, which would make it easier to find the source of contaminated food. (Maybe the FDA is too busy chasing down raw milk co-ops.)

Unfortunately, Big Meat appears all too eager to hide their actions from both concerned citizens and animal rights activists. Consider the rash of legislation designed to deter actions like the Humane Society’s:

The animal advocacy group Mercy for Animals sent an undercover investigator to E6 Cattle Company in Texas, where he filmed calf abuse over a two-week period. To prevent such whistleblowing, several states have passed so-called “Ag-gag” laws that would make it illegal to clandestinely film inside slaughterhouses, sparking what animal rights activists fear will be a nationwide trend. . . . “They’re trying to criminalize someone being an eyewitness to a crime,” Jeff Kerr, [PETA]’s general counsel, said.

One of Chinese dissident Ai WeiWei’s biggest “offenses” against the Chinese government was trying to publicize the names of the children killed when shoddy schools collapsed after an earthquake. Criminalization of exposes of contamination and animal abuse in America’s heartland could be one more step toward the convergence of Chinese and US politico-economic structures.

X-Posted: Concurring Opinions.

The FDA’s Move to Combat Prescription Drug Abuse: Educating Patients and Physicians

The Food and Drug Administration (FDA) announced a new risk-reduction program this month to help curb abuse of prescription painkillers. The program, called the Risk Evaluation and Mitigation Strategy (REMS), is targeted at manufacturers of long-acting and extended-release opioids. It requires that these manufacturers develop new medication guides for patients and educational materials for prescribing physicians. Each company has 120 days to submit materials to the FDA for review.

According to the FDA, the focus of the REMS plan is to educate doctors about proper pain management and patient selection, and to improve patient awareness about how to use these drugs safely. The medication guides for patients should include consumer friendly language that explains safe use and disposal. The drugs targeted by the REMS plan include oxycodone, methadone and morphine.

As the plan stands now, physicians are not required to review the educational materials. To help generate interest, the FDA plans to offer continuing education credits for physicians who receive the education. The ultimate goal is to make this training mandatory through congressional approval that would link the training to licensing for physicians who prescribe controlled substances.

The FDA hopes that REMS education will cut down the misuse of prescription painkillers without restricting access. There are an estimated one million emergency room visits a year as a result of prescription drug abuse, and the FDA estimates that more than 33 million Americans misused opioids during 2007. That same year, deaths from drug overdose were second only to motor vehicle crashes among leading causes of unintentional injury death in the U.S.

Encouraging safe disposal of medications is key. Over half of all nonmedical painkiller users get their pills “from a friend or relative for free.” Doctors have also been found to prescribe more doses of painkillers than patients actually use, and patients don’t always dispose of unused medications properly.

What can you do to help combat prescription drug abuse? The Drug Enforcement Administration is sponsoring the second National Prescription Drug Take-Back Day this Saturday. You can find a collection site near you by clicking here. Last year, more than 121 tons of prescription drugs were collected at nearly 4,100 locations. It’s a good reason to extend that spring cleaning to your medicine cabinet!

FDA Recalls and Selective Analysis

Researchers at the National Research Center for Women & Families and the Cleveland Clinic published a controversial report in the Archives of Internal Medicine in February.   The research team, led by Diana Zuckerman, analyzed high-risk medical device recalls from 2005 to 2009.  The report concludes that “reform of the [510(k)] regulatory process is needed to ensure the safety of medical devices.”

510(k) Process: Cause for Concern?

Zuckerman’s team determined that of the 113 recalls from 2005 through 2009, eighty (71%) medical devices — or the vast majority of those recalled — passed through the 510(k) process.  Twenty-one (19%) medical devices had passed through the more rigorous premarket approval process and eight (7%) were exempted from review.

Consumer advocates and the study authors argue that the disproportionate number of medical devices recalled after being reviewed under the 510(k) process demonstrates the need to reform the review process.   But do these statistics demonstrate a flaw in the 510(k) process?

Advanced Medical Technology Association (AdvaMed), an industry lobbying group says no.  It calls the study flawed.  Why?  The vast majority of devices (~90%) are cleared through the 510(k) process.   Therefore, it would be expected that more recalls are for 510(k) cleared devices.  A 2010 AdvaMed report, analyzed the recall rates for the PMA approval and 510(k) clearance processes.  The report demonstrated that the overall recall rate was very low for both — less than 1% and that PMA approved devices were more likely to be recalled.

In fact, during the Zuckerman study period, 19,000 devices were cleared through the 510(k) process, making the overall recall rate for 510(k) cleared devices approximately 0.4%.

When NPR asked Zuckerman to compare her study with the AdvaMed study, she agreed that most devices had not been recalled. “But I’m taking the public health perspective. How many people have been harmed by these products? We know that 112.6 million devices have been recalled in the last five years. That’s a lot of products. We know thousands of people have died. And those are deaths that did not have to happen.”

But what about all the lives saved?  Mark Adelman, MD, of the NYU Langone Medical Center in New York City, counters, “While some lives have been lost by expedited approval, many lives have been saved by getting better devices to market quickly. How many lives have been saved by the 510(k) fast track?”  Public health advocates, like Zuckerman, would offer a more complete analysis if they took account of both the risks and the benefits in their evaluation of the FDA approval processes.

Misclassification and Proper Review Path?

What if the processes are adequate, but some devices get thrown in the wrong review bucket?  Physicians Rita Redberg and Sanket Dhruva of USC San Francisco wrote in the invited commentary that “Zuckerman and colleagues demonstrate the dangers to patient safety posed by these innumerable device misclassifications.”  The Zuckerman report focused on “high-risk” recalls, or “those that could cause serious health problems or death.”

