Venture Capitalists Complain of ‘Regulatory Challenges,’ FDA Responds

Writing in this month’s Fortune, Dan Primack is the latest to raise the alarm about indications that venture capital funding of life sciences startups is on the decline.  The decline in funding is cause for concern because venture capital-funded startups are, in the words of Tracy Lefteroff of PricewaterhouseCoopers, “where all the drugs are coming from[.]“  “[L]arge pharma[,]” Lefteroff explains, has “been extremely ineffective at developing pipeline drugs internally.”

While there are still “plenty of venture dollars … going into the [life sciences] sector,” Primack reports, they are going to mature companies.  Startups, on the other hand, “are having a much tougher go of it, with 17% fewer raising venture capital during the first three quarters of 2011 than during the same period in 2010.”  According to Primack, “a number of veteran VC firms are formally ending their pursuit of pharma startups.”

What explains the increasing reluctance to invest in the life sciences sector?  The venture capitalists blame “regulatory challenges,” primarily “the hostile FDA.”   Primack quotes Kate Mitchell, co-founder and Managing Director of Scale Venture Partners, a venture capital firm which recently announced that it will make no new healthcare investments, as follows: “It just takes a lot longer now to get approval than it used to, or to even know what the [Food & Drug Administration] is thinking.  One of our companies, Prestwick Pharmaceuticals, supposedly was put on a ‘fast track,’ but it still took another three years before receiving FDA approval.  It’s incredibly frustrating and means we need to invest more to keep the companies running.”

The Medical Innovation and Competitiveness (MedIC) Coalition, a group of “life science investors, innovators and entrepreneurs,” has been lobbying hard for the FDA to approve more drugs and devices more quickly, that is, without the careful review of efficacy and safety that it currently undertakes.  Specifically, they have prioritized “[r]ebalancing benefit-risk assessments in the drug and device approval processes to appropriately reflect the value of new therapies to patients in need” and “[e]xpanding the accelerated approval pathway into a progressive approval system for drugs, diagnostics and medical devices.”  MedIC also believes that the FDA’s conflict of interest policy threatens to “hinder[] patient access to new treatments.”  It argues for increased “utilization of non-government outside experts to facilitate and strengthen the FDA review and approval process,” presumably experts who would be barred from serving by the FDA’s current conflicts policy.

Not all of MedIC’s priorities are so extreme.  They have also called for more timely, consistent, and transparent decision-making at FDA, while acknowledging that to achieve these ends the agency must be “well resourced and endowed with state-of-the-art scientific tools, clinical input, processes and procedures.”  With this, even the most ardent consumer advocate can agree, and the FDA has recently acted to improve its decision-making in ways that do not risk sacrificing health and safety.  This is a promising development.  The results of a recent survey of venture capitalists suggests that increasing the predictability and speed of the FDA’s decision-making would have a higher impact on their willingness to invest in the life sciences sector than would “rebalancing” the agency’s weighing of safety and efficacy.

FDA’s ‘Bad Ad’ Program is in Full Effect

Last spring, the Food and Drug Administration (FDA) launched the Truthful Prescription Drug Advertising and Promotion Program (known more accessibly as the “Bad Ad Program“). The goal of the program is to enlist the help of health care professionals, consumers, and industry representatives in noting FDA violations and reporting activities and messages that are false or misleading. Common drug marketing violations include omitting or downplaying risk, overstating effectiveness, promoting off-label uses and making misleading drug comparisons. The program is run by the FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC), which is responsible for “ensuring truthful advertising and promotion of prescription drugs.”

The FDA published a year-end report in May noting that the program has been successful in raising awareness. DDMAC received 328 reports of potentially untruthful or misleading promotions in one year, with the majority of those submitted by health care professionals (188 reports) and consumers (116 reports). The report notes that prior to the Bad Ad program, the FDA received an average of about 104 reports per year.

And the Bad Ad tips are still coming in. Just at the end of last month, DDMAC issued a reprimand letter to Pfizer’s Vice President of US Regulatory Affairs regarding misleading advertising of drugs on the company’s Lipitor website. A complaint to the Bad Ad program observed that the links from the Lipitor site led to pages for the drugs Caduet (for high cholesterol and blood pressure), Norvasc (for high blood pressure), and Chantix (for smoking cessation). But each of those pages failed to note any of the risk information associated with the drugs, which is a violation of the Federal Food, Drug, and Cosmetic Act.

