- As previously covered on this blog, on January 19, 2017, the U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) published a proposed rule to update its regulations regarding the importation, interstate movement, and environmental release of certain genetically engineered (GE) organisms in response to advances in genetic engineering and the Agency’s understanding of the plant pest and noxious weed risk posed by genetically engineered organisms. These requirements have not been comprehensively revised since they were established in 1987.
- On November 7, 2017, APHIS published a notice in the Federal Register (82 Fed. Reg. 51582) announcing its withdrawal of the January 19th proposed rule. In withdrawing the proposed rule, APHIS cited stakeholder feedback critical of the proposed revisions. As previously covered on our blog this summer, in comments submitted to APHIS, industry stakeholders applauded the Agency’s proposed rule as underscoring the need to promote innovation in biotechnology and for proposing to ease regulation of gene-edited products. But at the same time, industry called out a number of proposed revisions as improperly expanding USDA’s review process in certain respects which could effectively hamstring developers before they can even begin testing products.
- In its November 7th withdrawal of the proposed rule, APHIS stated that it is committed to exploring “a full range of policy alternatives” and that the Agency will “re-engage with stakeholders to determine the most effective, science-based approach for regulating the products of modern biotechnology while protecting plant health.” Now that APHIS has decided to go back to the drawing board, industry has an opportunity to work with APHIS to develop revised requirements to facilitate a regulatory framework that promotes innovation in biotechnology.
New regulations issued on November 7, 2017 by FDA will make it easier for companies to offer certain types of genetic tests directly-to-consumers, without a health-care provider intermediary.
The first regulation finalizes a new medical device classification for “autosomal recessive carrier screening gene mutation detection systems.” This regulation essentially codifies classification already established by FDA in response to a request by 23andMe, and enables other laboratories to offer their DTC tests according to the criteria specified in the classification regulation. These tests may be offered without the need for FDA premarket review.
Similarly, the second regulation finalizes a new medical device classification for DTC “genetic health risk assessment” (GHR) (i.e., predictive) tests. The classification specifies the conditions under which these tests may be marketed, and includes the requirement for a 510(k) premarket notification to FDA. However, in a Federal Register Notice, also issued yesterday, FDA proposes to exempt GHR tests from the 510(k) premarket submission requirement after a lab has successfully obtained FDA clearance of its first GHR assay. Comments to this proposed exemption are being accepted by FDA until January 8.
- As previously reported on this blog, legislation requiring labeling of genetically modified (GM) foods and food ingredients was signed into law on July 29, 2016. This law directs the U.S. Department of Agriculture (USDA) to develop regulations and standards to create mandatory disclosure requirements for bio-engineered foods by July 2018. On June 28, 2017, USDA’s Agricultural Marketing Service (AMS) posted a list of 30 questions to obtain stakeholder input to facilitate the drafting of mandatory disclosure requirements to implement the National Bioengineered Food Disclosure Law. One of those questions is:
- “Will AMS require disclosure for food that contains highly refined products, such as oils or sugars derived from bioengineered crops?”
- USDA has not yet posted the comments it has received, which were due by August 25, 2017; however, several organizations have posted the comments they submitted in response to the questions. Among the organizations supporting disclosure were the Grocery Manufacturers Assn. (GMA), the International Dairy Foods Assn. (IDFA)and the Consumers Union. Noting that excluding highly refined ingredients (HRI) from the scope of the mandatory disclosure standard would result in roughly 80% fewer products being subject to the disclosure requirements under the federal law, GMA wrote, “A clear, simple, and consistent mandatory disclosure standard that includes HRI will assist manufacturers in educating consumers about biotechnology as a safe and beneficial method of plant breeding.”
- In contrast, the Information Technology & Innovation Foundation (ITIF) and The Biotechnology Innovation Organization (BIO) are opposed to mandatory disclosure of HRI. ITIF suggested that some refined products do not contain residual DNA sequences and that “[t]here are not analytical methods that would allow such products to be identified as coming from ‘GM’ plants or animals vs. others.”
