A US court case by 1 000 plaintiffs against pharmaceutical company Merck has been dragging on since 2011, writes Gregory Curfman in JAMA Network, who poses the question: to what extent does our society want to immunise pharmaceutical companies from liability for not warning consumers about the adverse effects of drugs?
After 13 years in multiple courts at all levels of the federal judiciary, the plaintiffs in this case have not yet been provided a legal remedy for their injury. It is time for justice to be served.
He writes:
Since being approved by the FDA in 1995 for the prevention and treatment of osteoporosis, alendronate (Fosamax) has been observed to be associated with an unusual type of fracture – one which occurs spontaneously in the subtrochanteric segment of the femur, unrelated to trauma.
These low-energy full-thickness fractures are referred to as atypical femoral fractures. Since the alendronate mechanism of action is to reduce the rate of bone turnover, the drug increases bone density with the aim of reducing the risk of fractures. The occurrence of atypical femoral fractures was therefore unanticipated but is now well documented.
Atypical femoral fractures are believed to result from structural changes and potential instability in bone due to alendronate-induced reduction in the rate of bone turnover.2
In 2011, a group of around 1 000 plaintiffs who had been affected by atypical femoral fractures while receiving alendronate filed a lawsuit against Merck. The lawsuits were later combined in multi-district litigation in New Jersey.
The plaintiffs’ claim was that from 1995, when the drug was approved, until January 2011, the FDA-approved label for alendronate did not include a warning of the risk of atypical femoral fractures, despite the manufacturer having been aware of the problem for years.
Such a product liability claim is referred to in the law as a failure-to-warn claim. The drug manufacturer is responsible for the accuracy and completeness of the drug label, including providing updates when new information about adverse effects becomes available.
People affected by an adverse action from a medication not adequately described in the label may pursue a failure-to-warn claim.
The lawsuit against Merck has continued for 13 years and has been reviewed at all levels of the federal court system – district court, circuit court, and the Supreme Court.
Throughout this long legal journey, the plaintiffs have not received a just legal remedy.
Pre-empted
For its part, Merck has consistently argued that the plaintiff’s state law claim is pre-empted by federal law.
Pre-emption is an established legal doctrine – based on the Supremacy Clause of Article VI, Clause 2, of the Constitution – that when state law and federal law conflict, federal law takes precedence and pre-empts state law.
State-level lawsuits may therefore be pre-empted under certain circumstances when it is impossible to comply with both state and federal law.
For the plaintiff’s lawsuit against Merck to be pre-empted, two criteria must be met. First, Merck must fully inform the FDA of the clinical features of the adverse effect and provide an accurate and complete description of the problem.
Second, the FDA, being fully informed by the manufacturer of the nature of the adverse effect, must explicitly disapprove a change to the drug label to warn of atypical femoral fractures.
The injured plaintiffs argue that Merck never proposed a valid label change, and so the FDA could not reject a valid label change.
Consequently, the plaintiffs argue that neither of the twp criteria required for pre-emption was met in this case.
In 2008, Merck submitted a request to the FDA to update the alendronate label to include a warning about femoral fractures. This type of request is referred to as a Prior Approval Supplement (PAS), as the FDA must approve the proposed label change before it can take effect.
The FDA declined Merck’s request to update the alendronate label, but in the legal arguments in the lawsuit there has been persistent disagreement between the two parties about the FDA’s reasoning.
Merck has argued that the FDA declined the PAS because FDA scientists were not persuaded by the evidence that atypical femoral fractures were caused by alendronate. In contrast, the injured plaintiffs have argued that the FDA declined the PAS because Merck’s proposed label update was not an accurate description of atypical femoral fractures.
Stress fractures
Numerous times in the proposed update, Merck referred to atypical femoral fractures as stress fractures and suggested that clinicians should consider other risk factors, such as alcohol use, vitamin D deficiency, or too much physical exercise, as underlying causes.
The injured plaintiffs have argued that the FDA declined Merck’s proposed label change because FDA scientists thought that the use of the term stress fracture mischaracterised a very serious type of fracture, while most clinicians consider stress fractures to be relatively minor hairline fractures that develop in response to overuse injuries, such as in long-distance runners.
The plaintiffs have said that the FDA did not reject an accurate warning because Merck never submitted one. Instead, the injured plaintiffs believe that Merck was downplaying the adverse effect by refusing to use the term atypical femoral fracture in the proposed warning and that the FDA would have accepted an accurate warning.
In the FDA response to Merck, the agency made it clear that it would consider a revised warning if Merck would use the proper terminology (atypical femoral fracture) and provide an accurate update to the alendronate label.
Instead, Merck withdrew the PAS. Merck also could have placed its own updated warning on the alendronate label without advance FDA approval, an action referred to as Changes Being Effected (CBE).
Merck never implemented a CBE.
Responsibility of Merck
The plaintiffs argue that it was never impossible for Merck to change its label, and maintaining the accuracy of the drug label is always the responsibility of the manufacturer. Impossibility pre-emption, the plaintiffs argue, is not justified by the facts or the law.
Nevertheless, the judge in the US District Court for the District of New Jersey, the last court to enter an opinion in the case, did not agree with the plaintiffs’ interpretation and ruled that their case was pre-empted.
After this ruling, the plaintiffs appealed to the US Court of Appeals for the Third Circuit, where the case is now under review.
Throughout the litigation, Merck proffered the argument that the FDA recognises that there can be risk of over-warning about the adverse effects of drugs. In the case of alendronate, a warning on the label about atypical femoral fractures might discourage doctors from prescribing the drug for patients who might otherwise benefit.
As a counter-argument, withholding information about serious adverse effects of drugs because of concern about over-warning cannot be right: doctors and patients must be informed about potentially serious adverse effects, even if they are uncommon, so they can objectively weigh the risks and benefits for themselves.
Since 2007, the FDA has had the statutory authority to mandate changes to drug labels to include safety warnings based on its evaluation of new information about risks and benefits.
In the case of alendronate, the FDA did not use that authority until 2011, long after many individuals had been harmed.
Even though the manufacturer is responsible for its label at all times, the FDA may need to apply its statutory authority proactively to mandate label changes to appropriately warn patients and their physicians when warnings are indicated by clinical evidence.
When federal statutes are written, lawmakers may include an express pre-emption clause, which states that the provisions of federal law contained in the statute will generally pre-empt state law actions.
Such is the case with the Medical Device Amendments of the Food, Drug, and Cosmetic Act in 21 USC 360k(a) (2000); FDCA § 521(a). The express pre-emption clause for medical devices may block many state-level product liability lawsuits (FDA approval of a device becomes part of federal law).
A similar express pre-emption clause was not included in the Food, Drug, and Cosmetic Act for drugs. Congress believed that product liability litigation has an important role, along with FDA regulation, in securing the safety of drugs and intentionally did not include a drug pre-emption clause.
The case involving atypical femoral fractures caused by alendronate is now in the hands of the Third Circuit Court of Appeals, and the outcome will have broad implications for ensuring the safety of prescription drugs.
To what extent does our society want to immunise pharmaceutical companies from liability for not warning consumers about the adverse effects of drugs?
After 13 years in multiple courts at all levels of the federal judiciary, the plaintiffs in this case have not yet been provided a legal remedy for their injury. It is time for justice to be served.
Curfman (MD) is executive editor of JAMA
JAMA Network article – Fosamax Fractures—Justice Has Not Been Served (Open access)
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