The FDA states that “by omitting the most serious and frequently occurring risks associated with Caduet, Chantix, and Norvasc, the webpage misleadingly suggests that these drugs are safer than have been demonstrated.” The letter ends with a request that Pfizer immediately stop the dissemination of violative promotional materials for the drugs. The company was to have submitted a written response to the complaint by September 14^th that states how they will comply with the request.

While the Bad Ad program may be working to raise awareness among health professionals and consumers, one violation may not be enough to induce compliance from pharmaceutical companies. In fact, DDMAC already chided Pfizer in March of 2009 for omitting risk information for Caduet and Chantix. In that case, Pfizer sponsored links for the drugs on Internet search engines. The sites linked to did not mention any risk information and therefore, presumably,  can be said to have also represented the products in a manner which, as above, suggests that these drugs are safer than have been demonstrated.” The most recent letter states that “DDMAC is concerned that Pfizer is continuing to promote its products in a similarly violative manner.” A citizen’s task force is a good way for the FDA to multiply their eyes and ears to keep tabs on misleading and/or violative advertisement. We’ll see what further successes the next year-end report for the Bad Ad program can show. Or, perhaps, success might also be measured in the absence of violations.

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.

Generic Drugs, Cost-Effectiveness, and Confidence

Smarter prescribing and better medication management are linchpins of current efforts to care for those with chronic medical conditions in a more consistent, coordinated, and, it is hoped, affordable manner.  A study reported in last month’s Health Affairs found that using medication to control patients’ blood sugar levels and lower their blood pressure and cholesterol is not just cost-effective, it can actually save money by reducing “downstream complications and the use of health services that outweigh the cost of the medications themselves.”  Notably, these cost savings can only be achieved if the medications in question are generics.  The authors conclude that “in a health care system strapped for resources, physicians will increasingly use generics, and patients will have to expect that most of their medications will be generic.”

As the authors also note, resistance to generics, on the part of both patients and their doctors, is longstanding and persistent.  Some of this can be chalked up to the intense and wide-ranging marketing campaigns that innovator companies mount on behalf of branded drugs.  Branded medications used to treat chronic conditions are especially heavily marketed, including through the use of free samples.  Numerous studies (here’s a recent one out of Vermont) show that physicians with sample closets in their offices are less likely than those without sample closets to prescribe generics where appropriate.

Interestingly, the Centers for Medicare and Medicaid Services announced earlier this year that Medicaid Part D prescription drug plans “may incur expenses related to distribution of and reporting on generic drug samples, provided to members within a physician’s office setting, under the plan’s administrative cost structure if doing so is consistent with a cost effective drug utilization management program.”  CMS explained that generic samples have the potential to reduce the government’s overall costs and to promote compliance with drug therapies by reducing enrollees’ current and future cost sharing expenses.  (George Van Antwerp argues here that CMS overstates the benefits of generic samples, but only because generic fill rates are rising so fast without them.)

Marketing is not the whole story behind lingering resistance to generics, though.  As the New York Times recently reported, most generic drugs are manufactured in “a shadowy network of facilities in China and India that are rarely visited by government inspectors, who sometimes cannot even find the plants.”  While plants in the United States are inspected at least once every two years, the Food and Drug Administration has historically lacked the resources to provide the same level of oversight to foreign facilities.  An “epoch-making” agreement between the FDA and generic drug manufacturers will, assuming it is approved by Congress, change this.  The manufacturers have agreed to pay $299 million in annual fees to, among other things, fund inspections of foreign plants on the same schedule that applies to domestic plants.  As the Times notes: “[T]he generic drug industry is no longer a motley collection of struggling mom-and-pop companies.  Years of consolidation have created giants like Israel-based Teva Pharmaceuticals that understand that their businesses depend on winning the confidence of patients and regulators alike, and they can afford to pay the fees needed to achieve that confidence.”

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.

