Science and Law
13th November 2013

Will Traditional NSAIDs Be the Next Big Pharmaceutical Litigation?

In September 2004, Merck withdrew its blockbuster, prescription pain medication Vioxx in the wake of over 10,000 legal cases and nearly 200 class actions alleging adverse cardiovascular events from exposure to the drug.

Will Traditional NSAIDs Be the Next Big Pharmaceutical Litigation?

In September 2004, Merck withdrew its blockbuster, prescription pain medication Vioxx in the wake of over 10,000 legal cases and nearly 200 class actions alleging adverse cardiovascular events from exposure to the drug. Reeling from a number of multi-million dollar verdicts in various jurisdictions, Merck ultimately announced legal settlements with the US Attorney’s Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx for close to a billion dollars. Lawsuits involving heart attacks and strokes against other COX-2-specific prescription pain killers (e.g., Celebrex and Bextra) followed.

The COX-2 litigation was among the largest pharmaceutical personal injury legal actions in US history. And yet those legal actions may be only the beginning. Mass tort personal injury litigation involving other prescription and over-the-counter (OTC) non-steroidal anti-inflammatory (NSAID) drugs may be looming.

What Are NSAIDs?

Non-steroidal anti-inflammatory drugs (NSAIDs) are arguably the largest and most widely used drug class in the world. Every major pharmaceutical manufacturer in the world markets drugs that reduce inflammation by inhibiting the prostaglandin pathway, including well-known brands such as the following: Motrin (ibuprofen), Naprosyn (naproxen), and Voltaren (diclofenac).

NSAIDs exert their physiological action on the body by inhibiting the cyclooxygenase enzymes (COX-1 and COX-2). Because COX-1 appears to mediate the synthesis of prostaglandins responsible for protection of the stomach lining, inhibition of this enzyme is associated with gastrointestinal side effects. COX-2 was considered to be responsible for the synthetic pathway of prostaglandins related to pain and inflammation. Newer prescription agents (e.g., Vioxx, Celebrex, and Bextra) therefore aimed to be selective for the COX-2 enzyme. The idea was that these so-called “COX-2 inhibitors” would provide pain relief without associated gastrointestinal side effects.

All NSAIDs Have Cardiovascular Risks

Starting with the publication of the VIGOR study in September 2001, it became clear that Vioxx was associated with an increased risk of myocardial infarction and stroke. While the initial focus was on the COX-2 selective agents, by 2005, it became clear that other NSAIDs (including the OTC versions) also carried with them increased risk of cardiovascular side effects. By the 2005/2006 timeframe, meta-analyses were published linking not only COX-2 specific drugs, but also traditional (i.e., nonspecific agents) NSAIDs to increased cardiovascular risks. In 2005, FDA requested labeling changes for all NSAIDs highlighting the risk of cardiovascular events with these agents. The European Medicines Agency followed suit soon after, but concluded that the overall benefit-risk balance for NSAIDs “remains favorable.”

Large epidemiologic and randomized controlled studies have recently been conducted confirming the cardiovascular risks of NSAIDs and additional studies, including the PRECISION Study (Celebrex and ibuprofen) are underway. Most recently, a large systematic review was published concluding that “NSAIDs used in clinical practice, except naproxen are associated with an increased risk of AMI at high doses or in persons with diagnosed coronary heart disease.” From this study, it appears that cardiovascular risks are small but consistently elevated in almost all NSAIDS.

In October 2012 the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) finalized their review of recently published data and concluded:

“For diclofenac, the latest evidence appears to show a consistent but small increase in the risk of cardiovascular side effects for diclofenac compared with other NSAIDs, similar to the risks of COX-2 inhibitors, another class of painkillers.”

In June 2013, the EMA Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) endorsed the PRAC recommendation, stating:

“Overall, the benefits of this medicine are greater than its risks, but there is a small risk of heart attack or stroke in patients taking systemic diclofenac regularly, especially at high doses (150 mg daily) and for long periods.”

Will the Floodgates open?

Based on the widespread use of this drug class, taken in conjunction with the large amount of science that has been published in the recent past, it seems reasonable to predict that FDA will take some sort of action in the near future. For example, back in 2005, FDA held Advisory Committee hearings on COX-2 inhibitors and they evaluated studies related to traditional NSAIDs.

New FDA actions, including the potential for Advisory Committee hearings, could affect both Rx and OTC NSAIDs and set the stage for a reenactment of the “aspirin wars,” pitting one product against another. All of which will provide fodder for future litigation.  Depending on the nature of FDA’s action, what kind of studies they insist that the manufacturers conduct, and the nature of the changes imposed on the product’s warnings, litigation that follows could be significant.

Some Important Questions for the Future

As the scrutiny on the cardiovascular risks of NSAIDs mounts, some questions will be critical to address.

  • Are the cardiovascular risks truly a class-wide effect or do some NSAID molecules carry a greater risk than others?
  • Are the risks similar or different for acute myocardial infarction, stroke, and vascular death?
  • Are the safety risks only relevant for individuals with preexisting cardiovascular risk factors or is there a risk for all individuals?
  • Is the risk limited to high dose/long-term exposure or should individuals taking normal doses on a short-term basis (including those using OTC products) have a cause of concern?
  • Since most of the studies are observational in nature, what role does bias and/or residual confounding play in the interpretation of the findings?

Clearly, if litigation ensues, it will be important to address some or all of these questions moving forward.

What Steps Can You Take?

If you or your client faces the risk of litigation involving cardiovascular risk from traditional NSAIDs there is clearly lots of work to be done. Among the tasks that should you should consider seeking scientific support include the following:

  • Review and evaluate product labeling history
  • Develop a keen understanding of the pharmacology
  • Develop your expert team – past relationships are key!
  • Identify and evaluate all of the relevant science – there are dozens of published and ongoing studies
  • Analyze FDA spontaneous event reporting (AERS and FAERS data)
  • Evaluate what was known about cardiovascular risks (and when it was known) related to the product of interest

We will be posting on each of these topics in coming weeks and months as the NSAID situation heats up. Stay tuned!

About Innovative Science Solutions

Innovative Science Solutions (ISS) is a leading scientific consulting firm for the worldwide pharmaceutical, biotechnology, and medical device industries. We are an expert team of scientists, regulatory strategists, and consultants providing a wide range of fully-integrated services to industry and counsel including:

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