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Reproduced with permission from Product Safety & Li-ability Reporter, 39 PSLR 321, 03/28/2011. Copyright 2011 by The Bureau of National Affairs, Inc. (800-372-1033) http://www.bna.com Arguments of Parties, Amici. In the next preemption case set for argument, generic drug manufacturers (pe- titioners) and their amici argued that distinctions in thelaw and regulations governing branded versus generic This Time in Generic Drug Labeling Dispute products, particularly a mandate that generic labels bethe same as those for their branded counterparts, war- Following preemption decisions in medical device, rant preemption (39 PSLR 130, 2/7/11). And they con- brand-name drug, and vaccine cases, the U.S. Su- tended that they operate on thin margins, and said state preme Court is now poised to determine the viabil- tort claims would burden the Food and Drug Adminis- ity of failure-to-warn claims against makers of generic tration and impose duties and costs on manufacturers drugs, whose products account for the overwhelming that would undermine the goals of the Hatch-Waxman majority of prescriptions filled in the United States Amendments, which created an expedited approval (Pliva Inc. v. Mensing, U.S., No. 09-993, brief filed process to make generic drugs more affordable (39 2/24/11; Actavis Elizabeth LLC v. Mensing, U.S., No. 09- 1039, brief filed 2/24/11; Actavis Inc. v. Demahy, U.S., But the injured plaintiffs (respondents) and their No. 09-1501, brief filed 2/24/11).
amici asserted that the impossibility and frustration-of- Oral argument is scheduled for March 30.
purpose implied preemption arguments failed against On its own, the case is significant in part because of branded drug makers in Wyeth v. Levine, 555 U.S. ___ the sheer number of people who use generic drugs. To- (2009) (37 PSLR 274, 3/9/09), which rejected preemp- gether with other preemption-related activity on the Su- tion of failure-to-warn claims against branded drug preme Court this term, the case is part of ‘‘an extraor- makers absent ‘‘clear evidence’’ the FDA would have dinary time for preemption law,’’ Nicholas Wittner, pro- rejected the proposed label change. The petitioners fessor of law at Michigan State University’s College of maintained that neither argument overcomes the pre- Law, told BNA in an interview. Wittner teaches product sumption against preemption as applied in a generic liability law and is an expert on preemption in product A pro-preemption decision would create a distinction Already this term, the court decided Williamson v. between two classes of plaintiffs: those who used Mazda Motor of America Inc., an auto preemption case brand-name medication could pursue warning-based (39 PSLR 210, 2/28/11), ordered a state court to revisit a claims under Levine, while those who used generics pro-preemption ruling in Priester v. Ford Motor Co. (39 would be barred from suing. That distinction would, it- PSLR 238, 3/7/11), involving auto glazing, decided the self, undermine the ‘‘sameness’’ requirements behind Bruesewitz v. Wyeth vaccine case (39 PSLR 212, the Hatch-Waxman Amendments, some of the respon- 2/28/11), denied a petition for review in McNeil PPC Inc. v. Valdes, a case involving cold medication (39 PSLR 78,1/24/11), and has a pending petition for review in Farinav. Nokia Inc., a cell phone radiation preemption case,Wittner said. ‘‘Preemption has become an enormous is-sue on a variety of fronts. The court is paying tremen-dous attention.’’ COPYRIGHT 2011 BY THE BUREAU OF NATIONAL AFFAIRS, INC.
categorical preemption of failure-to-warn claims, butdisagreed with the courts below and with the respon- ‘‘Preemption has become an enormous issue on a dents’ regulatory interpretation of how a generic manu-facturer may get a drug label changed.
variety of fronts. The court is paying tremendous Rosenbaum said she expects the justices will be inter- ested in what the government has to say, especially given the petitioners’ arguments that allowing state tortclaims would burden the Food and Drug Administra- ‘‘It’s too jarring to think you’d have a system An estimated 70 percent of prescriptions in the United States are filled with generic drugs. The indus- where we’re trying to encourage generics and we try is expected to grow at an annual rate of more than7.8 percent, according to an amicus brief by the Ameri- have preemption on one side of the line and can Medical Association and several state medical asso-ciations. Generic drugs generate $60 billion in U.S.
sales annually, according to an amicus brief by healthcare economists.
There are more than 1,000 cases pending in federal and state courts involving metoclopramide, the drug atissue in this case, according to manufacturer ActavisInc.