Sunscreen Labeling Rules Revamped

Last month, the Food and Drug Administration (FDA) released new regulations for sunscreen manufacturers to update rules from over 30 years ago. The new regulations, which will take effect in 2012, require that sunscreen manufacturers prove certain labeling claims before they can be used on packaging. In an effort to avoid consumer confusion, the FDA is regulating when sunscreens can claim broad-spectrum protection or water resistance and is also setting a sun protection factor (SPF) cap at 50.

According to the new rules, only sunscreens that block both ultraviolet A (UVA) and ultraviolet B (UVB) rays can be labeled to have broad spectrum protection. While UVB rays are the primary cause of sunburn, UVA rays contribute to skin cancer risk and premature aging. Sunscreens that are not broad spectrum or with SPF values less than 15 will be given the following warning label:

Skin Cancer/Skin Aging Alert:  Spending time in the sun increases your risk of skin cancer and early skin aging. This product has been shown only to help prevent sunburn, not skin cancer or early skin aging.

In addition, sunscreens can no longer be labeled as waterproof or sweatproof, and manufacturers cannot use the term “sunblock” on their packaging. The FDA remains concerned with exaggerated claims, as no sunscreen can block the sun entirely, nor are any of them completely waterproof. Instead, sunscreens can be called “water resistant” and must be marked as either 40 or 80 minutes, depending on how long the SPF protection will last. Finally, the FDA is requiring any sunscreens with rates above SPF 50 be labeled as “SPF 50+”, given that data suggest no additional protection above that level.

In issuing these new regulations, the FDA is targeting rising skin cancer rates among Americans. The Centers for Disease Control and Prevention (CDC) reports that skin cancer is the most common form of cancer in the United States with 58,000 new cases diagnosed and around 8,000 deaths per year. The hope is that the new regulations will make it easier for consumers to choose the best sun protection and that this will help decrease the incidence of skin cancer.

As welcome as these new regulations are, they are subject to two major criticisms. The first is that the amount of sunscreen used by manufacturers to determine SPF values is not consistent with actual use by consumers. In testing, two milligrams of lotion are used for every square centimeter of skin. Scientific American reports that most people use only one fifth to one half of that quantity, meaning that their skin is not fully protected at the labeled SPF level. Secondly, the FDA assumes for designation purposes that consumers will always follow the directions on their sunscreen products. In practice, sunscreen users fail to reapply as often as directed (which is at least every two hours during sun exposure).

Even with these limitations, the new system is a marked improvement to the 1978 regulations. Consumers can protect themselves even before the new regulations take effect in 2012– the FDA recommends that individuals use sunscreen with an SPF of at least 15 and a broad spectrum rating to protect from the full range of sunlight. In addition to purchasing the right sunscreen products and following directions, the FDA encourages that people wear proper clothing and limit sun exposure to help protect skin from UV rays.

The Junk Food Marketing Debate: A First Amendment Right or Just Making Sure Kids Aren’t What They Eat?

Remember the Omnibus Appropriations Act of 2009 (H.R. 1105) that President Obama signed on March 11, 2009?   No?  Good, me neither, but my excuse is that I was busy applying to law schools.  If you and I had been paying closer/any (take your pick) attention, we would have seen that the Act included, among other things, a provision calling for the Federal Trade Commission, the Centers for Disease Control and Prevention, the Food and Drug Administration, and the Department of Agriculture to create an Interagency Working Group on Marketed Food to Children (”Working Group”) composed of representatives from each agency.  The Working Group would research and recommend standards for the marketing and advertising of food to children age 17 years and younger.   These recommendations would be presented to Congress down the road.

Well, a couple of years passed, but in April 2011 the Working Group released its 26-page “Preliminary Proposed Nutrition Principles to Guide Industry Self-Regulatory Efforts” for public comment (which you can submit by clicking here before July 14). The Working Group notes that

… in the FTC’s 2008 study on Marketing Food to Children and Adolescents, three food categories — breakfast cereal, restaurant foods, and snack foods — represented approximately 70% of food marketing expenditures directed to children under 12. Similarly, three categories of foods — carbonated beverages, restaurant foods, and non-carbonated beverages — represented 69% of the food marketing expenditures for adolescents ages 12-17 year….  [Overall] [t]he categories most heavily marketed to children and adolescents, ages 2 -17 years are: breakfast cereals; snack foods; candy; dairy products; baked goods; carbonated beverages; fruit juice and non-carbonated beverages; prepared foods and meals; frozen and chilled deserts; and restaurant foods. The Working Group is therefore recommending that the food industry focus its efforts on ensuring that any advertising or marketing of food products within these ten categories meet the nutrition principles set out below. (Emphasis added.)

