Medicolegal aspects of generic drugs

Question: A doctor writes a refill for 0.075-mg Synthroid, which the pharmacist substituted with a generic l-thyroxine preparation. The doctor’s prescription did not specify "do not substitute," and the pharmacist did not call for approval before switching. One year later, the patient was noted to be in atrial fibrillation with a suppressed serum TSH (thyroid-stimulating hormone) level, but there was no earlier EKG or serum TSH measurement for comparison. Which of the following is best?

A. A generic drug is identical to the branded version in chemical composition and bioavailability.

B. Thyroxine has a narrow therapeutic index, so substitution with a generic version is forbidden.

C. The doctor should have checked serum TSH every 3 months.

D. The pharmacist should have asked for physician approval before switching.

E. In a malpractice lawsuit against the doctor, the patient’s biggest legal hurdle is to prove breach and causation.

Answer: E. Although a generic drug contains the same active chemical as its brand-name analogue and is considered "bioequivalent," it is not identical as to bioavailability (see below).

For some drugs, the health care provider should exercise greater caution when using generics, as the therapeutic window is narrow and toxicity may result. Thyroxine is such an example, but use of the generic version is still entirely within the standard of care. Checking serum TSH levels in this case is a good idea, but this does not have to be done every 3 months unless there is another change in preparation or clinical signs and/or symptoms so dictate.

Under many state statutes, there is no requirement for a pharmacist to seek physician approval prior to generic substitution, unless it is plainly written into the prescription. Choice E is best in this hypothetical situation, because the tort of negligence requires a plaintiff to prove the defendant’s breach of duty as well as causation, and both elements will face defense rebuttal under the given facts.

The U.S. Food and Drug Administration is the governmental body that regulates prescription drugs. In 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act, popularly known as the Hatch-Waxman Act. This allowed generic versions of drugs to proliferate, but it also extended patent life for proprietary drug manufacturers whose profits were threatened by the onslaught of the cheaper generic copycats.

In order for the FDA to ensure that generics were equivalently safe and effective without requiring the same stringent clinical trials, it relied on the concept of bioequivalence, which is a statistical interpretation of a drug’s bioavailability. The latter measures the rate and extent of a drug’s absorption, generally defined by its maximum plasma concentration (C-max) and the area under the curve (AUC).

The FDA defines bioequivalence as "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." In statistical terms, this translates into allowing a generic to vary from 80% to 125% of the original drug.

Bioequivalent drugs are tabulated in the FDA’s Orange Book, which pharmacists rely upon when switching preparations.

In the vast majority of cases, a difference in bioavailability of a generic drug ranging from 20% less to 25% more than a brand-name drug exerts no effect on therapeutic outcome. However, in drugs with a narrow therapeutic index (the FDA’s preferred term is narrow therapeutic ratio), there is only a small difference between therapeutic and toxic plasma levels, usually less than a twofold difference between the median lethal dose and the median effective dose. Generic substitution should therefore proceed, if at all, with careful dose titration and monitoring. Some examples of drugs with a narrow therapeutic index are warfarin, digoxin, phenytoin, cyclosporin, levothyroxine, lithium, carbamazepine, clonidine, minoxidil, and theophylline.

The case of Winn Dixie of Montgomery, Inc. v. Colburn (709 So.2d 1222 [Ala. 1998]) illustrates some of the issues faced by drug substitution, although this case did not involve an actual generic switch.

In Colburn, the doctor wrote a prescription for Sedapap, a non–codeine-containing compound, to treat his patient’s migraine, but the pharmacist negligently substituted it with Fiorinal #3, which contains codeine. The doctor had checked off on the line "product selection permitted," which meant a generic substitution was acceptable. The pharmacy’s computer drug profile erroneously listed Sedapap and Fiorinal #3 as being equivalent, whereas they are in fact different compounds, therapeutically equivalent but not having generic bioequivalence.

It turned out the patient had a known serious allergy to codeine and developed an anaphylactic reaction after taking the substituted drug. The court found for the plaintiff, and held both the pharmacist and the drugstore liable for damages of $130,000. There was evidence at trial that the pharmacist had called the doctor’s office, which did not give approval for the substitution!

It is estimated that three-quarters of prescriptions are filled with generic substitutes, the law and the substantial cost savings prompting formularies to offer them to an eager public. Numerous state statutes have been enacted to regulate generic substitutions, although these laws vary in important aspects, such as permissible versus mandatory (automatic) substitutions, the roles of pharmacist and prescribing doctor, and exceptions to generic drug switch.

