Civil Liability Threatens Pharmaceutical Companies, But Risks Can Be Mitigated
Pharmaceutical manufacturers are starting to worry that the recent trend in court decisions may leave them open to civil liability lawsuits.
To guard against this, companies need to consider how to mitigate risk in their choice of pipeline projects and in the way in which they conduct those projects.
Tailoring therapies to smaller patient populations, prioritizing projects in which the underlying science is better understood and for which well-vetted biomarkers have been developed, and choosing compounds for which toxicity is predictable will help to mitigate risk.
Designing studies to answer specific questions in an unambiguous manner, supporting continuing research into the development of better models of metabolism and toxicity, and working closely with the FDA to explore compound safety and efficacy will argue convincingly against fraud.
This is particularly important because of recent events taking place in federal courts.
In March, the U.
S.
Supreme Court's 4-4 vote allowed 27 Michigan residents to bring suit against Warner-Lambert for damages incurred by its diabetes drug Rezulin, which the company removed from the market in 2000 after reports of liver damage.
[Warner-Lambert Co.
v.
Kent, 128 S.
Ct.
1168 (2008) (per curium) in which Chief Justice John Roberts recused himself because of his investment in Pfizer, Warner-Lambert's parent company.
] Although Michigan law generally prohibits product liability lawsuits against manufacturers of FDA-approved drugs, people can sue if they can show that FDA approval was obtained fraudulently.
The Supreme Court was asked whether the FDA's approval of the drug in 1997 pre-empted Michigan law and blocked the plaintiffs from bringing suit against the manufacturer.
Their tie vote left standing an earlier opinion by the U.
S.
Court of Appeals for the 2nd Circuit that the Supreme Court's 2001 decision in Buckman v.
Plaintiffs' Legal Committee, which concerned medical device law and is unrelated to Michigan's immunity statute, did not apply in this case, allowing the suit to go forward.
Riegel Could Set the Stage A recent ruling in Riegel v.
Medtronic asserted that the FDA's pre-market approval of a balloon catheter pre-empted states from hearing cases alleging fraud on the FDA.
However, charges of manufacturing defects were not necessarily pre-empted.
In other words, Medtronic's catheter had passed the rigorous testing required by the FDA, and the company had complied with all regulatory requirements for approval.
A state court hearing liability claims would not be allowed to second-guess what the FDA had already approved.
However, if there was evidence that manufacturing specifications were not met in the particular medical device in question, restitution could probably be sought.
In October of this year, the Supreme Court will hear the case of Levine v.
Wyeth, which will not be complicated by state laws such as Michigan's.
In this case, Vermont state law failure-to-warn claims challenge the FDA's prior approval of a drug label.
Ethics and FDA Funding under Scrutiny These important cases come at a time when the ethics of drug makers and the capabilities of the under-funded FDA are being publicly questioned.
The argument of pre-emption assumes that the FDA, as a federal agency, is solely responsible for evaluating a potential product's efficacy and safety according to the regulations it has devised, and that it can and will deal with issues of fraud should they arise.
Allowing plaintiffs to argue fraud-on-the-FDA claims, some argue, would only hamper the agency's ability to do its job.
More serious considerations have been voiced by Justice Stephen Breyer concerning the appropriateness of allowing the lay-person to make decisions on matters of medical science.
The Supreme Court decided in favor of the manufacturer in Riegel v.
Medtronic, a case involving a product that was still on the market.
However, in Warner-Lambert v.
Kent, the Court did not block litigation on a product that had been removed from the market due to numerous and severe adverse events.
This suggests that products removed from the market due to significant adverse events may be targets for litigation in the future.
As state courts continue to challenge the authority of FDA scientists to decide, as Justice Breyer puts it, whether a drug is "on balance, going to save people or, on balance, going to hurt people," and instead assert the findings of a 12-person jury with no particular expertise, they may well open the door to class-action lawsuits involving FDA-approved products.
