Science and Law
7th January 2016

Pharmacogenomics and Product Liability Claims

Genomics is a topic of interest that is growing in the news and moving its way into the courtroom. We have been following the impact of genomics on litigation in a variety of areas, including its impact on pharmaceutical product liability litigation.

Pharmacogenomics and Product Liability Claims

Genomics is a topic of interest that is growing in the news and moving its way into the courtroom. We have been following the impact of genomics on litigation in a variety of areas, including its impact on pharmaceutical product liability litigation.

In a recent DRI article, James Beck identifies the following 6 ways in which pharmacogenomics may impact product liability litigation:

  • Pharmacogenomics Claims Concerning Safety
  • Pharmacogenomics Claims Concerning Efficacy
  • Pharmacogenomic Conditions Supporting Alternative Cause Defenses
  • Using Pharmacogenomic Conditions to Defeat Medical Monitoring Claims
  • Using Pharmacogenomic Conditions to Defeat Failure-to-Recall Claims
  • Pharmacogenomic Discovery

 

Beck states that currently most of the claims focusing on pharmacogenomics and safety have lacked scientific support and therefore worked in the favor of the defense. For example, Beck discusses a number of cases in which plaintiffs claimed to be possible carriers of adverse genetic markers and therefore suffered adverse consequences of pharmacotherapy. However, because none of these plaintiffs were tested for adverse genetic markers, these liability assertions did not prevail.

Because of the rapid advances being made in fields of molecular biology and sequences technologies, the costs for sequencing human genetic information has decreased dramatically, as shown in the figure below.

 

 

Based on these advances, it is likely the courts will increasingly require plaintiffs to undergo genetic testing when presenting pharmacogenomic cases. Below, we provide a few examples of medications in which its efficacy and safety and known to be affected by specific genomic profiles.

 

Ziagen (abacavir)

Abacavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Unfortunately, abacavir is limited by its adverse effect of serious and sometimes fatal hypersensitivity reactions. In 2002, two research groups reported an association between the diagnosis of abacavir induced hypersensitivity reactions and carriers of the HLA-B*5701 allele. This association was further confirmed through several more independent studies. Then, in early 2008, The New England Journal of Medicine published “HLA-B*5701 Screening for Hypersensitivity to Abacavir” which discussed an effective screening tool for prospectively identifying carriers of the HLA-B*5701 allele. Later that year, the FDA updated abacavir’s existing black box warning and contraindications to include the association between hypersensitivity reactions and HLA-B*5701 allele (the current label is available HERE).

This is an example of a medication for which the pharmacogenomic parameters impacting an adverse reaction are well understood. It has been well established that if a patient carries the HLA-B*5701 allele, they are at a very high risk of developing a hypersensitivity reaction. Due to the company’s diligent labeling, which includes a black box warning and a contraindication, if a plaintiff with the HLA-B*5701 allele claims that they were injured by the product, the company’s defense is clearly that the product is adequately labeled.

 

Plavix (clopidogrel)

Clopidgrel is a prodrug, which provides platelet inhibition through its active metabolite. Hence, impairment of clopidgrel’s metabolism decreases its effectiveness. As the enzyme, CYP2C19 is involved in clopidogrel’s metabolism, CYP2C19 poor metabolizers experience reduced effectiveness. In 2009, the FDA added a “Pharmacogenomics” section to clopidogrel’s label describing the effects the various CYP2C19 alleles have on the metabolism of clopidogrel. About one year later, the FDA elevated this information to a black box warning (the current label is available HERE).

Much like abacavir, clopidogrel is a medication for which the pharmacogenomic parameters are well understood. Patients who poorly metabolize clopidogrel experience decreased efficacy, which in some patients, could prevent them from receiving adequate preventative therapy or treatment. Again, this product is adequately labeled and has a black box warning. Thus, in a situation where a plaintiff might claim that the product injured them in some way based on their CYP2C19 status, the defense is clearly that the product is adequately labeled.

 

Platinol (cisplatin)

Cisplatin is indicated as therapy for metastatic testicular tumors, metastatic ovarian tumors, and advanced bladder cancer. A notable side-effect related to cisplatin is ototoxicity (i.e. damage to the inner ear), often referred to as cisplatin induced ototoxicity (CIO). This condition has been documented to occur as quickly as after a single dose and as delayed as months to years post-therapy, with severity ranging from tinnitus to deafness. According to the most recent label, CIO has been reported to occur in up to 31% of all patients after the first dose and at a higher rate in children, with an estimated 40-60% affected. Although studies conducted with the goal of identifying patients with increased risk of developing CIO have identified a number of clinical factors (e.g. dose, age, exposure to cranial irradiation, other ototoxic insults) as well as genetic factors (e.g. TPMT, COMT, XPC, ABCC3, GSTs, LRP2, ACYP2) which may contribute, much remains unknown. Given this ambiguity, cisplatin’s label states the following warning in the “Adverse Reactions: Ototoxicity” section, “genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may contribute to cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs” (the current label is available HERE).

In this example, the pharmacogenomics surrounding cisplatin’s adverse reaction, CIO, are not well understood and remain under investigation. However, the label certainly warns that some genetic factors may contribute to this adverse reaction, and this likely reflects the ambiguity of the current state of the science. In a situation where a plaintiff is claiming that they were injured by the product based on their genetic profile, the company may mount a defense that the product is adequately labeled based on the state of the science. This also highlights the need for attorneys and their clients to constantly monitor and keep up-to-date on the latest science.

 

Gemzar (gemcitabine) and Paraplatin (carboplatin)

Green et al. recently published “Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities” in which they successfully attempted to identify genetic markers associated with gemcitabine/carboplatin-induced myelosuppression. The authors’ exome sequenced 32 patients who experienced high neutropenia and thrombocytopenia, as well as those who experienced virtually no myelosuppression. Then, they compared the results through six different bioinformatics strategies. Once potential genetic variants were identified, the variants were validated in an additional 291 patients through correlating their genetic variation with their myelosuppression. The authors concluded that rs1453542 in OR4D6 is correlated with gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 is correlated with gemcitabine/carboplatin-induced thrombocytopenia.

The above example highlights the fact that new pharmacogenomic science is constantly emerging, and it is important for attorneys and their clients to stay up to date and fresh on the latest science.

Genomics is Changing Causation Evidence in the Courtroom Forever.

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