The report states that “[o]f the recalled devices cleared for market through the 510(k) process, 12% were marketed for risky or life sustaining Class III indications, which are required by law to undergo a full PMA regulatory review.”  In an email to MedPage Today, study author Steven Nissen, MD, of the Cleveland Clinic, elaborated:

There should be NO recalls for ‘serious injuries or death’ amongst 510(k) approved devices. The FDA is supposed to require a PMA for Class III devices, those used to sustain life or preserve health. If a PMA is required for devices used to support or sustain life, why were so many of the devices recalled for ‘serious injury or death’ originally approved using 510(k)?

Unfortunately, Nissen conflates risk of injury with the life-sustaining capacity of the device.  Although the failure of a Class III device will more likely result in serious injury or death, medical devices in all three Classes may cause serious injury or death if improperly designed or manufactured.  But maybe there is something to this.

Strengthening 510(k) process

What about the steps the FDA has already taken to improve the process?  In late 2009, the FDA began a review of its 510(k) process.  Last August, 55 recommendations were issued by two working groups.  In January, the FDA announced the adoption of 25 changes to the 410(k) process to take place this year.

According to Dr. Jerry Avorn, a professor of medicine at Harvard Medical School in Boston, “The current FDA leadership has been trying to improve the carefulness of device review, and that is very good for patients. But those attempts have been met by self-serving complaints from the device industry that better review and surveillance will somehow stifle innovation, which is not the case.”  Avorn suggests that both industry innovation and consumer safety can be achieved.

Meanwhile, the Institute of Medicine is working on a comprehensive report, commissioned by the FDA, on what’s wrong with medical device regulation. That’s due later this year.

Left to Our Own Devices?

Lucia Burgos sued Satiety, Inc. after an experimental stomach stapling device perforated her esophagus.  Her first complaint was dismissed on preemption grounds, but she was given permission to “replead her claims as state-law parallel claims.”  So called “state-law parallel claims” are state law tort claims where the duty that the defendant manufacturer is alleged to have violated stems from the Food Drug & Cosmetic Act or its implementing regulations.  Such claims are not preempted because they do not impose additional duties on defendants, beyond those imposed by Congress and the Food & Drug Administration.

Ms. Burgos amended her complaint to state two new claims, including a state law negligence cause of action founded on Satiety’s alleged failure to manufacture the device in conformance with the requirements of its investigational device exemption (IDE).  Ms. Burgos believes that it was the device (as opposed to human error) that caused her injury because of an incident report filed by her treatment team, but, because the documentation supporting the FDA’s grant of an IDE is confidential, her complaint does not specify how the device deviated from the IDE.  On April 5, 2011, Judge John Gleeson of the Eastern District of New York held that Ms. Burgos had stated a claim for negligence and that, despite the lack of specifics, her suit could proceed “to a brief and strictly-cabined period of discovery in order to determine the terms of Satiety’s IDE, and to explore whether or not the specific device used in her procedure was manufactured in accordance with the IDE.”

The Burgos case is of interest to civil procedure buffs because of what the BNA Medical Research Law & Policy Report characterized as Judge Gleeson’s “liberal approach” to the pleading of parallel claims, but it is important to the rest of us, too, because of what it tells us about the state of the products liability backstop to FDA’s oversight of medical devices.  In the words of Ms. Burgos’ attorney, there is only a “narrow window” for parallel claims.

The limited recourse that those injured by medical devices have in court makes the FDA’s pre-market clearance and approval processes and its post-market surveillance and recall oversight efforts that much more important.  Testimony given earlier this month by Marcia Crosse, Health Care Director at the Government Accountability Office, before the Senate’s Special Committee on Aging suggests that there is cause for concern.  As Ms. Crosse explained, in January 2009 the GAO issued a report in which it “found that a significant number of high-risk devices-including device types that FDA has identified as implantable; life sustaining; or posing a significant risk to the health, safety, or welfare of a patient-were cleared for the U.S. market through FDA’s less stringent 510(k) review process.”  Section 510(k) of the FD&C Act allows for streamlined review and clearance of devices that are shown to be substantially equivalent to devices already on the market.  Data from clinical trials is typically not required to make this showing.

The FDA agreed with the GAO’s 2009 recommendations.  If the devices at issue did not actually belong in the highest-risk class, Class III, they should be re-classified.  On the other hand, if they did belong in Class III, they should be subject to the more stringent premarket approval process, which typically requires clinical data in support of an agency determination that a device is safe and effective for its intended use.  In her testimony, Ms. Crosse noted that, to date, the FDA has issued a final rule reclassifying one device — a blood test for herpes — from Class III to Class II.  Rules regarding the classification of another five devices are pending.  “There are still 26 types of high-risk devices, including, for example, automated external defibrillators and implantable hip joints, that can enter the market via 510(k).”  Moreover, since January 2009, “FDA cleared at least 67 individual submissions that fall within 12 of these class III device types through the 510(k) process.”

While the GAO has not completed its review of the FDA’s post-market activities, Ms. Crosse testified that their “preliminary findings suggest that shortcomings in FDA’s oversight of the medical device recall process may limit the agency’s ability to ensure that the highest-risk recalls are being implemented in an effective and timely manner. These shortcomings span the entire range of the agency’s oversight activities-from the lack of a broad-based program to systematically assess trends in recalls, to inconsistencies in the way FDA ensures the effective completion of individual recalls.”

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