The government argued in support of manufacturer What’s at Stake? ‘‘The question is whether, for the Wyeth Inc. in the vaccine case Bruesewitz v. Wyeth Inc., majority of prescriptions filled, consumers would be and observers told BNA afterward the court seemed able to hold manufacturers responsible, and will manu- particularly interested in hearing how government facturers of the majority of drugs used have incentives agencies handle vaccine research and safety issues.
to keep those drugs safe,’’ Adina Rosenbaum of Public While declining to predict the outcome of the generic Citizen told BNA. Public Citizen, together with the drugs case, Rosenbaum said the court ‘‘should’’ hold American Association of Retired Persons (AARP), sub- there is no preemption here, based on the reasoning of mitted an amicus brief supporting respondents Gladys Wyeth v. Levine: The court affirmed the presumption against preemption, and held manufacturers respon- Bert W. Rein of Wiley Rein LLP in Washington, D.C., who represented Wyeth Inc. in the Wyeth v. Levine case, told BNA this case presents difficult questions.
‘‘It’s not easy to sort out the equities,’’ Rein said.
fered some perspective, drawing on the recent William- ‘‘What’s going to be interesting is, will there be a re- son decision as well as some previous preemption rul- thinking of the balance between the need for a uniform ings. ‘‘Now, there is a stronger lineup against preemp- label and the people who say the label isn’t good tion’’ than there was when the court decided Geier v. American Honda Motor Co. (28 PSLR 464, 5/29/00), in The Food, Drug, and Cosmetic Act ‘‘wasn’t written which a 5-4 court ruled that conflict preemption prin- with the idea of multiple sellers of the same drug,’’ Rein ciples barred claims that a car should have been said, noting that in Levine, the court did not consider a equipped with an air bag. Justice Stephen Breyer wrote the majority opinion in Geier; retired Justice John PaulStevens wrote the dissent.
Because new side effects and new information may become apparent years after approval, ‘‘The label can’t ‘‘Now, you have justices who are either unfriendly to be a dead letter. There may be reasons to change the la- [implied] preemption or defer to the Solicitor General,’’ bel,’’ Rein said. ‘‘The problem is you can’t have eight Wittner said. Justice Clarence Thomas has ‘‘antipathy’’ people changing the label. Managing the post-approval to frustration-of-purpose preemption, Justice Ruth Bader Ginsburg ‘‘rarely finds preemption,’’ and Justice Brian Wolfman, co-director of the Institute of Public Sonia M. Sotomayor is ‘‘skeptical’’ toward preemption, Representation at Georgetown University Law Center, Wittner said. ‘‘We don’t know for certain’’ where Jus- expressed concern over the dual system that would tice Elena Kagan stands on preemption, ‘‘but briefs emerge from a pro-preemption decision. ‘‘If generic filed while she was solicitor general suggest she frowns manufacturers are right, it ascribes to Congress an in- on implied preemption, and the Solicitor General’s of- tent to have that asymmetry. No rational Congress fice has been aggressive against preemption.’’ would derive a system like that. Either both are liable or Breyer, ‘‘who has assumed a prominent role on the neither are liable. It’s too jarring to think you’d have a court,’’ deferred to then-Solicitor General Kagan, who system where we’re trying to encourage generics and filed a brief for the government in support of the Wil- we have preemption on one side of the line and not the liamsons, Wittner noted. Justice Anthony M. Kennedy can be a swing vote, and often votes with Breyer. And,‘‘putting aside Williamson, Chief Justice John G. Rob- Solicitor General to Participate. The court has granted erts Jr., and Justices Samuel A. Alito Jr., and Antonin the U.S. Solicitor General’s motion to participate in oral Scalia find preemption,’’ Wittner said.
argument. In amicus briefs filed in support of the re- Wittner also noted that the Obama administration is spondents, the government staked a position against COPYRIGHT 2011 BY THE BUREAU OF NATIONAL AFFAIRS, INC.
In Wyeth v. Levine, the vote was 6–3: Stevens wrote facturers could not use the CBE or PAS process to meet the majority opinion, joined by Kennedy, retired Justice their federal duty, they nonetheless ‘‘should provide ad- David H. Souter, Ginsburg, and Breyer. Thomas con- equate supporting information to FDA, and FDA will curred separately; critical of implied preemption. Alito determine whether the labeling for the generic and authored the dissenting opinion, joined by Roberts and listed drugs should be revised,’’ the government’s brief A drug is misbranded under the federal Food, Drug, Fifth, Eighth Circuits Allow Generic Drug Claims. At is- and Cosmetic Act if ‘‘its labeling [does not] bear  *** sue are decisions from the U.S. Court of Appeals for the adequate warnings *** against unsafe dosage or meth- Fifth Circuit, Demahy v. Actavis Inc. (38 PSLR 40, ods or duration of administration or application,’’ the 1/18/10); and the Eighth Circuit, Mensing v. Pliva Inc. brief said, citing 21 U.S.C. § 352 (f)(2).