- While USDA develops mandatory disclosure requirements for bio-engineered foods, a number of class action laws suit have been filed suggesting that products containing GM ingredients are falsely labeled as natural. For example, last week, the U.S. Supreme Court refused to hear a bid by Conagra Brands Inc. to avoid a class-action lawsuit concerning cooking oil labeled 100% natural that contains GM ingredients (see S. News). And earlier this month, Frito-Lay North America agreed to not make any non-GMO claims on certain products “unless the claim is certified by an independent third-party certification organization”(see Food Navigator).
- We will continue to monitor developments on the National Bioengineered Food Disclosure Standard and report them to you here.
A recent investigation by CNN brought to light the expanding and allegedly inappropriate use of the prescription drug Nuedexta in nursing homes throughout the country. Nuedexta is FDA-approved to treat a rare condition known as pseudobulbar affect (PBA).
What is Pseudobulbar Affect?
Pseudobulbar affect is characterized by sudden and uncontrollable laughing or crying. It is associated with people who have multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALM), known as Lou Gehrig’s disease. Avanir Pharmaceuticals has been aggressively targeting elderly nursing home residents with the drug, the CNN investigation found, although PBA reportedly impacts less than 1 percent of Americans, based on a calculation using the drug maker’s own figures.
What the Investigation Revealed
Nuedexta prescription use in nursing homes is rising at a rapid rate, even though Avanir Pharmaceuticals acknowledges that the drug has not been extensively studied in elderly patients, according to CNN.
CNN found that Avanir Pharmaceutical’s sales force is focused on expanding the drug’s use among elderly patients suffering from dementia and Alzheimer’s disease, coupled with “high-volume prescribing and advocacy efforts by doctors receiving payments from the company.”
Since 2012, more than half of all Nuedexta pills have gone to long-term care facilities, according to data obtained from QuintilesIMS, which tracks pharmaceutical sales. Total sales of Nuedexta reached almost $300 million that year.
In response to requests to be interviewed for the CNN article, Avanir reportedly responded by email with a statement that PBA is often “misunderstood” and that the condition can affect people with dementia and other neurological disorders that are common in nursing home residents.
Nuedexta is approved by the Food and Drug Administration (FDA) to treat anyone with PBA, including those with neurological conditions such as dementia. But geriatric physicians, dementia researchers, and other medical experts reportedly told CNN that PBA is extremely rare in dementia patients.
How Can Nuedexta Impact Nursing Home Residents?
One study of 194 patients with Alzheimer’s disease found that patients taking Nuedexta suffered more than twice as many falls as those patients taking a placebo.
CNN reports that Lon Schneider, director of the University of Southern California’s California Alzheimer’s Disease Center, reviewed information from several hundred reports obtained by CNN through the Freedom of Information Act. Schneider expressed concern about potential interactions between Nuedexta and other medications intended to treat problematic behaviors. These medications may include antipsychotic drugs, antidepressants, and anti-anxiety medication which are often given to nursing home residents to suppress anxiety or aggression that may occur with Alzheimer’s disease and other dementia types.
Why Are Doctors Prescribing Nuedexta to Nursing Home Residents?
According to CNN’s analysis of government data, between 2013 and 2016, Avanir and its parent company, Otsuka, paid almost $14 million to physicians for Nuedexta-related consulting, promotional speaking, and other services. The companies also spent $4.6 million on travel and dining costs. CNN found that in 2015 nearly half the Nuedexta claims filed with Medicare came from doctors who had received money or other perks.
According to the investigation, state regulators have found that doctors may inappropriately diagnose nursing home residents with PBA to justify the use of Nuedexta to treat confusion, agitation, and unruly behavior. Further, doctors may inappropriately diagnose nursing home residents with PBA to justify the use of Nuedexta to treat confusion, agitation, and unruly behavior. A diagnosis of PBA may be used because “off-label” prescriptions written by doctors using Nuedexta to treat patients who have not been diagnosed with PBA would typically not be covered by Medicare.
