Direct to Consumer Genetic Testing and the Over-Production of Genetic Information

bernstein-gaia-lgCross Posted at HealthLawProf Blog

23andMe, the Internet genetic testing company, which offered genetic testing for health conditions and ancestry, has received extensive publicity in recent months. In November 2013, the FDA ordered 23andMe to stop marketing its health-related genetic test results to customers because their product is a “device”, which requires FDA approval. In its letter to 23andMe the FDA focused on the harms of consumers’ interpretation of genetic test results without the appropriate medical guidance.

And for sure, consumers’ independent interpretation of genetic results is potentially harmful. But, another important concern not addressed by the FDA is the need to regulate and constrain the production of genetic information in the first place – at the time that a consumer decides which tests to take. Direct to consumer genetic testing companies, like 23andMe, usually offers a battery of multiple tests that the consumer purchases without careful selection of what information is desirable to her. And, although genetic information can help improve and control health outcomes, not all genetic information is made equal and not all tests results are similarly desirable for all people. In my essay Direct to Consumer Genetic Testing: Gatekeeping the Production of Genetic Information, I discuss the problem of indiscriminate production of genetic information and argue for the need for a medical gatekeeper not just for the interpretation of genetic test results but earlier on to guide consumers through the selection of tests.

The guidance of a medical practitioner (particularly a genetic counselor) at the test selection stage is important to avoid the production of genetic information that is unsuitable for the specific person who wants to undergo testing. First, some people may prefer not to know certain genetic information about themselves because there are no effective preventive measures, and they do not want to live with the knowledge that they are likely to incur a certain genetic disease. For example, currently, the most effective prevention for breast cancer is a mastectomy. Some women would welcome the information and the ability to prevent the disease. But, others may not view this as a preventive measure they can endure and would prefer not to undergo a genetic test for the breast cancer genetic mutations. Second, some genetic tests convey little information. Certain positive genetic test results indicate only a slightly higher probability of incurring the disease than the likelihood in the general population. Finally, some genetic tests may lack solid scientific validity, whether due to the state of the science or the effect of many mutations and environment factors that act in conjunction. For all these reasons, catering the selection of genetic information to the person testing can be as important as regulating the interpretation of the results stage.


Massachusetts’ Ban on “Prescribing and Dispensing” Zohydro: The Arguments For and Against Preemption

Kate Greenwood_high res 2011 comp

Cross-Posted at Bill of Health

As Kurt Karst reported at FDA Law Blog, here, drug maker Zogenix has filed a Motion for Temporary Restraining Order and Preliminary Injunction challenging Massachusetts’ decision to “prohibit the prescribing and dispensing” of the company’s extended-release hydrocodone capsule, Zohydro ER. At a hearing on Tuesday, Judge Rya Zobel told the parties that she is likely to decide in the company’s favor. While Zogenix argues that Massachusetts’ action is unconstitutional for a number of reasons, including that it violates the dormant Commerce Clause and the Contracts Clause, Karst predicts that Judge Zobel will grant Zogenix’ motion on preemption grounds.

Zogenix argues in its Memorandum that “[t]he emergency declaration issued by Governor Patrick, and related order by the Commissioner of the Department of Public Health (DPH), purported to ban Zohydro™ ER based on safety concerns that squarely conflict with – and are therefore preempted by – FDA’s determination that Zohydro ER® is safe and effective and may be marketed and sold in the United States.”  Zogenix notes that the reason Massachusetts gave for banning Zohydro—that the drug lacks abuse-deterrence features—was expressly considered by the Food and Drug Administration during the course of the approval process.  FDA concluded that Zohydro’s benefits, in particular the fact that it contains no acetaminophen, outweighed the risks posed by its lack of such features.

Zogenix acknowledges that the Supreme Court’s decision in Wyeth v. Levine stands for the proposition that when the FDA approves the contents of a drug’s label, the agency merely establishes “a ‘floor’ upon which state tort requirements may build.” But, the company argues, “this is not a labeling case; it is a case about the safety and efficacy vel non of a drug already found to be safe and effective.”  If Massachusetts’ ban is upheld, Zogenix concludes, “Congress’s objectives to promote the public health through FDA drug approvals could be directly contravened by a potential flood of state policy disagreements.”