(37 PSLR 1232, 12/7/09). First the Eighth Circuit, and This reflects the premise, noted in Levine, that a then the Fifth Circuit, said federal law does not preempt manufacturer bears responsibility for the content of its failure-to-warn suits against generic drug companies.
label at all times, the United States said. Under 21 The suits involve metoclopramide, a generic equiva- C.F.R. § 201.57(e), a prescription drug’s label ‘‘shall be lent to the branded drug Reglan. Plaintiffs Julie revised to include a warning as soon as there is reason- Demahy and Gladys Mensing alleged they developed able evidence of an association of a serious hazard with tardive dyskinesia, an involuntary movement disorder, after using metoclopramide for several years to treat For preemption purposes, the question is whether the gastroesophageal reflux. They claimed the defendants generic drugs that Mensing and Demahy took were failed to warn about the risks of long-term use. Demahy misbranded under 21 U.S.C. 352(f)(2) and the standard used metoclopramide manufactured by Actavis Inc.; of 21 C.F.R. 201.57(e). That approach reconciles the Mensing took medication made by Pliva Inc., Teva Hatch-Waxman Amendments’ ‘‘same as’’ requirement Pharmaceuticals USA Inc., UDL Laboratories Inc., and with the FDCA’s misbranding standard and FDA’s implementing regulation and fulfills Congress’ inten- Both the Fifth and Eighth Circuits said the manufac- tion that failure-to-warn suits would provide compensa- turer could have effected a warning change, thereby tion for consumers and motivate manufacturers to pro- complying with state and federal requirements. The vide adequate warnings, the government said.
Eighth Circuit said it need not resolve an ongoing dis-pute over whether generic companies could use the The cases should be allowed to proceed, according to ‘‘changes being effected’’ or CBE provision, allowing a unilateral change, because they could have used other Public Health Issues: NCSL. The National Conference means. The Fifth Circuit said the CBE was permissible.
of State Legislatures, the American Medical Association The Ninth Circuit also recently voiced its view on pre- and several state medical associations, and a group of emption of failure-to-warn claims involving generic health care economists described some practical public drugs. In a case involving over-the-counter ibuprofen, health ramifications they said would follow a decision the court said such claims are allowed (39 PSLR 105, 1/31/11). According to the Ninth Circuit, federal regula- According to the NCSL, the disparate liability tions allow generic manufacturers to use the CBE pro- schemes that would follow a pro-preemption ruling cess and the prior approval supplement (PAS) process, ‘‘would unsettle bedrock assumptions that have guided and to ask the FDA to send Dear Doctor letters to health state law in this field for decades.’’ All the states have care professionals. A generic failure-to-warn case is adopted carefully drawn policies on generic drug sub- stitution, ‘‘which encourage and often require the dis- A Supreme Court decision ‘‘may clarify some dis- pensing of generic drugs except where the patient has a puted specifics about how the generic scheme works,’’ Rosenbaum noted. But she said that for this case, the And generic drugs are required to be dispensed in disagreement ‘‘doesn’t matter that much. The bottom various public health care programs, the NCSL ob- line is, [the generic drug manufacturers] haven’t shown served. These policies have been a significant factor in it was impossible to comply. At the very least, it seems the burgeoning demand for generic drugs, the NCSL everyone agrees they could have presented information to the FDA to get a label approved.’’ Out of candor to their citizens, states might opt to in- Wolfman, who was one of the attorneys representing form the public of the disparity that would follow a pro- Diana Levine in the branded drug case that went to the preemption ruling, NCLS suggested. But it said a mes- Supreme Court, said ‘‘the more fundamental’’ point of sage that ‘‘[m]anufacturers of generic drugs cannot be the court’s decision in Wyeth v. Levine was not the liable for failure to warn of health risks associated with availability of the CBE, but that ‘‘it was the basic obliga- their products’’ could lead some patients—at least those tion of any drug manufacturer to keep its label current, financially able to do so—‘‘to spurn generic drugs, un- so the label isn’t false or misleading.’’ dermining the policies of the Hatch-Waxman Act and Amici Support Respondents. Some 14 amici, including state generic substitution laws alike.’’ the United States, Rep. Henry Waxman (D-Calif.), law Moreover, some doctors may be deterred from pre- professors, health care economists, medical experts, scribing generic drugs if they knew they could be on the and the National Council of State Legislatures, filed hook alone if a generic drug caused a patient to suffer briefs supporting Demahy and Mensing.