How to Mitigate Risk Regardless of how the courts ultimately decide, here are some steps that pharmaceutical companies can take now to mitigate risk in the future: oForget the concept of blockbuster drugs.
Although only a decade ago, blockbusters were the holy grail of the pharmaceutical industry, it is increasingly obvious that drugs should be tailored to smaller, more specific patient populations to avoid the widespread, devastating adverse events that have been under public scrutiny lately.
oChoose indications for which more of the biology of the mechanism of action and the repercussions of modulating it is really understood.
If licensing a candidate from another company, look beyond that company's discovery research efforts to verify and supplement their findings.
For in-house discovery efforts, resist the urge to move candidates forward until detailed knowledge of the pertinent biology has been documented and validated by the findings of other researchers.
oChoose compounds for which metabolism and toxicity can be predicted from structure.
Consider metabolic stability, the possibility of active metabolites, and whether these metabolites are likely to cause development-limiting toxicity or side-effects.
oChoose disease states/indications for which well-vetted biomarkers have been developed, or plan to co-develop biomarkers with your therapy.
The trend away from "one-size-fits-all" blockbuster drugs to more individualized therapies requires patient diagnosis and disease state monitoring.
As a result, biomarker test kits will become part of the pharmaceutical product.
oSupport research into the development of more predictive in vitro and in silico models of toxicity.
If this is not something your company can do in house, consider joining consortia or supporting academic research in this direction.
Make it clear to the FDA and to the public that you acknowledge the lack of adequately predictive models of toxicity, and that you are actively involved in remedying the situation.
oEnsure the careful planning of preclinical and clinical studies.
Each should be designed to answer a specific question in such a way that results are not ambiguous.
Complex studies designed to answer multiple questions are not recommended.
All too often the complexity obscures and confuses the results.
oLook for (and suspect) toxicological responses.
If there is any question, look further.
Compounds "killed" early in the development process are far less expensive than those that fail in Phase III or are removed from the market due to patient injury.
oBe diligent about reporting all study results to the FDA; be clear that you are interested in developing safe and effective medicines for patients in need and that you have a strong interest in moving the science forward both in the disease area of your project and in understanding any underlying toxicity issues.
To guard against this, companies need to consider how to mitigate risk in their choice of pipeline projects and in the way in which they conduct those projects.
Tailoring therapies to smaller patient populations, prioritizing projects in which the underlying science is better understood and for which well-vetted biomarkers have been developed, and choosing compounds for which toxicity is predictable will help to mitigate risk.
Designing studies to answer specific questions in an unambiguous manner, supporting continuing research into the development of better models of metabolism and toxicity, and working closely with the FDA to explore compound safety and efficacy will argue convincingly against fraud.
This is particularly important because of recent events taking place in federal courts.
In March, the U.
S.
Supreme Court's 4-4 vote allowed 27 Michigan residents to bring suit against Warner-Lambert for damages incurred by its diabetes drug Rezulin, which the company removed from the market in 2000 after reports of liver damage.
[Warner-Lambert Co.
v.
Kent, 128 S.
Ct.
1168 (2008) (per curium) in which Chief Justice John Roberts recused himself because of his investment in Pfizer, Warner-Lambert's parent company.
] Although Michigan law generally prohibits product liability lawsuits against manufacturers of FDA-approved drugs, people can sue if they can show that FDA approval was obtained fraudulently.
The Supreme Court was asked whether the FDA's approval of the drug in 1997 pre-empted Michigan law and blocked the plaintiffs from bringing suit against the manufacturer.
Their tie vote left standing an earlier opinion by the U.
S.
Court of Appeals for the 2nd Circuit that the Supreme Court's 2001 decision in Buckman v.
Plaintiffs' Legal Committee, which concerned medical device law and is unrelated to Michigan's immunity statute, did not apply in this case, allowing the suit to go forward.
Riegel Could Set the Stage A recent ruling in Riegel v.
Medtronic asserted that the FDA's pre-market approval of a balloon catheter pre-empted states from hearing cases alleging fraud on the FDA.
