Filed under: Clinical Research, Drugs & Devices, Food and Drug Administration (FDA)
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[.]”
Filed under: Drugs & Devices, Food and Drug Administration (FDA), Litigation and Liability
Debate continues regarding the Food and Drug Administration (FDA) proposed rule that would allow generic drug manufacturers to independently make changes to a drug label on the basis of newly acquired safety information. The proposed rule trails a trilogy of Supreme Court decisions tackling questions of federal preemption in the pharmaceutical realm: Wyeth v. Levine (2009), PLIVA v. Mensing (2011), and Bartlett v. Mutual Pharmaceutical (2013). In Wyeth v. Levine (2009), the Supreme Court held that the federal Food, Drug, and Cosmetic Act (FDCA) does not preempt failure to warn claims for brand name, also called reference listed drugs (RLD). Taken together, PLIVA and Bartlett establish that the FDCA does, however, impliedly preempt both state tort law failure to warn and design defect claims against generic pharmaceutical manufacturers.
Why such seemingly opposite results regarding preemption? It’s the result of FDA regulations and the statute. The regulations provide that RLD manufacturers are able to update product labeling prior to FDA review of the change in a changes-being-effected (“CBE-0”) supplement. This mechanism originated from a 1965 enforcement discretion policy in which the FDA recognized that some labeling changes ought to be implemented as soon as possible in order to adequately protect consumers. The procedure is now contained in 21 C.F.R. 314.70, allowing RLD manufacturers to makes such labeling changes upon submission of a CBE-0 supplement in several circumstances, including the addition or strengthening of a contraindication, adverse reaction, warning, or precaution shown by newly-acquired or discovered scientific evidence.
As for the statute, the Hatch-Waxman Act of 1984 amended the FDCA to create the abbreviated new drug application (ANDA), or generic drug approval process. Approval of a generic drug product is based on the concept of bioequivalence, which means the generic is identical to the RLD for purposes of safety and efficacy. The legislation explicitly requires that generic drug applicants must submit “information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug…” FDCA §505(j)(2)(A)(v); 21 U.S.C. 355(j)(2)(A)(v). Congress included this provision to facilitate the acceptance of these products by physicians, pharmacists, and patients, as well as ensure uniformity for bioequivalent products. Identical labels also helped bolster substitution of generic drugs for brand name drugs as a means to impart cost-savings onto both the government and consumers. Until the publication of the recent proposed rule, the FDA has maintained the position that the statute prohibits generic manufacturers from deviating from a label identical to that of the RLD, expressed in 57 Fed. Reg. 17950, 17961 (1992).
The FDA now proposes to add a provision to the regulation to bring parity to the RLD and generic realm in terms of the availability of the CBE-0 supplement for labeling changes. The FDA acknowledges that the proposed rule would alter the long-standing policy that the labeling of generics must be identical to the RLD. As support for the change in position, the FDA cites changed circumstances:
[A]s the generic drug industry has matured and captured an increasing share of the market, tension has grown between the requirement that a generic drug have the same labeling as its RLD, which facilitates substitution of a generic drug for the prescribed product, and the need for an ANDA holder to be able to independently update its labeling as part of its independent responsibility to ensure that the labeling is up-to-date.
An FDA press release further emphasizes that the generic share of the market is currently over 80% of U.S. prescriptions. The proposed rule discusses Wyeth, PLIVA, and Bartlett, noticeably understating that the rule “may” eliminate preemption for generic drugs.
Two years ago, legislators attempted such a change at the statutory level. Companion bills, both entitled Patient Safety and Generic Labeling Improvement Act, were introduced in the House (HB 4384) and Senate (S 2295), which would have amended the FDCA to make the CBE-0 supplement available to generic manufacturers by law. Both died. The bill language read as follows:
(A) Notwithstanding any other provision of this Act, the holder of an approved application under this subsection may change the labeling of a drug so approved in the same manner authorized by regulation for the holder of an approved new drug application under subsection (b).
(B) In the event of a labeling change made under subparagraph (A), the Secretary may order conforming changes to the labeling of the equivalent listed drug and each drug approved under this subsection that corresponds to such listed drug.
Now, another group of legislators is taking a different stance. On January 22, nearly 30 members of Congress signed a letter addressed to the Commissioner of the FDA, Dr. Margaret Hamburg, expressing “grave concerns” about the proposed regulation. The letter questions the authority to promulgate such a rule given the statutory language and urges that it would lead to inconsistency in drug messages to consumers and physicians alike. The letter states that the proposed rule would “conflict directly with the statute, thwart the law’s purposes and objectives, and impose significant costs on the drug industry and healthcare consumers.” The letter directs the Commissioner to answer 11 enumerated questions by February 5 in order to “assist the Committee(s) in better understanding the decision making process.” Related press releases can be found here and here.