Prescriptions drugs cost $269.2 billion in 2011, a significant portion of total national health spending of $2.7 trillion, and are expected to cost even more, according to estimates by the Centers for Medicare and Medicaid Services. Increasing use of generics should attenuate this escalating price tag. For example, a recent study of drugs in disease prevention reported that whereas blood pressure reduction with a brand-name drug would cost an estimated $53,000 per quality-adjusted life-year (QALY), this figure would drop dramatically to less than $8,000 with the use of a generic substitute (Health Aff. (Millwood) 2011;30:1351-7).

Two 2013 U.S. Supreme Court cases address additional issues surrounding generic drugs.

In Mutual Pharmaceutical Co. v. Bartlett (133 S. Ct. 2466 [2013]), the court held that a generic manufacturer cannot be held liable for inadequate warnings if its labeling faithfully tracks that of the proprietary drug – in this case, the nonsteroidal anti-inflammatory drug sulindac. Federal law forbids any deviation from the parent label, and trumps any other legal premises otherwise afforded by state tort law. It was a case that dealt with failure to adequately warn of the rare but serious complication of toxic epidermal necrolysis, which the patient developed after using a generic version of the drug.

In Federal Trade Commission v. Actavis (133 S. Ct. 2223 [2013]), the court held that “reverse payment” agreements are subject to antitrust scrutiny to ensure they are not anticompetitive. The general issue concerns vulnerable brand-name drugs about to lose their patent protection. A generic firm would place its version into the marketplace before the parent drug’s expiration date. To avoid a costly legal battle and loss of profits in the interim, the proprietary drug manufacturer would be incentivized to negotiate for a rollback of the generic drug’s release in exchange for a payout (“pay-for-delay”).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. It is adapted from the author’s book, "Medical Malpractice: Understanding the Law, Managing the Risk" (2006). For additional information, readers may contact the author at [email protected].

Question: A doctor writes a refill for 0.075-mg Synthroid, which the pharmacist substituted with a generic l-thyroxine preparation. The doctor’s prescription did not specify "do not substitute," and the pharmacist did not call for approval before switching. One year later, the patient was noted to be in atrial fibrillation with a suppressed serum TSH (thyroid-stimulating hormone) level, but there was no earlier EKG or serum TSH measurement for comparison. Which of the following is best?

A. A generic drug is identical to the branded version in chemical composition and bioavailability.

B. Thyroxine has a narrow therapeutic index, so substitution with a generic version is forbidden.

C. The doctor should have checked serum TSH every 3 months.

D. The pharmacist should have asked for physician approval before switching.

E. In a malpractice lawsuit against the doctor, the patient’s biggest legal hurdle is to prove breach and causation.

Answer: E. Although a generic drug contains the same active chemical as its brand-name analogue and is considered "bioequivalent," it is not identical as to bioavailability (see below).

For some drugs, the health care provider should exercise greater caution when using generics, as the therapeutic window is narrow and toxicity may result. Thyroxine is such an example, but use of the generic version is still entirely within the standard of care. Checking serum TSH levels in this case is a good idea, but this does not have to be done every 3 months unless there is another change in preparation or clinical signs and/or symptoms so dictate.

Under many state statutes, there is no requirement for a pharmacist to seek physician approval prior to generic substitution, unless it is plainly written into the prescription. Choice E is best in this hypothetical situation, because the tort of negligence requires a plaintiff to prove the defendant’s breach of duty as well as causation, and both elements will face defense rebuttal under the given facts.

The U.S. Food and Drug Administration is the governmental body that regulates prescription drugs. In 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act, popularly known as the Hatch-Waxman Act. This allowed generic versions of drugs to proliferate, but it also extended patent life for proprietary drug manufacturers whose profits were threatened by the onslaught of the cheaper generic copycats.

In order for the FDA to ensure that generics were equivalently safe and effective without requiring the same stringent clinical trials, it relied on the concept of bioequivalence, which is a statistical interpretation of a drug’s bioavailability. The latter measures the rate and extent of a drug’s absorption, generally defined by its maximum plasma concentration (C-max) and the area under the curve (AUC).

The FDA defines bioequivalence as "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." In statistical terms, this translates into allowing a generic to vary from 80% to 125% of the original drug.

Bioequivalent drugs are tabulated in the FDA’s Orange Book, which pharmacists rely upon when switching preparations.

In the vast majority of cases, a difference in bioavailability of a generic drug ranging from 20% less to 25% more than a brand-name drug exerts no effect on therapeutic outcome. However, in drugs with a narrow therapeutic index (the FDA’s preferred term is narrow therapeutic ratio), there is only a small difference between therapeutic and toxic plasma levels, usually less than a twofold difference between the median lethal dose and the median effective dose. Generic substitution should therefore proceed, if at all, with careful dose titration and monitoring. Some examples of drugs with a narrow therapeutic index are warfarin, digoxin, phenytoin, cyclosporin, levothyroxine, lithium, carbamazepine, clonidine, minoxidil, and theophylline.