According to the United States, FDA regulations re- According to the brief, in the absence of any indica- quire both branded and generic drug manufacturers tion that Congress intended such a regime, the manu- alike to act upon new safety information that warrants facturers advance arguments based on Buckman v. added or strengthened warnings. Although the manu- Plaintiffs’ Legal Committee, 531 U.S. 341 (2001), and Arkansas Louisiana Gas Co. v. Hall, 453 U.S. 571 based on information that had been available for more (1981), to the effect that tort law duties of care are in- than a decade, Graves said. ‘‘There is little need to compatible with the FDA’s exercise of its statutory re- speculate regarding the FDA’s reaction to that same in- formation had generic manufacturers submitted it ear- But the claims here are plain tort claims, based on lier in connection with a proposed labeling change.’’ traditional state-law duties, not the ‘‘fraud-on-the-agency’’ claims at issue in Buckman. Moreover, theclaims here, unlike the claims at issue in Buckman orArkLa, do not entail any sort of collateral attack on the FDA’s action or decision, NCLS said.
Full text of the Constitutional Accountability Pharmacovigilance Responsibilities. Addressing drug manufacturers’ responsibilities of pharmacovigilance, the American Medical Association, as well as severalstate medical associations, observed that Canada and Full text of the Graves brief is available at European Union countries expressly impose post- marketing risk-management duties on brand-name andgeneric manufacturers alike.
Full text of the AAJ brief is available at The statutory framework and case law ‘‘supports the notion of an affirmative duty owed by drug manufactur- Full text of the Coalition Against Censorship ers in the United States—regardless of their position in line—to maintain the accuracy and adequacy of labels for products they sell,’’ their brief urged.
Full text of the torts’ professors brief is avail- Later-Emerging Risks. Several briefs pointed to ex- amples of risks that did not become apparent until drugs had been available as generic products for manyyears.
Full text of the AMA brief is available at These include the diet drug fenfluramine, which was introduced to the U.S. market in 1973 and withdrawn in Full text of the brief by the states is available late 1997, after two scientific articles brought to light significant cardiac and pulmonary side effects; and Ter- butaline sulfate, which was approved in the 1970s as anasthma drug, and later evolved into a treatment for pre- Full text of the brief by the administrative law term labor in obstetrics patients. As of Feb. 17, 2011, and civil procedure scholars is available at the drug must carry a black box warning because of post-marketing safety reports of heart problems and possible deaths, as well as a lack of data demonstrating Full text of Rep. Henry A. Waxman’s brief is Terbutaline sulfate is only available in generic form; the brand name products have been discontinued by thecompanies that formerly made them, the medical asso- Full text of the United States’ brief is available ciations said. Terbutaline, therefore, is a stark example of a drug with ‘‘no surveillance oversight’’ by the brand- name drug maker, the brief noted: For some one-thirdof all drugs, there is no longer a branded product avail- Full text of the brief by former New England able, according to the health care economists.
Journal of Medicine editors is available at Metoclopramide, the drug at issue here, was first marketed as Reglan in 1979; the drug was available in generic form by the mid-1980s. As new risk information Full text of the brief by the National Council of continued to emerge, the FDA ordered significant label changes for safety issues in 2004 and 2009, more than 25 years after its launch, amici said.
Dr. Christy Graves, who prescribed metoclopramide Full text of the health care economists’ brief is to Julie Demahy, said the actual risk of tardive dyskine- sia from long-term use of the drug was at least 100 times higher than it was portrayed in the metoclopr- Full text of the Public Justice/AARP brief is amide warnings in effect from 1985 through 2009.
‘‘Such information was readily available to generic manufacturers through the FDA’s publicly available da-tabase of reported adverse drug reactions,’’ Graves saidin a brief. ‘‘All the generic manufacturers needed to dowas monitor the medical literature for articles on their Finally, several amici cited recent news about the an- own drug and periodically check the FDA database for algesic Darvon. Darvon, known generically as propoxy- new reports relating to metoclopramide.’’ phene, was approved in 1957. In November 2010, the When the FDA finally considered the evidence of FDA requested that all manufacturers of branded and metoclopramide-induced TD in 2008-2009, it acted ‘‘de- generic products remove their products from the mar- cisively and urgently’’ to add a black box warning, ket after determining the risks of severe cardiac side ef- COPYRIGHT 2011 BY THE BUREAU OF NATIONAL AFFAIRS, INC.
fects outweighed the benefits of the drug. In 2007, some ness, including state wage and hour laws, state dis- 21.3 million prescriptions were filled for the generic crimination laws, and state torts for negligent manufac- combination of propoxyphene and acetaminophen, ture. ‘‘It has achieved success without exemption from those laws, and has demonstrated no real need for ex- Jerome P. Kassirer, M.D., former Editor-in-Chief of emption from the claims at issue here,’’ the economists The New England Journal of Medicine, and Paul D.
