Brand-name manufacturers and many neurologists see danger in generic substitution, but the FDA insists that the practice is safe
In the war between brand-name drug companies and generics manufacturers, each side is almost religious in its orthodoxy and intransigence.
The ground they fight over is the patient. On one side are the large pharmaceutical companies, periodically joined by the disease-specific foundations they help fund. On the other side are public and private payers trying to keep drug costs down.
Caught in the middle are the Food and Drug Administration, Medicare, Medicaid, pharmacists and state legislatures. At stake is billions of dollars in drug costs. Trying to make sense of it, let alone trying to determine the truth, is exasperating.
“Hope springs eternal with the brand-name manufacturers,” says John Rector, general counsel for the National Community Pharmacists Association. “They always appear to find some way, some new way, to battle the generics.”
The current battle primarily is centered on antiepilepsy drugs, but manufacturers of immunosuppressants for transplant and cancer patients and arrhythmia drugs are also skirmishing. The fight is over the concept of bioequivalence.
For a generic to be approved by the FDA under the rules governing abbreviated new drug applications, it must contain the same active ingredients as the innovator drug, though inactive ingredients may vary. The generic formulation must be identical in strength, dosage form, and route of administration, and must have the same use indications as the original marketed drug. It must be bioequivalent to the innovator drug; meet the same batch requirements for identity, strength, purity, and quality; and be manufactured under the same strict standards required for innovator products.
Bioequivalence is further defined by a drug’s ability to dissolve in approximately the same amount of time as the innovator product. Based on information provided by the manufacturer of the generic, the FDA determines how much of the active ingredient enters the bloodstream, how fast it does so, and how long it takes to leave the body — what is known as bioavailability.
“The important issue is absorption rates,” says Harvard neurologist Steven Schachter, MD. “That is the gist of the issue for clinicians, societies, and foundations. There are repeated reports that there is a difference among the generic substitutions for many drugs in certain classes, such as epilepsy drugs.”
The National Kidney Foundation has repeatedly expressed concern that generic bioequivalence is lacking for many immunosuppressants used by transplant and cancer patients. These are said to have narrow therapeutic ranges within very specific dosing requirements. The American Heart Association has expressed similar concerns about antiarrhythmic drugs used to manage tachyarrhythmia.
The battle over antiepilepsy drugs (AEDs) now occurring in state legislatures best exemplifies the confusion and tension. The Epilepsy Foundation is particularly vocal. The foundation, a not-for-profit group supported in part by the drug industry, says switching to generics could cause life-threatening seizures.
Most of the action is taking place in state legislatures. The Epilepsy Foundation is proposing model legislation to the states about epilepsy drug generic substitution:
“A pharmacist may not interchange an antiepileptic drug or formulation of an antiepileptic drug, brand or generic, for the treatment of seizures (epilepsy) without prior notification of and the signed informed consent of such interchange from the prescribing physician and patient, or patient’s parent, legal guardian or spouse of such person.”
The laws governing generic substitution vary by state, regardless of whether payment is through a public insurer like Medicaid or through a private insurer. All states have laws requiring that brand drugs be dispensed if so ordered by a prescribing physician, but most states allow pharmacists to make a generic substitution if a prescription is not specifically marked “dispense as written” (DAW). In more than a dozen states, generic substitution is mandated unless a physician specifically marks a script DAW.
At the urging of the Epilepsy Foundation and other advocacy organizations, legislators in 18 states are considering laws that would ban generic substitution for epilepsy drugs. In 40 states, legislatures are considering laws that would require pharmacists to contact a physician to substitute a generic epilepsy drug, regardless of whether it was marked DAW or not. In Tennessee such a law was recently passed and signed by the governor, although it made exceptions for nursing homes, hospitals, and some assisted living facilities. (More information about state laws governing AEDs is available at www.epilepsy.com.)
In Ohio, legislation was recently proposed that would require pharmacists to notify physicians and patients when substituting a drug used to treat epilepsy. The Ohio Pharmacists Association (OPA) opposes the legislation because pharmacists are already required to inform a patient that he or she may refuse an available generic and prescribers always have the option of marking a prescription DAW. The OPA is concerned that the proposed law would “greatly reduce the efficiency of the pharmacist,” according to a statement issued by the OPA.
The role of carve outs
Generic proponents such as the Generics Pharmaceutical Manufacturers Association (GPhA) and the Pharmacy Care Management Association (PCMA), the pharmacy benefit management trade organization, call these attempts “carve-outs” because they separate specific therapeutic classes of drugs for an additional substitution requirement at the dispensing level.
“Carve-outs keep affordable medicines from consumers,” says Kathleen Jaeger, GPhA president and CEO. “These anti-generic-substitution policies run contrary to the FDA’s stating that the generics are the same medicines as the brands with the same benefits and results. They also increase state Medicaid program costs by millions of dollars without any credible, independent evidence-based studies that indicate that using a brand drug will result in a different outcome than using a generic.”
Four major brand-name drugs used for epilepsy are expected to lose patent protection and face generic competition between next year and 2010. The four drugs generated $5 billion in U.S. sales in 2006, according to IMS Health, meaning the state legislation could have a significant economic effect. (Some of the $5 billion is for sales of the drugs for other uses.)