Many more are expected to chime in. Originally scheduled to close mid-January, the FDA has extended the comment period until March 13, 2014.
Filed under: Bioethics, Drugs & Devices, Food and Drug Administration (FDA)
This month marks the effective date of new joint Principles for Responsible Clinical Trial Data Sharing issued by the European Federation of Pharmaceutical Industries and Manufacturers (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA). The Principles commit the organizations’ members to “sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials” of approved medications.
The Principles were developed in response to growing concerns about the difficulty of evaluating manufacturers’ safety and efficacy claims without access to the underlying data from clinical trials. For example, last year, following an intensive campaign by scientists skeptical about the claimed benefits of the antiviral medication Tamiflu, the company Roche agreed to provide access to clinical study reports on all of its Tamiflu studies. Under the new Principles, companies will presumptively be expected to comply with similar requests in the future.
Yet, the Principles do not go nearly as far as some transparency advocates might have hoped. First, all requests for disclosure will be evaluated by scientific review boards made up of experts not employed by the company, who will be charged with assessing the “qualifications of the requestor and the legitimacy of the research purpose.” Second, in order to avoid “free-riding or degradation of incentives for companies to invest in biomedical research,” the statement provides that companies have the right “to refuse to share proprietary information with their competitors.”
In a draft rule circulated last summer, the European Medicines Agency proposed a more extensive system of data sharing under which de-identified research data would be published proactively, without the need for a request, as soon as a positive or negative decision on a marketing application has been made or the application has been withdrawn. The proposal would also allow for the sharing of documents containing personal information, but only if the requestor is a natural or legal person established in the European Union and agrees to enter into a data-sharing agreement containing limits on the use and disclosure of the data.
The US FDA has also entered into the discussion, although far more cautiously than its European counterpart. In 2013, it issued a request for public comments on a proposal to make available data that is not only “de-identified” but also “masked,” a term defined to mean “data with information removed that could link it to a specific product or application.” Strategies to mask data could include “making available certain data from a random sample or appropriately chosen subset of subjects, restricting the data fields made available or pooling data where possible from studies of multiple members of a product class, without identifying the specific product.”
As European and American regulators consider these proposals, it will be important to monitor how companies respond to requests for disclosure made pursuant to the voluntary EFPIA-PhRMA policy. If a voluntary disclosure system does not appear to be resulting in the free flow of scientific information, regulators may conclude that the only alternative is to implement a mandatory approach.
Filed under: Drugs & Devices, Food and Drug Administration (FDA)
Cross-Posted at Bill of Health
At Regulatory Focus earlier this week, Alexander Gaffney wrote about what he characterized as “a torrent of studies” that FDA is conducting or has proposed conducting on prescription drug promotion, and, in particular, on direct-to-consumer advertisements. The studies include, among others, a survey study aimed at sussing out “the influence of DTC advertising in the examination room and on the relationships between healthcare professionals and patients”, a study exploring similarities and differences in the responses of adolescents and their parents to web-based prescription drug advertising, and a study that will use eye tracking technology to collect data on the effect of distracting audio and visuals on participants’ attention to risk information.
Gaffney speculates that “the proposed studies could indicate coming changes in FDA’s regulatory approach toward advertising[.]“ Another possibility is that the studies are part of an effort by FDA to build up the evidence base supporting its current regulatory approach. In a Tweet commenting on Gaffney’s article, Patricia Zettler–a Fellow at Stanford Law School’s Center for Law and the Biosciences who was formerly an Associate Chief Counsel for Drugs at FDA’s Office of Chief Counsel–asks whether the data generated by the studies could help insulate FDA from First Amendment challenges.
Commercial speech is only protected under the First Amendment if it is not false or–perhaps more relevant in the context of direct-to-consumer advertising–misleading. In Christopher Robertson’s recent essay in the Boston University Law Review, he argues that when the truth about a claim is known, as it likely the case with an on-label direct-to-consumer advertisement, it is sensible to put the burden on the government to “prov[e] that the true speech is misleading…given the epistemic value of truth and our aversion to paternalism, especially as a motivation for speech regulation.”