What Adverse Events Have Been Reported With Nuedexta Use By Nursing Home Patients?
Soon after Nuedexta came on the market, doctors, nurses, and nursing home patients’ family members began filing reports including rashes, dizziness, and falls as well as comas and death. CNN found that Nuedexta was listed as a “suspect” medication in nearly 1,000 adverse event reports received by the FDA. These reports disclosed side effects, drug interactions, and other issues. According to CNN, the FDA declined to comment on adverse events or the approval process for Nuedexta.
While the concept of “fake news” continues to trigger Twitter followers and grab headlines, the trade in counterfeit drugs is a worldwide problem of significant scale. This article discusses the problem and talks about some things trademark owners are doing to address the public safety issues posed by fake drugs.
Trademark counterfeiting? Most think of fake Rolex watches sold on city street corners or faux designer purses sold in suburban kitchens. While knock-off luxury goods may seem harmless, the economic harm inflicted on legitimate businesses—and the workers they employ—is enormous. The Federal Bureau of Investigation estimates that the dollar value of counterfeit goods sold in the U.S. at $200-250 billion annually. Many of North Carolina’s leading industries, including tobacco, furniture, apparel and pharmaceuticals, are among the most frequent targets of trademark counterfeiting. Also, according to Interpol, trademark counterfeiting often provides for a source of income and reliable import channel for those with other nefarious purposes, such as illegal drug or human trafficking and potentially even terror activities.
In addition to these very negative economic consequences, there is a particular level of harm associated with certain kinds of trademark counterfeiting. Counterfeit goods aren’t subject to the same regulatory standards and safety inspections as items produced by legitimate manufacturers. So, in areas of manufacture where quality control is important, counterfeit products fall short. Consider, for example, the potential harm that could be caused by substandard, bogus automobile tires or airplane parts.
Counterfeit pharmaceutical drugs are clearly an area where public safety concerns are paramount. Counterfeit medicines have been found in all areas of the globe, including the highly regulated U.S. market, and extend to medicines, vaccines, testing and diagnostic equipment, and other medical devices. Both branded and generic pharmaceutical products can be falsified. And sales are not just limited to the black market—such products make their way to hospitals and pharmacies, often through internet sales trade channels.
Lifestyle or “popular” drugs are often counterfeited, and there have been recent increases in cosmetic, weight loss and opioid drugs. However, such drugs are not limited to such trends—counterfeit malaria vaccines, cholesterol medications and cancer treatments can also be found in the U.S. The World Health Organization (WHO) estimates that an average of up to 10% of medicines are counterfeit, and in developing countries, that percentage is considerably higher.
The Center for Medicine in the Public Interest estimates the annual worldwide dollar value of counterfeit pharmaceuticals at $200 billion annually and rising. Sadly, the damage is far greater than lost sales. WHO estimates that approximately 200,000 people die each year as the result of ineffective counterfeit anti-malarial drugs.
Counterfeit medicines also may cause adverse affects or allergic reactions, and they may not effectively treat the ailment for which prescribed. They may promote drug resistant disease strains or contain no active ingredient, the wrong active ingredient, or the incorrect strength (too much or too little) or dosage of the intended ingredient. According to a WHO investigation, approximately 1/3 of such drugs contain no effective ingredient. Given the lack of inspection of counterfeit manufacturing facilities, such products are often produced under non-sterile circumstances, resulting in bacterial or other contamination. Clearly, the ways in which counterfeit drugs can cause serious negative patient outcomes are extensive and extreme.
Combating the Problem.
Drug companies, and their attorneys and security departments, take a multi-pronged approach to combating counterfeiting. Many of these efforts are used to combat counterfeiting generally, but some have been developed with particular focus toward the nuances of the counterfeit pharmaceutical market.