Carve-outs “undermine the patient’s access to generic medications, increase costs and increase a pharmacist’s workload,” says Mark Merritt, PCMA president. He views the proposed legislation as “one more attempt by brand manufacturers to force pharmacists to do their work for them by promoting the use of brand drugs. If physicians want to mark an epilepsy script DAW, they can and will.”
Generics proponents say that every time blockbuster drug patents are about to expire, the pharmaceutical companies — often through the foundations and professional organizations they support — try to make generic substitution for those drugs more difficult.
This is, in fact, a reoccurring story. In the late 1990s, the Epilepsy Foundation raised concerns about anecdotal reports that some patients experienced seizures and side effects after switching epilepsy drugs. Some of the episodes involved patients who had been switched to a generic from a branded drug. The foundation also expressed concern about cases in which patients were switched from one generic version of a drug to another generic version of the same drug.
Similar concerns were being expressed about other drugs. In 1998, DuPont had waged a campaign to convince state legislatures and state agencies to limit the ability of pharmacists to switch patients to warfarin. The company said that its anticoagulant Coumadin is a “narrow therapeutic index” drug, meaning that there is a narrow range of safe blood levels of the drug. Too little of the drug leads to strokes, and too much leads to internal bleeding. The implication was that the generic had a different therapeutic index.
There was a lot of money at stake. Back then, Coumadin was generating about $500 million in yearly sales for DuPont. The company pursued legislation in dozens of states to prohibit drug switching unless a druggist first got a doctor’s approval — essentially the same legislation that the Epilepsy Foundation wants now.
DuPont’s campaign worked: A number of states did pass laws requiring health system pharmacists to check with physicians.
The FDA wrote to doctors and said that the generic warfarin was equivalent. The agency said it viewed the efforts by DuPont as undermining the generics approval process by calling into question the underlying science. “There are no documented examples of a generic product manufactured to meet its approved specifications that could not be used interchangeably with the corresponding brand-name drug,” an FDA associate commissioner, Stuart Nightingale, MD, wrote to 200 medical groups in 1998.
“Additional clinical tests or examinations by the health care provider are not needed when a generic drug product is substituted for the brand-name product.”
The agency issued a public statement warning DuPont, “We cannot overstate the seriousness with which we regard DuPont’s false and misleading promotion of Coumadin.”
It’s medical, not political
The issue is medical, not political, says Harvard’s Schachter, a member of the board of directors of the Epilepsy Foundation. Of concern is that bioequivalence studies are generally performed on a limited number of healthy volunteers, not on patients.
Specifically, Schachter says, the bioequivalence of generic AEDs is not tested on patients with epilepsy. Doses used in studies may not yield relevant ranges of serum concentrations, and bioequivalence does not guarantee that a generic will produce the same therapeutic effect or result in the same adverse effects as the branded drug.
What’s more, “The characteristics of epilepsy and the potential serious ramifications of therapy failure must be considered,” says Schachter. “Epilepsy is not like other medical conditions, such as elevated cholesterol, because of the seriousness of seizure events. Epilepsy patients are particularly vulnerable to the disadvantages of generic products, since slight deviations in the serum concentrations of AEDs can be the difference between keeping a patient seizure-free and the occurrence of a breakthrough seizure. A breakthrough seizure after a long remission can have significant psychosocial and physical consequences for the epilepsy patient in areas of life such as employment and driving, and could lead to injury.”
Too serious to take any chances, he says. “I have no problem with generics. I believe they’re valuable to our society and to patients,” says Schachter. “If I could guarantee that each generic my patient was receiving was identical, I would feel more assured. But the generics themselves vary by manufacturer, and there can be dozens of manufacturers after the exclusivity period.”
Schachter is far from alone in his concern. In a study from the Strong Epilepsy Center at the University of Rochester (N.Y.) Medical Center, published last year in Applied Neurology, two thirds of reporting physicians said that a patient in their care experienced a breakthrough seizure when switched from a brand-name to a generic AED.
“Our online study shows that there is a significant problem, and there are consequences to this,” said Mark Berg, MD, who led the study.
Of the physicians who participated in the survey, 90 percent said they believed that generic substitution for a patient’s regular, effective AED might result in breakthrough seizures. One in three patients (34 percent) also believed this to be true. The overall effectiveness of generic AEDs also was a concern to 75 percent of the physicians and 65 percent of patients.
Notwithstanding the concerns of physicians, to date there has been no in-depth study of whether drug-switching actually can cause epileptic seizures. “There is a good deal of anecdotal evidence,” says Schachter, “and the issue is discussed by neurologists at every professional seminar or meeting.”
In May 2006, the Epilepsy Foundation convened a committee of medical experts to examine the question. The committee found a lack of authoritative studies showing that such drug switches cause problems, says Schachter, who chaired the committee. “We do believe that doctors should give explicit approval for drug switches. An attack can cause serious injury or death. The effects can be devastating.”
He said that the foundation is now studying the design of a study that can determine the effect of drug switching.
A breakthrough seizure can have serious consequences, so if there is a way “to guarantee that each generic was identical, I would feel assured,” says Steven Schachter, MD.