As I discussed previously here, courts called upon to decide whether an advertisement or form of advertising is true, false, or misleading are permitted “to look to the facts to determine ‘the actual effect speech will have.’” In Florida Bar v. Went for It, for example, the Supreme Court relied on the government’s “106-page summary of its 2-year study of lawyer advertising and solicitation to the District Court,” as well as an “anecdotal record . . . noteworthy for its breadth and detail” in upholding a thirty-day moratorium on direct-mail solicitation of accident victims and their families by personal injury lawyers. In Bronco Wine Company v. Jolly, a California appeals court held that a legislative finding that the descriptor “Napa” was inherently misleading was adequately supported by “the regulatory history of brand names of geographic significance,” hearing testimony, and a survey. By contrast, in Edenfield v. Fane, the Supreme Court invalidated a ban on in-person solicitation by accountants on the grounds that the Board of Accountancy failed to ”validate [its] suppositions[.]“
Commercial speech doctrine does not precisely specify the level of deception, or the form or degree of proof, necessary to justify speech-restrictive regulations like those that limit direct-to-consumer prescription drug advertising. The government might have to show that such advertising is more often deceptive than not. Or, as in Lanham Act false advertising cases, it might have to show that a substantial percentage (typically fifteen to twenty percent) of a company’s customers is misled by it. Or, a significant risk of deception might be sufficient. Notwithstanding this uncertainty, FDA is wise to prepare to defend (and even fend off) future First Amendment challenges to the laws and regulations governing direct-to consumer prescription drug advertising by building up the evidence base underlying them.
Filed under: Food and Drug Administration (FDA), Public Health
The Food and Drug Administration (FDA) has decisively entered the debate regarding the health risks of artificial trans fatty acids in foods. On November 8, the FDA announced its “tentative” determination that partially hydrogenated oils (PHOs), also known as trans fatty acids, are no longer generally recognized as safe for human consumption. The FDA cited research by the American Heart Association (AHA), the World Health Organization, the American Dietetic Association, the Institute of Medicine, and the FDA Food Advisory Committee Nutrition Subcommittee demonstrating that trans fats increase the risk of coronary heart disease. Trans fats simultaneously raise levels of bad cholesterol and lower good cholesterol, among other adverse negative health effects. In the FDA Press Release, Dr. Margaret Hamburg, Commissioner of the FDA, stated that reduction in trans fat intake “could prevent an additional 20,000 heart attacks and 7,000 deaths from heart disease each year – a critical step in the protection of Americans’ health.”
This is not the first move by the FDA to address the heavily documented health risks of trans fats. Ten years ago, the FDA implemented regulations that required information about the trans fatty acid content in foods and dietary supplements to be declared on the Nutrition Facts label. As a result, the label now identifies the total fat, saturated fat, and trans fat content. While not directly reducing or eliminating trans fats from American diets, the label requirement forced transparency on the part of food manufacturers and provided consumers with information on which to base purchasing decisions. It also incentivized manufacturers to scale down on the use trans fat in food production.
If the FDA determination is finalized, PHOs would no longer be permissible ingredients in food products without prior approval by the FDA as a safe food additive. Food additives, by statutory definition include substances that “result or may reasonably be expected to result, directly, or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use).” The definition excludes several types of substances that are regulated under separate provisions, including pesticide chemicals, pesticide chemical residues, and color additives. All food additives that are not generally recognized by qualified scientific experts to be safe under the conditions of use are thus classified as not safe for market entry. Only after a generally recognized as safe (GRAS) determination by the FDA may a food additive enter the market as an ingredient in any given food product.
The FDA has a well-established regulatory process for determining whether a food additive is GRAS. The FDA maintains GRAS listings in the Code of Federal Regulations that act as a sort of recipe for food manufacturers. These complete listings are available here, here, and here. Generally, if a food additive conforms to that published GRAS listing, including the specific amount, intended use, good manufacturing practices, and any limitations, it may be used as an ingredient without prior FDA assessment. For example, caffeine is a GRAS listed substance for use in cola-type beverages. When added to other food products, however, caffeine is no longer considered GRAS and the FDA can institute an enforcement action against those products where there is a concern about public safety. This scenario played out several years ago with regard to drinks combining alcohol and caffeine.
The announcement is seen by those in the health and nutrition fields as an energizing sign of life in a recently limp FDA. Marion Nestle, a professor at New York University, proclaimed in an interview with the New York Times “[t]he FDA is back!” Likewise, organizations such as the AHA and the Center for Science in the Public Interest (CSPI) that have been advocating for increased regulation over trans fats praise the FDA’s move, though they emphasize that action is long overdue. CSPI originally petitioned the FDA for inclusion of trans fat information on the label in 1994 and subsequently in 2003 to prohibit use of PHO as a food ingredient.
It appears that the FDA anticipates phasing-in of the GRAS requirements, and has solicited the public for feedback on several aspects of scope and implementation. Specifically, the FDA asks for data supporting other approaches, input on the estimated timeframe to reformulate products to bring them into conformance, special considerations for small business, and any other foreseen challenges to such an approach. The comment period is open until January 7, 2014.