While Massachusetts has not yet filed papers in opposition to Zogenix motion, there are a number of strong counter arguments it could make.  First, while Zogenix emphasizes that the FDA “expressly” considered Zohydro’s lack of abuse-deterrence features, this is not an express preemption case. The federal Food, Drug, and Cosmetic Act does not expressly preempt the Massachusetts ban. Similarly, Zogenix uses the word “conflict” in its Memorandum, but this is not a case in which it would be impossible for the company to comply with both federal and state law. As the United States noted in an amicus brief submitted in the Supreme Court’s most recent FDA preemption case, Mutual Pharmaceutical v. Bartlett,

the FDCA makes FDA approval a prerequisite for, inter alia, “introduc[ing] or deliver[ing] for introduction into interstate commerce” any “new drug.” … That text does not expressly require that an approved drug be made available in any particular State or that the manufacturer be guaranteed the ability to make it so.

Finally, Zogenix argues that it was Congress’ intent that the FDA promote the public health by approving drugs for sale.  One could as easily argue that it was Congress’ intent that the FDA do so without supplanting states’ authority to regulate the practice of medicine and against a backstop of states’ longstanding power to act as necessary to avert a public health emergency. The ban on prescribing and dispensing Zohydro was just one of a number of actions Massachusetts is taking as part of Governor Deval Patrick’s declaration that the “growing opioid addiction epidemic” in the state constitutes a public health emergency.

While Massachusetts can make a strong case against preemption, its case would be even stronger were Zohydro not a newly-approved drug.  In its amicus brief in Bartlett, the United States argues that a state law tort claim founded on an allegation that a drug had a “design defect” would not be preempted if it were based on “significant new evidence” that was not before the FDA when it approved the drug at issue. Even if Judge Zobel strikes down Massachusetts’ ban on Zohydro, then, there may be room for states to act with regard to other drugs under other circumstances.


States Tackle Biosimilar Substitution

paradiseLGjpg_1While the Food and Drug Administration (FDA) and the Federal Trade Commission contemplate the wide-ranging implications of recent legislation creating an abbreviated approval process for biologic products, states are busy tackling issues of pharmacist substitution.  The current implementation debate at the federal level focuses chiefly on the scope of scientific and technical assessments and the impact on market competition.  However, two aspects will prove essential for determinations of access to and costs of the resulting products: how the biologic products are to be named, and whether pharmacist substitution is appropriate.  The FDA has thus far sidestepped the naming question because of the nascent state of the pathway development and lack of tangible products, while states are just beginning to confront the issue of how to extend or adapt their pharmacist substitution laws.  As this abbreviated pathway develops and biosimilar and interchangeable biologics begin to enter the market, product identification and substitutability will have tremendous ramifications for physicians, patients, and payors.  Recognizing these issues, five states have enacted laws governing substitution practices for biologics, and legislation has been considered in over a dozen more. 

The Biologics Price Competition and Innovation Act of 2009, embedded within the Patient Protection and Affordable Care Act, grants the FDA the authority to implement an abbreviated approval pathway to market for new versions of existing biological products that have the same clinical indication, route of administration, dosage form, strength, and mechanism of action. Two tiers of biosimilarity are laid out in the BPCIA: biosimilarity and interchangeability.  Biosimilarity means the biosimilar biological product is “highly similar” to the reference product where no clinically meaningful differences exist in terms of safety, purity, and potency. 

Interchangeability requires that the product is biosimilar and the product can be substituted for the reference product without intervention of a prescribing health care provider.  An applicant must demonstrate the product will provide the same clinical result as the reference product in any given patient and that when “administered more than once to an individual, the risk in terms of safety of diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alteration or switch.”  The specific provisions can be found here.   This level of interchangeability is where state substitution laws come into play.  The statute leaves it to individual states to determine as a matter of state law whether an interchangeable product will be able to be substituted for a reference biologic and what requirements are associated with that substitution. 

Although all 50 states currently have statutes addressing generic drug substitution, these statutes do not apply to biologics, which are regulated by the FDA under a different federal statute.  Generic status is imparted by the FDA through therapeutic equivalence ratings, which connote that the generic product is bioequivalent, meaning for all purposes the same as, the reference product.  The laws vary state-by-state.  Some states, such as New Jersey, are “positive formulary” laws, where generics that may be substituted are identified in a formulary; other states, such as Minnesota, are “negative formulary” laws, where drugs that cannot be substituted are identified in a formulary.  However, when the physician indicates on the script that the drug is not to be substituted, typically with “may not substitute,” “dispense as written,” or similar language, the pharmacist is not allowed to dispense a generic.  If “brand only” is not indicated by the prescribing physician, thirty-six states have laws framed as allowing generic substitution, while the remaining fourteen are framed as mandating generic substitution.  Many laws also provide that there must be patient notification or consent to the substitution or that the drug dispensed by the pharmacist is less or equal price to the prescribed drug.  For a discussion of these laws, see here.