However, charges of manufacturing defects were not necessarily pre-empted.
In other words, Medtronic's catheter had passed the rigorous testing required by the FDA, and the company had complied with all regulatory requirements for approval.
A state court hearing liability claims would not be allowed to second-guess what the FDA had already approved.
However, if there was evidence that manufacturing specifications were not met in the particular medical device in question, restitution could probably be sought.
In October of this year, the Supreme Court will hear the case of Levine v.
Wyeth, which will not be complicated by state laws such as Michigan's.
In this case, Vermont state law failure-to-warn claims challenge the FDA's prior approval of a drug label.
Ethics and FDA Funding under Scrutiny These important cases come at a time when the ethics of drug makers and the capabilities of the under-funded FDA are being publicly questioned.
The argument of pre-emption assumes that the FDA, as a federal agency, is solely responsible for evaluating a potential product's efficacy and safety according to the regulations it has devised, and that it can and will deal with issues of fraud should they arise.
Allowing plaintiffs to argue fraud-on-the-FDA claims, some argue, would only hamper the agency's ability to do its job.
More serious considerations have been voiced by Justice Stephen Breyer concerning the appropriateness of allowing the lay-person to make decisions on matters of medical science.
The Supreme Court decided in favor of the manufacturer in Riegel v.
Medtronic, a case involving a product that was still on the market.
However, in Warner-Lambert v.
Kent, the Court did not block litigation on a product that had been removed from the market due to numerous and severe adverse events.
This suggests that products removed from the market due to significant adverse events may be targets for litigation in the future.
As state courts continue to challenge the authority of FDA scientists to decide, as Justice Breyer puts it, whether a drug is "on balance, going to save people or, on balance, going to hurt people," and instead assert the findings of a 12-person jury with no particular expertise, they may well open the door to class-action lawsuits involving FDA-approved products.
How to Mitigate Risk Regardless of how the courts ultimately decide, here are some steps that pharmaceutical companies can take now to mitigate risk in the future: oForget the concept of blockbuster drugs.
Although only a decade ago, blockbusters were the holy grail of the pharmaceutical industry, it is increasingly obvious that drugs should be tailored to smaller, more specific patient populations to avoid the widespread, devastating adverse events that have been under public scrutiny lately.
oChoose indications for which more of the biology of the mechanism of action and the repercussions of modulating it is really understood.
If licensing a candidate from another company, look beyond that company's discovery research efforts to verify and supplement their findings.
For in-house discovery efforts, resist the urge to move candidates forward until detailed knowledge of the pertinent biology has been documented and validated by the findings of other researchers.
oChoose compounds for which metabolism and toxicity can be predicted from structure.
Consider metabolic stability, the possibility of active metabolites, and whether these metabolites are likely to cause development-limiting toxicity or side-effects.
oChoose disease states/indications for which well-vetted biomarkers have been developed, or plan to co-develop biomarkers with your therapy.
The trend away from "one-size-fits-all" blockbuster drugs to more individualized therapies requires patient diagnosis and disease state monitoring.
As a result, biomarker test kits will become part of the pharmaceutical product.
oSupport research into the development of more predictive in vitro and in silico models of toxicity.
If this is not something your company can do in house, consider joining consortia or supporting academic research in this direction.
Make it clear to the FDA and to the public that you acknowledge the lack of adequately predictive models of toxicity, and that you are actively involved in remedying the situation.
oEnsure the careful planning of preclinical and clinical studies.
Each should be designed to answer a specific question in such a way that results are not ambiguous.
Complex studies designed to answer multiple questions are not recommended.
All too often the complexity obscures and confuses the results.
oLook for (and suspect) toxicological responses.
If there is any question, look further.
Compounds "killed" early in the development process are far less expensive than those that fail in Phase III or are removed from the market due to patient injury.
oBe diligent about reporting all study results to the FDA; be clear that you are interested in developing safe and effective medicines for patients in need and that you have a strong interest in moving the science forward both in the disease area of your project and in understanding any underlying toxicity issues.
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