The counterfeiting problem can appear daunting, given an array of unknown manufacturing sources, the breadth of possible sales outlets, and the strong consumer preference for the “cheap but name brand” combination. Successful anti-counterfeiting practices do not generally follow a reactive “Whack-A-Mole” approach, attempting to squelch every low-level advertisement or email blast that comes out. Rather, systematic and strategic prosecution, akin to practices used in the intelligence community, is preferred. Investigations of networks and relationships, rather than merely products and sellers, can help identify high-payoff targets, the disruption of which can have positive effects across several echelons of the counterfeit trade. Focusing limited enforcement resources on valuable choke points which contribute to an ecosystem response can often be the most fruitful and strategic approach.
Counterfeit pharmaceuticals in particular, given their specific methods of typical advertisement and sale, are prone to certain forms of interdiction over others. It is well known that counterfeit pharmaceuticals are advertised heavily on both internet ads and email “spam” messages, all of which attempt to direct a prospective purchaser to a product-ordering website. Attempting to interdict the advertising messages, which are often sent by botnets or third-parties through a referral-affiliate relationship, or to shut down specific websites, is a losing proposition. This is the case because there are hundreds of thousands or more of each, and the costs to re-establish a confiscated website are negligible compared to the significant enforcement costs. However, academic researchers working with industry and enforcement contacts identified several potential chokepoints on which these sorts of pharmaceutical sales pathways rely. See Dharmdasani et al., “Priceless: The Role of Payments in Abuse-advertised Goods,” CCS ’12, October 16–18, 2012, Raleigh, N.C. One key chokepoint relationship for online transactions is a seller’s host bank, nearly always non-U.S. and non-EU, that is willing to accept abusive credit card transactions related to these unlawful goods from card processors such as Visa and MasterCard.
Nearly all online counterfeit pharmaceutical revenue can flow through these concentrated banking relationships, and researchers discovered that intercepting just one or two of these banking relationships, and seizing related funds, could have ripple effects disrupting thousands of drug transaction websites and referral affiliates. For example, a 2011 study determined that across 95% of spam e-mail for pharmaceuticals and similar goods, only three acquiring bank institutions were used. Id. This research demonstrates a guiding principal of anti-counterfeiting efforts: enforcement is most successful where the “termination cost [to the counterfeiter] is inevitably far higher— in fines, in lost holdback, in time and in opportunity cost—than the cost of the intervention itself [by the rights holder]. … [R]elatively concentrated actions with key . . . institutions can have outsized impacts.” Id.
Targeted investigations and enforcement are only one aspect of a comprehensive anti-counterfeiting approach. Successful rights holders employ a broad-based strategy, involving secured supply chain management, thorough technology and distribution agreements with market partners, and high-tech security solutions such as secure packaging, microchips, holograms, and the like. The combination of many of these controls can make enforcement actions easier and more productive, and thus reduce the prevalence and success of counterfeit competitors. In addition, it is important to inform consumers and retailers about both the dangers of counterfeits and the value of accessing authentic products. Pharmaceutical companies should engage in advertising to alert the marketplace to the dangers of counterfeit pharmaceuticals and to also assist others in identifying counterfeit drugs – including examination of packaging and medicines for quality, condition, spelling and grammar; and checking manufacturing and expiration dates and batch numbers on both exterior and interior packaging.
The problem of fake drugs is in fact very real news and companies here in North Carolina and around the world are taking steps to defend their brands and protect their customers in the marketplace.
Authentic Vial Counterfeit Vial
This article originally was published in the August 2017 edition of the Newsletter of the Board of Legal Specialization, a publication of the North Carolina State Bar.
Monsanto is catching a lot of heat now that a court has unsealed documents that cast the company in a negative light and suggest that it was responsible for providing false assertions to the government and public regarding the safety of Roundup. As the most popular herbicide in the world, Roundup and similar products produced by Monsanto are used across the globe for the elimination of pests from lawns, crops, gardens and nurseries. It has provided research that opposes the belief Roundup’s main active ingredient can cause cancer, but the documents unsealed by the court show that these accounts were misleading and, in some cases, false.