Legislation regarding substitution of interchangeable biologic products has been introduced in at least 18 states over the last few years and has passed in Florida, North Dakota, Oregon, Utah, and Virginia  Other states considering legislation were Arizona, Arkansas, California, Colorado, Delaware, Illinois, Indiana, Maryland, Massachusetts, Mississippi, Pennsylvania, Texas, and Washington.  California’s bill was initially approved by both the House and Senate and subsequently vetoed by the Governor.  The FDA Law Blog posted a useful state legislation scorecard back in September 2013, though it has not been updated.

Basic elements of the bills include a requirement for pharmacists to notify prescribers and/or patients that the interchangeable biologic has been dispensed within a certain timeframe; record-keeping requirements on the part of prescribers and pharmacists for a certain period of time; the right for the prescriber to prohibit substitution; the right for patients to refuse an interchangeable product; and a requirement that the state Board of Pharmacy will maintain a list of interchangeable biosimilars.  The laws passed in Oregon, Virginia, and Utah also include a sunset clause of two years for the pharmacist notification provision.  A comparison of these five laws is represented in Figure 1; parenthesis within the columns denotes the relevant section of each bill.

State Notification Recordkeeping Prescriber Prohibition Patient Refusal BoP List
Florida HB 365; FL Stat. 465.0252 Yes, prescription holder, with price difference   (2(c)) Pharmacist, for 2 years. (2(d);  3) Yes, can only dispense if “prescribing health care provider does not express a preference against substitution.” (2(b)) Yes, person holding prescription(2(c)) Yes. (4)
North Dakota  SB 2190; ND Cent. Code 19-02.1 Yes, both prescription holder (2(c)) and prescriber within 24 hours. (2(d)) Yes, both pharmacist and practitioner for 5 years.  (2(e)) Yes, can substitute if no brand medically necessary” note on written, oral or e-transmittal.  (2(b)) Yes. (2(c)) Yes. (3)
Oregon SB 460; ORS Ch. 689 Yes, both prescription holder (2(c)) and practitioner or staff within 3 days. (2(d)) Yes, pharmacist/cy for 3 years.     (2(e)) Yes, can only substitute where no prohibition. (2(b)) N/A Yes. (3)
Utah SB 78; UT Code 58-17b-605.5 Yes, both prescription holder (7) and prescriber within 3 days (8(a)). Also counsel on use of and expected response to product      (2(d)) Yes, pharmacist to note Rx and substitution on “file copy.” ( 7) Yes, substitution only is not prohibited (2(e)); notation of “dispense as written” (6(a)) Yes, purchaser must request of consent to substitution.      (2(a)) N/A
Virginia SB 1285: VA Code 54.1-3408.04 Yes, notify patient of substitution (B) and cost (D), and prescriber or staff within 5 days (C).  Also label req. Yes, pharmacist and prescriber for 2 years. (B) Yes, can note “brand medically necessary” (A(i)) Yes, can insist on Rx.  (A(ii)) N/A



Pom Wonderful v. Coca-Cola: Will the Supreme Court’s Decision Have Implications Beyond “Pomegranate Blueberry Flavored Blend of 5 Juices”?

Kate Greenwood_high res 2011 compCross-Posted at Bill of Health

On April 21st, the Supreme Court will hear oral argument in Pom Wonderful v. The Coca-Cola Company, a case in which Pom sued Coke under Section 43(a) of the Lanham Act arguing that Coke’s product “Pomegranate Blueberry Flavored Blend of 5 Juices” was misleadingly named.  Coke countered that the suit should be dismissed because the name was specifically authorized by the Food and Drug Administration’s regulations governing flavored juice blends, and both the District Court and the Ninth Circuit Court of Appeals agreed.

In its opening brief filed last week, Pom argues that neither the provisions of the Food, Drug and Cosmetic Act governing food and beverage labeling generally, nor the regulations that specifically address juice blends, precludes the application of the Lanham Act to Coke’s misleading juice label.  This conclusion, per Pom,

“follows inexorably from this Court’s holding in Wyeth v. Levine … that FDA’s approval of a drug label does not displace state failure-to-warn suits challenging the adequacy of the warning. … Following Wyeth, there can be no serious argument that the provisions of the FDCA are in ‘irreconcilable conflict’ with the Lanham Act.  FDA does not even generally review—much less approve—particular food labels; nothing even arguably prevented Coca-Cola from designing its label to avoid misleading consumers; and FDA has given no indication that its juice-naming rules set the outer bounds of labeling regulation.”