The case of Winn Dixie of Montgomery, Inc. v. Colburn (709 So.2d 1222 [Ala. 1998]) illustrates some of the issues faced by drug substitution, although this case did not involve an actual generic switch.

In Colburn, the doctor wrote a prescription for Sedapap, a non–codeine-containing compound, to treat his patient’s migraine, but the pharmacist negligently substituted it with Fiorinal #3, which contains codeine. The doctor had checked off on the line "product selection permitted," which meant a generic substitution was acceptable. The pharmacy’s computer drug profile erroneously listed Sedapap and Fiorinal #3 as being equivalent, whereas they are in fact different compounds, therapeutically equivalent but not having generic bioequivalence.

It turned out the patient had a known serious allergy to codeine and developed an anaphylactic reaction after taking the substituted drug. The court found for the plaintiff, and held both the pharmacist and the drugstore liable for damages of $130,000. There was evidence at trial that the pharmacist had called the doctor’s office, which did not give approval for the substitution!

It is estimated that three-quarters of prescriptions are filled with generic substitutes, the law and the substantial cost savings prompting formularies to offer them to an eager public. Numerous state statutes have been enacted to regulate generic substitutions, although these laws vary in important aspects, such as permissible versus mandatory (automatic) substitutions, the roles of pharmacist and prescribing doctor, and exceptions to generic drug switch.

Prescriptions drugs cost $269.2 billion in 2011, a significant portion of total national health spending of $2.7 trillion, and are expected to cost even more, according to estimates by the Centers for Medicare and Medicaid Services. Increasing use of generics should attenuate this escalating price tag. For example, a recent study of drugs in disease prevention reported that whereas blood pressure reduction with a brand-name drug would cost an estimated $53,000 per quality-adjusted life-year (QALY), this figure would drop dramatically to less than $8,000 with the use of a generic substitute (Health Aff. (Millwood) 2011;30:1351-7).

Two 2013 U.S. Supreme Court cases address additional issues surrounding generic drugs.

In Mutual Pharmaceutical Co. v. Bartlett (133 S. Ct. 2466 [2013]), the court held that a generic manufacturer cannot be held liable for inadequate warnings if its labeling faithfully tracks that of the proprietary drug – in this case, the nonsteroidal anti-inflammatory drug sulindac. Federal law forbids any deviation from the parent label, and trumps any other legal premises otherwise afforded by state tort law. It was a case that dealt with failure to adequately warn of the rare but serious complication of toxic epidermal necrolysis, which the patient developed after using a generic version of the drug.

In Federal Trade Commission v. Actavis (133 S. Ct. 2223 [2013]), the court held that “reverse payment” agreements are subject to antitrust scrutiny to ensure they are not anticompetitive. The general issue concerns vulnerable brand-name drugs about to lose their patent protection. A generic firm would place its version into the marketplace before the parent drug’s expiration date. To avoid a costly legal battle and loss of profits in the interim, the proprietary drug manufacturer would be incentivized to negotiate for a rollback of the generic drug’s release in exchange for a payout (“pay-for-delay”).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. It is adapted from the author’s book, "Medical Malpractice: Understanding the Law, Managing the Risk" (2006). For additional information, readers may contact the author at [email protected].

Question: A doctor writes a refill for 0.075-mg Synthroid, which the pharmacist substituted with a generic l-thyroxine preparation. The doctor’s prescription did not specify "do not substitute," and the pharmacist did not call for approval before switching. One year later, the patient was noted to be in atrial fibrillation with a suppressed serum TSH (thyroid-stimulating hormone) level, but there was no earlier EKG or serum TSH measurement for comparison. Which of the following is best?

A. A generic drug is identical to the branded version in chemical composition and bioavailability.

B. Thyroxine has a narrow therapeutic index, so substitution with a generic version is forbidden.

C. The doctor should have checked serum TSH every 3 months.

D. The pharmacist should have asked for physician approval before switching.

E. In a malpractice lawsuit against the doctor, the patient’s biggest legal hurdle is to prove breach and causation.

Answer: E. Although a generic drug contains the same active chemical as its brand-name analogue and is considered "bioequivalent," it is not identical as to bioavailability (see below).

For some drugs, the health care provider should exercise greater caution when using generics, as the therapeutic window is narrow and toxicity may result. Thyroxine is such an example, but use of the generic version is still entirely within the standard of care. Checking serum TSH levels in this case is a good idea, but this does not have to be done every 3 months unless there is another change in preparation or clinical signs and/or symptoms so dictate.

Under many state statutes, there is no requirement for a pharmacist to seek physician approval prior to generic substitution, unless it is plainly written into the prescription. Choice E is best in this hypothetical situation, because the tort of negligence requires a plaintiff to prove the defendant’s breach of duty as well as causation, and both elements will face defense rebuttal under the given facts.