The Working Group focuses on two nutritional principles “that both improve the nutritional quality of foods marketed to children and can be feasibly implemented by industry with sufficient time to accomplish reformulation,” namely, “Meaningful Contribution to a Healthful Diet” (Principle A)  and “Nutrients with Negative Impact on Health or Weight”  (Principle B).  Principle A ensures that foods marketed to children contain two or more of the following food groups: “fruit, vegetable, whole grain, fat-free or low-fat milk products, fish, extra lean meat or poultry, eggs, nuts and seeds, or beans.”  Principle B ensures that foods marketed to children have limited amounts of saturated fat, trans fat, sodium, and added sugars.  The Working Group makes sure to point out (several times in fact) that its recommendation are based on the 2010 Dietary Guidelines for Americans.

Really, this all sounds quite sensible, if not a little over-protective… but considering, as The Washington Post has reported, that Type 2 diabetes has significantly increased among people age 20 years and younger, what else can this country do to curb obesity and poor eating habits?  Even if we could reduce the cost of nutrient-rich and quality foods so that everyone could afford them, how do we neutralize the marketing of junk food to children?  In a report last month, NPR noted how

[the Working Group] broke from the past by seeking to include 12- to 17-year-olds in its guidelines. Traditionally, limits on marketing focused on the very young. But the government sought to expand them to older children, in part because they are heavy consumers of social media, cell phone messages and online games — the new frontier for ads.

That new frontier of advertising to children through online games — also known as “advergaming” (forgive my use of Wikipedia but Merriam-Webster doesn’t list the word) — includes Asylum 626 and Hotel 626, two advergames sponsored by Doritos.  As NPR reported,

“[w]hat we’re talking about are very complicated and very subtle forms of marketing that aren’t always clear as such,” says Kathryn Montgomery, a professor of communications at American University and an advocate for limiting food ads to teens.

[...]

Montgomery says such ads work subliminally and use friends to influence other friends.

But efforts to restrict ads to teens draw lots of opposition from the food and advertising industries. The industries say the overlap between teen and adult audiences makes the proposed restrictions impractical.

Critics, including the U.S. Chamber of Commerce, have questioned the constitutionality and logic of the Working Group’s nutritional proposals.  The Hill’s Healthwatch has reported that some critics see a First Amendment issue because

“[w]hat they’re doing is trying to simultaneously … suppress speech, while insulating it from judicial review,” said Northwestern law Professor Martin Redish, one of the panelists at a Chamber of Commerce discussion Thursday. “Because if these regulations were truly just advisory, there would be no case or controversy.”

[...]

“Industry’s rights are being violated here,” Redish said, “but there’s something deeper and darker that’s going on: The government is treating us like sheep.”

While constrained to commercial speech, Redish said that attitude has broader implications. People, he said, “can’t be sheep in the commercial realm and then all of a sudden, in the political realm, they’re free-thinking adults who can make basic choices.”

NPR has reported that other critics question the logic behind the proposal and the implicated age range.

Elaine Kolish directs an industry-funded program called the Children’s Food and Beverage Advertising Initiative. For the past five years this initiative sponsored its own voluntary standards that focus only on the 12-and-under set.

“You know, we let kids drive and we let them hold jobs when they’re 16. They can get married in some states, and they can join the military with permission, and they can be held criminally responsible for their actions in a number of situations,” she says. “So I think that the notion that you’d have to have nutrition standards that say you can’t let a kid see an ad for a french fry but you can let them join the military doesn’t really make a lot of sense.”

So where do we go from here?  Is industry self-regulation the answer to making products that better fit on MyPlate?  As I’ve noted in a previous post about McDonald’s Happy Meal toys, sometimes the answer can be stricter parenting (just say “no”).  Yet how can parents instill and maintain healthy eating habits in their kids when advertisements for unhealthy food bombard them through television, social media, and online games?