Stolley, M.D., M.P.H., epidemiologist, public health ex-pert, and former NEJM editorial board member, said Public Citizen, AARP. The AARP and Public Citizen re- only half of newly discovered serious adverse drug re- called that at hearings on the Hatch-Waxman Amend- actions are detected and documented within seven ments, generic drug industry representatives ‘‘recog- years after drug approval. Clinical trials typically study nized their continuing responsibility for their products only a few hundred or a few thousand people, and only Generic drug companies often are in the best position Federal law authorizes generic drug approval ‘‘when to take early action to address risks that come to light brand-name drugs’ legal protections end, not because once the branded drug’s patent exclusivity period ends, their safety profile has been definitely established,’’ because once generics are available, they often have the majority market share for the drug, according to thePublic Citizen/AARP brief.
Tort Claims Provide Incentives. The Hatch-Waxman in- According to Public Citizen/AARP, the manufacturers centives were intended to provide a means to deliver argued that litigating a case on the merits may require drug products equally safe as, yet less expensive, than speculation about how the FDA would have responded branded medication. States should not be foreclosed to their efforts to seek an enhanced warning. But in Le- vine, AARP and Public Citizen said, the court held that needed incentives to generic drug manufacturers to re- ‘‘absent clear evidence’’ that the FDA would not have port safety information to the FDA, the health care approved a label change, it was not impossible for the manufacturer to comply with state and federal require- Acknowledging the petitioners’ point that branded ments. The court, therefore, recognized that state tort manufacturers generally have greater access to their claims are not preempted because they might involve own unpublished drug-specific risk information than do speculation about agency action, the brief argued.
generic manufacturers, the economists said, ‘‘The ap-propriate comparison is not between branded and ge- Waxman: No Intent to Preempt. Rep. Henry A. Wax- neric manufacturers but between a product’s manufac- man, the architect of the Hatch-Waxman Amendments, turer and consumers.’’ State-law failure-to-warn litiga- affirmed that Congress did not intend categorically to tion mitigates this information asymmetry by aligning preempt failure-to-warn claims against generic drug the incentives of drug manufacturers and consumers.
The economists didn’t buy the theory that allowing Congress did include express preemption in legisla- state-law failure-to-warn litigation would cause a del- tion for medical devices in 1976 and for vaccines in uge of information that the FDA ‘‘neither wants nor 1986, the brief said. But the 1962 amendments to the needs.’’ The FDA is, after all, in the business of protect- FDCA, said, in part, that the amendments shall not be ing the public’s health, the economists said. And history construed as invalidating any provision of state law shows that manufacturers tend to under-report risk, not ‘‘unless there is a direct and positive conflict between such amendments and such provisions of State law.’’ The economists also said the manufacturers’ amici The Supreme Court’s recent decision in Bruesewitz v. incorrectly assume that the FDA is equipped to address Wyeth, finding preemption of design defect claims all health risk issues without the aid of reporting incen- against vaccine manufacturers, supports a finding of no preemption here, Waxman said. The Bruesewitz court The economists also discounted the generic drug expressed concern about preempting state claims when makers’ argument that because Congress meant their there was no federal remedy. In the vaccine cases, Con- products to be affordable, it must have intended to ex- gress established a no-fault compensation scheme. But empt them from the economic burdens associated with no such scheme is in place for generic drugs, and there production, including the cost of reporting available is no indication that Congress sought to displace tradi- risk information. The generic industry remains subject tional state-law tort remedies, he said.
to a wide range of laws that impose costs of doing busi-
of the authors and THE JOURNAL and not those of Failure of Estrogen Plus Progestin Therapy for Prevention Suzanne W. Fletcher, MD, MSc The WHI is the first randomized primary prevention trialof postmenopausal hormones, and the part of the study thatcompared estrogen/progestin with placebo was terminatedearly. The data and safety monitoring board (DSMB) rec-PPROXIMATELY 38% OF POSTMENOPAUSAL