In its brief opposing Pom’s petition for certiorari, Coke distinguished Wyeth, noting that the provisions of the FDCA governing drug labeling do not expressly preempt state regulation.  The provisions of the FDCA governing food and beverage labels, by contrast, “expressly supplant State laws—including those that imposed more ‘stringent’ requirements[.]”  This, Coke argued, shows that the food and beverage statutory provisions and their implementing regulations “were not intended as a ‘floor’ but rather as the exclusive body of regulation to which food and beverage labels would be subject.”

In her latest article, The Magical Thinking of Food Labeling: The NLEA as a Failed Statute, Diana Winters decries the time and money courts deciding food and beverage labeling cases must spend “negotiating the interaction between federal and state law, with inconsistent outcomes”.  Read more


Clinical Trials of Primary Care Drugs: Could Smaller Be Better?

Kate Greenwood_high res 2011 comp

Cross-Posted at Bill of Health

Lately it seems that each passing day brings another article about the cost of orphan drugs.  Earlier this week at FiercePharma, Tracy Staton reported that the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) has asked Alexion Pharmaceuticals to justify the price of its drug Soliris which is, per Staton, “the most expensive drug in the world” at around $569,000 a year.  Specifically, NICE seeks “‘clarification from the company on aspects of the manufacturing, research and development costs’” of the drug.  According to Staton, this latest development in a review process characterized by “halting progress” is “a departure from NICE’s usual calculations, which typically focus on quality-of-life years and the like.”

Pushback by NICE and other payers notwithstanding, the orphan drug market is growing.  As I blogged about here, in 2013 EvaluatePharma estimated that “the worldwide orphan drug market is set to grow to $127 [billion], a compound annual growth rate of +7.4% per year between 2012 and 2018[,]” which “is double that of the overall prescription drug market, excluding generics, which is set to grow at +3.7% per year.”  In a recent article in the New England Journal of Medicine, venture-capital investors Robert Kocher and Bryan Roberts note that “more than half of the 139 drugs approved by the FDA since 2009 are for orphan diseases” and suggest that there is a risk of “systematically underinvesting in other important areas of medicine.”

Kocher and Roberts’ explain that one reason that orphan drugs attract investment is that their development costs are low.  The problem or potential problem of underinvestment in diseases like depression and diabetes could therefore be addressed, they contend, by bringing the cost of developing treatments for these common conditions in line with the cost of developing treatments for rare diseases.  And, they argue, one promising approach to doing so is to reduce clinical trial costs by reducing the size of clinical trials.  In the report I cited above, EvaluatePharma estimated that for orphan drugs regulators require a median phase III trial size of 528 patients, at an estimated average cost of $85 million, whereas for non-orphan drugs they require 2,234 patients, at an estimated average cost of $186 million.

Kocher and Roberts believe that “most clinical development programs go far past the point of diminishing returns for frequent safety events, but they do not go far enough to permit detection of rare events.”  They therefore advocate for a package of reforms, including (1) “[r]edesigning trials to include fewer patients,” (2) “providing conditional approval of drugs,” and (3) “requiring postmarketing surveillance[.]”  The last two proposals are relatively uncontroversial; the first is much more so.  In a 2011 article in JAMA, for example, Aaron Kesselheim and colleagues found that “although both newly approved orphan and nonorphan cancer drugs in [their] sample were tested in relatively small numbers of patients prior to approval,” there was a higher rate of adverse events associated with the orphan drugs, suggesting safety concerns.  Kesselheim and colleagues argued that rather than extending the flexibility on clinical trial size that is currently afforded to orphan drugs, Congress should consider restricting it, to “first-in-class drugs or those that treat a condition for which no other treatments are available[.]”

Legislation or a change in the Food and Drug Administration’s position to allow for an across-the-board reduction in clinical trial size seems highly unlikely.  That said, both Congress and the FDA have demonstrated a willingness to work to reduce development costs, including by allowing for surrogate outcomes where appropriate and by speeding the agency’s approval process.  Moreover, in certain cases, governments have reduced sponsors’ development costs directly.  As Hester Plumridge reported in the Wall Street Journal in January, the “unfavorable economics” of antibiotics development are changing, in part because “[r]esearch funding is beginning to flow[.]”


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