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

The Disturbing Rise in Drug Shortages: A “Multifactorial” Problem

With the Annual Meeting of the American Society of Clinical Oncology this past week came a wave of news stories about cancer and cancer treatment.  Frank Pasquale highlights a disturbing warning issued by oncologists at the meeting, that “cancer medicines desperately needed by sick children and adults are in short supply, undermining the ability of U.S. doctors to administer treatments.”  Supplies of other medicines are running short, too, including treatments for anaphylactic shock, attention deficit hyperactivity disorder, cardiac arrest, cystic fibrosis, and infertility.

Writing for the AP, Lauran Neergaard reports that “[t]he problem of scarce supplies or even completely unavailable medications isn’t a new one but it’s getting markedly worse.”  According to Lancet Oncology, there were a record 211 drug shortages in 2011, up from 166 in 2009, 149 in 2008, 129 in 2007, and 70 in 2006.  Neergard adds that “another 89 drug shortages have occurred in the first three months of this year[.]”

Most of the medicines that have run short are sterile injectable drugs, which are complex and time-consuming to manufacture.  (The anesthesia drug sodium thiopental which I blogged about here falls into this category.)  And, most, or even all, of the shortfall drugs are no longer subject to protection from a patent or Food & Drug Administration-administered exclusivity period, so the innovator firms that developed them are subject to competition from generic manufacturers.  The resultant lower prices and slimmer profit margins mean that, in the words of leading oncologist Dr. Richard Schilsky, the manufacturers’ return on investment is “pretty low.”

Among the reasons cited for the rise in drug shortages are the inherent challenges of manufacturing sterile injectable drugs, the low return on investment facing generic manufacturers, which has led the number of manufacturers of any given generic drug to dwindle, drug company mergers, which can result in the discontinuation of one of two similar products, the time it takes the FDA to approve applications to make manufacturing changes, for example a change in the source of a drug’s active ingredient, and the failure of the FDA to act expeditiously in investigating manufacturing problems and clearing plants to resume production once the problems have been resolved.

The Preserving Access to Lifesaving Medications Act, introduced in February by Senators Robert Casey and Amy Klobuchar, would require manufacturers to notify FDA “of a discontinuance, interruption, or other adjustment of the manufacture of the drug that would likely result in a shortage of such drug[.]“  Per Lauran Neergard, the FDA “was able to prevent 38 close calls from turning into shortages last year by speeding approval of manufacturing changes or urging competing companies to get ready to meet a shortfall.”  The FDA has even permitted (temporarily) the import of medicines approved outside the United States when necessary to mitigate shortages.

Participants in a Drug Shortages Summit convened late last year by the American Society of Clinical Oncology and others recommended that additional legislative and regulatory reforms be explored, ranging from providing incentives to manufacturers in exchange for a guarantee that they continue producing critical drugs, to charging manufacturers fees to fund expedited FDA review of applications for permission to manufacture generic drugs, to requiring manufacturing redundancies (e.g. that more than one source for a drug’s active ingredient be identified) as a condition of approval.  Interestingly, while some participants in the Drug Shortages Summit argued that products liability exposure could cause companies to withdraw drugs from the market, the manufacturers who attended denied this, calling the decision “multifactorial.”  There is evidence to support the manufacturers’ claim.  As I discussed here, in late 2004, after Chiron Corporation announced that it would not be able to provide flu vaccine for the United States market that year due to manufacturing issues, Congress brought the flu vaccine into the Vaccine Injury Compensation Program fold.  Unfortunately, liability relief did not result in an increase in the number of manufacturers in the flu vaccine market.  Targeted reforms like those that the Summit participants recommend be explored seem more likely to be effective at ensuring a steady, reliable supply of vital medicines.

Controlling the Controllers of Controlled Substances

Despite their name and extensive government regulation, controlled dangerous substances (”CDS”) are far from controlled.  Licensed  health care providers are essential cogs in the prescription drug control machine.  Many faithfully execute their responsibility to prescribe CDS only where necessary and appropriate to relieve patient pain.  But sadly, some professionals are aggravating the situation.  Significant percentages of the professional licensing cases that I prosecuted in my previous position as a deputy attorney general in New Jersey involved abuse of prescribed CDS by patients and licensed professionals.

Some professionals are completely complicit, brazenly selling prescriptions (and their professional integrity) from their offices or cars.