The research that was presented to defend the safety of its products was in fact, ghostwritten and attributed to academics. It also claimed that a senior EPA official attempted to dismiss a report from the United States Department of Health and Human Services that the product could in fact be linked to the deaths of numerous people who suffered from non-Hodgkin’s lymphoma. The evidence tells a story of arguments within the Environmental Protection Agency and conflicting beliefs over whether Roundup and similar products were safe to use.
Emails between Monsanto executives and Jess Rowland of the EPA discuss an effort to disrupt the efforts of the Department of Health and Human Services to make its own determination and review of the product. Rowland states in the emails that he should receive a medal if he is able to succeed in his interference.
World Health Organization Classifies Products as Carcinogenic
The growing litigation over Roundup was sparked off by the classification of Roundup as a carcinogen, due to the discovery of a link between glyphosate and cancer in animals and the destruction of DNA and chromosomes in human cells. Despite the research provided by the WHO, Monsanto went to great lengths to continue the defense of its product and to assert that it was as safe to consume as salt.
While Monsanto claims that glyphosate is safe, those who have come forward with claims against the company allege that Monsanto has repeatedly falsified research and information in order to fool the government and the public. In its defense, Monsanto has claimed that the unsealed documents are being presented out of context and that they provide isolated information. Numerous health agencies around the world have presented conflicting arguments over the safety of these products, so the science has not been settled just yet.
Fresh off his noticeably smooth confirmation, the new Commissioner of Food and Drugs, Dr. Scott Gottlieb, appeared before Congress last Thursday and unveiled his strategic initiatives and priorities for the Trump Food and Drug Administration (“FDA”). These run the gamut from improving regulatory science and policies to streamlining clinical trials to spurring innovation on behalf of patients. Two initiatives, in particular, merit closer attention and discussion: combating opioid abuse and addressing drug price increases through more, accelerated generic competition.
In his first post to the FDA Voice blog, Dr. Gottlieb wrote:
As Commissioner, my highest initial priority is to take immediate steps to reduce the scope of the epidemic of opioid addiction. . . . I believe it is within the scope of FDA’s regulatory tools – and our societal obligations – to take whatever steps we can, under our existing legal authorities, to ensure that exposure to opioids is occurring under only appropriate clinical circumstances, and for appropriate patients.
First among these steps, the Commissioner is establishing an Opioid Policy Steering Committee, comprised of “some of the agency’s most senior career leaders, to explore and develop additional tools or strategies FDA can use to confront this epidemic.” The strategies under consideration include (1) mandatory education for health care professionals about (i) appropriate prescribing recommendations; (ii) how to identify the risk of abuse in individual patients; and (iii) how to get addicted patients into treatment; and (2) working more closely with provider groups to develop standards for prescribing opioids in different clinical settings, so that “the number of opioid doses that an individual patient can be prescribed is more closely tailored to the medical indication.”
Limiting the availability of prescription pain medication is a dicey proposition, however. As Dr. Gottlieb acknowledged, certain situations “require a 30-day supply” and, “[i]n those cases, we want to make sure patients have what they need. But there are plenty of situations where the best prescription is a two- or three-day course of treatment.” The individualized medical judgments and circumstances that drive opioid prescribing likely mean that no single approach is likely to strike the proper balance between over-prescribing and ensuring sufficient access to adequate pain management. Interestingly, the variability between opioid prescribers and patients did not stop the Centers for Medicare and Medicaid Services from proposing hard limits on opioid dosing for non-cancer pain or palliative/end-of-life care (i.e., chronic pain) for Medicare Advantage Organizations and Prescription Drug Plan Sponsors.