The U.S. Food and Drug Administration is the governmental body that regulates prescription drugs. In 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act, popularly known as the Hatch-Waxman Act. This allowed generic versions of drugs to proliferate, but it also extended patent life for proprietary drug manufacturers whose profits were threatened by the onslaught of the cheaper generic copycats.

In order for the FDA to ensure that generics were equivalently safe and effective without requiring the same stringent clinical trials, it relied on the concept of bioequivalence, which is a statistical interpretation of a drug’s bioavailability. The latter measures the rate and extent of a drug’s absorption, generally defined by its maximum plasma concentration (C-max) and the area under the curve (AUC).

The FDA defines bioequivalence as "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." In statistical terms, this translates into allowing a generic to vary from 80% to 125% of the original drug.

Bioequivalent drugs are tabulated in the FDA’s Orange Book, which pharmacists rely upon when switching preparations.

In the vast majority of cases, a difference in bioavailability of a generic drug ranging from 20% less to 25% more than a brand-name drug exerts no effect on therapeutic outcome. However, in drugs with a narrow therapeutic index (the FDA’s preferred term is narrow therapeutic ratio), there is only a small difference between therapeutic and toxic plasma levels, usually less than a twofold difference between the median lethal dose and the median effective dose. Generic substitution should therefore proceed, if at all, with careful dose titration and monitoring. Some examples of drugs with a narrow therapeutic index are warfarin, digoxin, phenytoin, cyclosporin, levothyroxine, lithium, carbamazepine, clonidine, minoxidil, and theophylline.

The case of Winn Dixie of Montgomery, Inc. v. Colburn (709 So.2d 1222 [Ala. 1998]) illustrates some of the issues faced by drug substitution, although this case did not involve an actual generic switch.

In Colburn, the doctor wrote a prescription for Sedapap, a non–codeine-containing compound, to treat his patient’s migraine, but the pharmacist negligently substituted it with Fiorinal #3, which contains codeine. The doctor had checked off on the line "product selection permitted," which meant a generic substitution was acceptable. The pharmacy’s computer drug profile erroneously listed Sedapap and Fiorinal #3 as being equivalent, whereas they are in fact different compounds, therapeutically equivalent but not having generic bioequivalence.

It turned out the patient had a known serious allergy to codeine and developed an anaphylactic reaction after taking the substituted drug. The court found for the plaintiff, and held both the pharmacist and the drugstore liable for damages of $130,000. There was evidence at trial that the pharmacist had called the doctor’s office, which did not give approval for the substitution!

It is estimated that three-quarters of prescriptions are filled with generic substitutes, the law and the substantial cost savings prompting formularies to offer them to an eager public. Numerous state statutes have been enacted to regulate generic substitutions, although these laws vary in important aspects, such as permissible versus mandatory (automatic) substitutions, the roles of pharmacist and prescribing doctor, and exceptions to generic drug switch.

Prescriptions drugs cost $269.2 billion in 2011, a significant portion of total national health spending of $2.7 trillion, and are expected to cost even more, according to estimates by the Centers for Medicare and Medicaid Services. Increasing use of generics should attenuate this escalating price tag. For example, a recent study of drugs in disease prevention reported that whereas blood pressure reduction with a brand-name drug would cost an estimated $53,000 per quality-adjusted life-year (QALY), this figure would drop dramatically to less than $8,000 with the use of a generic substitute (Health Aff. (Millwood) 2011;30:1351-7).

Two 2013 U.S. Supreme Court cases address additional issues surrounding generic drugs.

In Mutual Pharmaceutical Co. v. Bartlett (133 S. Ct. 2466 [2013]), the court held that a generic manufacturer cannot be held liable for inadequate warnings if its labeling faithfully tracks that of the proprietary drug – in this case, the nonsteroidal anti-inflammatory drug sulindac. Federal law forbids any deviation from the parent label, and trumps any other legal premises otherwise afforded by state tort law. It was a case that dealt with failure to adequately warn of the rare but serious complication of toxic epidermal necrolysis, which the patient developed after using a generic version of the drug.

In Federal Trade Commission v. Actavis (133 S. Ct. 2223 [2013]), the court held that “reverse payment” agreements are subject to antitrust scrutiny to ensure they are not anticompetitive. The general issue concerns vulnerable brand-name drugs about to lose their patent protection. A generic firm would place its version into the marketplace before the parent drug’s expiration date. To avoid a costly legal battle and loss of profits in the interim, the proprietary drug manufacturer would be incentivized to negotiate for a rollback of the generic drug’s release in exchange for a payout (“pay-for-delay”).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. It is adapted from the author’s book, "Medical Malpractice: Understanding the Law, Managing the Risk" (2006). For additional information, readers may contact the author at [email protected].