Others aid and abet misuse by writing prescriptions too freely, for varying reasons and to varying degrees of culpability.  Some wear rose-colored glasses and miss tell-tale warning signs or just like to make people happy and have trouble confronting their patients.   Still others lack the training to know what types of questions to ask to identify drug-seeking behavior or how to effectively and safely combine different drugs to treat patients’ particular problems. Patients can be very skilled at keeping their providers in the dark, so some providers simply do not know that they are feeding a habit.   Others rationalize that it is better to keep their patients coming back for treatment than to send them to the streets for illegal drugs.

And, of course, others conscientiously wrestle with how to balance the need to relieve the very real pain they or their patients are experiencing with the reality that they or their patients are developing addictions.  It’s a thorny thicket, for sure.

No matter the reason, the problem of prescription drug abuse is intensifying, and we need to try something new.  This Spring, the Office of National Drug Control Policy (ONDCP) unveiled “Epidemic: Responding to America’s Prescription Drug Abuse Crisis,” which is “a multi-agency plan aimed at reducing the ‘epidemic’ of prescription drug abuse in the U.S. — including the FDA-backed education program that zeros-in on reducing the misuse and misprescribing of opioids.”  This plan has four main components: improving education of patients and health care providers; expanding state-based prescription drug monitoring programs; improving means for proper disposal of unused CDS from homes; and stepping up enforcement to reduce “pill mills” and doctor-shopping.

As part the education part of the plan, the FDA is working to implement a “Risk Evaluation and Mitigation Strategy (REMS)” for extended-release and long-acting opioid products, such as OxyContin and Duragesic (full list of drugs available here).  As FDA’s consumer update regarding this initiative summarizes, “[t]he new REMS plan focuses primarily on: educating doctors about proper pain management, patient selection, and other requirements and improving patient awareness about how to use these drugs safely.”  On May 16, 2011, FDA met with an Industry Working Group to discuss these ideas, including how to assess the effectiveness of the REMS plan.

Although generally I applaud any effort to better educate practitioners about the dangers of CDS, I worry how valuable this plan will be once implemented.  For one, it requires drug companies to prepare the educational materials.    Each has an interest in presenting its drug in the best light so that doctors are not afraid to prescribe it.  Would not government-funded, unbiased academic detailers, expert in pain and addiction medicine, be more effective?

In addition, the REMS plan does not require doctor training.  If we don’t even lead the horse to water, how can we ever quench its thirst?   How can we hope to affect the prescribing practices of health care providers who do not receive critical training?  It seems indisputably reasonable to require training in CDS prescribing before a practitioner is entrusted with the phenomenal responsibility to write prescriptions for CDS.   (According to a November 18, 2010 article by Susan Okie, M.D. in the New England Journal of Medicine, two FDA advisory committees agree with this requirement.)   This is especially crucial in states like New Jersey, where a medical license is plenary, and thus any licensed physician, regardless how little training in pain management s/he has had, may prescribe pain medicine.

Reportedly, other federal agencies are lobbying Congress to require mandatory physician training as a condition to receiving the Drug Enforcement Administration registration number that doctors must have to prescribe controlled substances.  But generally, the federal DEA registration process looks to state law.  If state law permits a physician to prescribe CDS, there normally is not a separate federal requirement.  This policy respects that licensing is among the states’ traditional police powers.  I expect that Congress is well aware that individual state licensing boards would bristle at Washington dictating the rules governing the practice of professions within their borders.

Not surprisingly, then, some states are not waiting for Congress to act.  According to Dr. Okie, the licensing boards in California, Rhode Island, and West Virginia require some degree of pain-management training.  We need to know what their experiences have been.  Is the training making a difference?  Is there any evidence that requiring training is discouraging doctors from prescribing CDS to patients in pain?

Dr. Okie’s article also details a law that is scheduled to go into effect in Washington state in mid-2011 that will require doctors who prescribe opioids to enter their patients’ clinical responses to treatment in a statewide database and to consult with a pain specialist if the prescribed dose exceeds a threshold.  The hope is that physicians who have thus far not changed their prescribing in response to voluntary educational programs and treatment guidelines may respond if their treatment success is being measured.  But some fear there are too few pain specialists to satisfy the demands imposed by this law.  Some practitioners and patients fear this will just drive patients to street drugs like heroin.