In fact, pain patients already have struggled under bright-line limitations on opioids. As we previously reported, the State of Massachusetts enacted a new law in March 2016 that prohibits “a practitioner [from] issu[ing] a prescription for more than a 7-day supply . . . [w]hen issuing a prescription for an opiate to an adult patient for outpatient use for the first time [or] to a minor,” the first such limitation legislatively imposed by any state.” Mass. Gen. Laws ch. 94C, § 19D (2016). Massachusetts physicians surveyed following the law’s enactment complained that “the pendulum has swung too far, depriving pain patients of needed relief,” and that “regulations won’t solve the addiction problem . . . . Instead, they make doctors reluctant to prescribe opioids.”
Broadly targeting opioids as a class of drugs also may cast too wide a net. A recent article in the journal Substance Abuse reported “[t]he US opioid epidemic has changed profoundly in the last 3 years” in that “[h]eroin and fentanyl have come to dominate an escalating epidemic of lethal opioid overdose, whereas opioids commonly obtained by prescription play a minor role, accounting for no more than 15% of reported deaths in 2015.” The article urged that the changing etiology of opioid overdose “require[s] substantial recalibration of the US policy response.”
What is clear—and what Dr. Gottlieb seems to recognize—is that opioid abuse and addiction are dynamic issues that differ from prescriber to prescriber and from one patient to another. Those variables may make a one-size-fits-all”strategy unviable.
During a budget hearing before the House Committee on Appropriations, Dr. Gottlieb testified that, “while the FDA does not have a direct role in drug pricing, we can take steps to facilitate entry of lower-cost alternatives to the market.” He identified policy challenges that the last Congress had attempted to address through legislation designed to expedite access to affordable drugs. Such legislation included the CREATES Act, which we previously analyzed. The proposed law sought to prevent brand-name drug companies from using FDA safety rules (i.e., Risk Evaluation and Mitigation Strategies (REMS) and requirements thereunder, e.g., Elements to Assure Safe Use (ETASU)) for medicines with higher risk potential to block or delay generic entry. “FDA has an important role to play in making sure that its statutory and regulatory processes are working as intended,” Gottlieb told Congress, “not being manipulated in ways that FDA and Congress did not intend.”
In response to growing political pressure in Washington to expedite drug reviews, Dr. Gottlieb assured lawmakers that biomarkers, new technologies, and more efficient clinical trial designs would make it possible to shorten the regulatory process. But accelerated approval of expensive, investigational (albeit life-saving) therapies has raised concerns among health policy experts.
A recent op-ed published by the New England Journal of Medicine (NEJM) cautioned that
accelerated approval can lead to situations in which private payers may choose not to cover a drug because of high cost and lack of evidence of clinical efficacy, thereby thwarting the pathway’s goal of getting potentially important therapies to patients earlier, while major government payers are forced to cover the product, directing substantial tax dollars to drugs not yet shown to have clinical benefit.
The NEJM article’s authors argue that any biopharma company granted an accelerated approval should be subject to certain price restrictions until the confirmatory trials are completed, reasoning that “the price paid by taxpayers should reflect the strength of the available evidence about the drug’s clinical impact.” Additionally, they proposed that all drugs moving through an accelerated-approval pathway should be subject to formal economic impact analyses after one to two years on the market, possibly funded by an increase in the user fees for manufacturers that use this pathway.
Dr. Gottlieb is also evaluating the generic drug and biosimilar review and approval process. More specifically, Dr. Gottlieb is looking at measures to facilitate communication between the industry and FDA, address complex molecules, and to speed up the approval of biosimilar products.
These recommendations are not without some appeal. Despite seeking to deliver more “bang” for the taxpayer’s “buck,” however, prospectively capping the federal reimbursement for a high-cost drug product still subject to additional clinical trials and/or other R&D may create a financial disincentive to pharmaceutical manufacturers to foot the expense of developing breakthrough drugs to fill an unmet medical need.
To deliver on the promises of reducing the incidence of opioid abuse and lowering drug prices, Dr. Gottlieb’s FDA must navigate the competing interests and thorny health policy issues highlighted above.