Florida, too, which reportedly is the source of eighty-five percent of the nation’s oxycodone and is known as the nation’s “Pill Mill Capital,” is taking bold steps to address prescription drug abuse.  In addition to increasing oversight of clinics, pharmacies, and wholesale distributors of CDS, its new statute signed into law on June 3, 2011 subjects physicians to administrative and criminal penalties for violating prescriptive regulations governing CDS prescribing.  For example, doctors will face a minimum of a six month suspension and $10,000 fine if they overprescribe CDS.  The law also requires certain doctors to register with the State and restricts their ability to prescribe certain controlled substances.  Doctors also must meet more exacting requirements for record keeping, prescription writing, and treatment plans for those receiving CDS.

The Florida law also authorizes the state to create a prescription-drug monitoring database that will help law enforcement track which providers may be indiscriminately prescribing CDS.  Upon request, treating physicians will have access to this data to inform their treatment decisions.  Approximately 34 other states are operating similar databases, although each has its own rules regarding what entities may access the data, what drugs must be reported, etc.

It is beyond the scope of this post to address the policy pros and cons of all of the provisions in Florida’s new law.  With respect to the prescription drug monitoring database, however, I long have thought it would be valuable to provide prescribing providers access to integrated pharmacy records.  I investigated many physicians who had their patients sign agreements promising only to receive CDS from that doctor.   Investigative pharmacy sweeps helped me learn that this doctor was one of many the patients were using to feed their habit.  But doctors in New Jersey have not had any access to this information unless their patients granted it to them.

But that is about to change.  Although it took years to enact, N.J.S.A. 45:1-45 - 1-52 authorizes New Jersey’s prescription monitoring program.  Section 1-46 specifically permits New Jersey physicians to access the program’s data concerning their patients (although physicians are not required to do so).  The same section also permits New Jersey to enter interoperability agreements with other states so that each state may access the other’s data.  The database is not up and running yet, but on April 7, 2011, New Jersey awarded a four-year contract to a company in Ohio to develop the database.

Once this database is operating, it will offer NJ doctors an opportunity to identify which patients are doctor-shopping and tailor their treatment accordingly.  Undoubtedly, there are risks with this system.  Patients may resent that their doctor did not trust them, for example.  In addition, doctors who primarily treat patients in chronic pain could trigger greater scrutiny from regulators because their prescribing of CDS will outpace other providers.  Regulators will need to carefully exercise their investigative powers so as not to discourage physicians from prescribing appropriate CDS.  These risks, however, seem worth the benefit of identifying patients in need of addiction counseling and treatment and reducing diversion.

But we should not rest on assumptions and hopes.  Rather, we should keenly watch what happens in places like California, Rhode Island, West Virginia, Washington, and Florida to evaluate what works and doesn’t.  Professors Diane Hoffmann (see, e.g., here and here [subscription required]) and Anita J. Tarjian (see, e.g., here) at the University of Maryland and Interim Dean Sandra Johnson at Saint Louis University School of Law (see, e.g., here), among others, raise significant concerns that aggressive enforcement of CDS restrictions can discourage physicians from prescribing CDS, which leaves un- and under-treated patients in pain.  This is unacceptable.  We should regulate with an appreciation for the strides achieved by efforts like the Mayday Pain Project to provide better care to patients suffering in pain.  By taking measured steps and being willing to tinker with our enforcement regimes as we learn, we may ensure we do not deprive patients of needed medications or scare ethical, competent pain physicians from serving their patients’ needs.

Perhaps the Federation of State Medical Boards will help lead this effort to learn from these varied efforts at the state and federal level.   According to its 2011 Annual Report, over 40 state boards have adopted the Federation’s Model Policy for the Use of Controlled Substances for the Treatment of Pain.  Clearly, state boards, without ceding their independence, look to the Federation for guidance, akin to how states view the ABA’s Model Rules of Professional Conduct.  Its policy paints in relatively broad strokes and has not been updated in more than seven years.  It would be helpful if the Federation would update its policy to reflect the current state of law and research in this area, including the impact of various reform efforts, to help state boards find balance between reining in indiscriminate CDS prescribing and the need to provide medically appropriate palliative care to patients in need.

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!

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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