J Epikpsy 1990;3:55-59 0 1990 Demos Publications

EFA Commentarv J

The Epilepsy Foundation of America (EFA), togeth- er with leading neurologists and others in the epilepsy movement, have closely followed reports of the thera- peutic failure of generic antiepileptic drugs. The EFA views the increased implementation of mandatory substitution provisions in health-care plans with great concern given the serious implications to an individ- ual with epilepsy, including status epilepticus death, which may result following loss of seizure control.

While EFA supports the cost benefits potentially available through the use of generic drug formula- tions to control seizures, it believes that there is an urgent need for stricter oversight of manufacturing, quality control, and assurance of bioavailability of generic as well as brand-name products.

A major area of concern relates to positions taken by the Food and Drug Administration (FDA) that the consequences of epilepsy are not as serious as they are judged to be by the epilepsy community. The apparent misperceptions have influenced vari- ous decisions of the FDA relating to epilepsy. The EFA’s questions regarding generic formulations fall within six broad areas of concern: (1) the determina- tion of bioequivalency; (2) procedures governing drug recalls; (3) the reliability and interpretation of ad- verse drug reports; (4) quality control and surveil- lance; (5) product labeling; and (6) mandatory sub- stitution policies.

Questions of Bioequivalency Since 1987, the EFA has expressed concerns regard-

ing the bioavailability of generic antiepileptic drugs. Are all generic antiepileptic drugs interchangeable or therapeutically bioavailable? Some generic formula- tions of antiepileptic drugs may not be therapeutically equivalent among people with epilepsy. This is es- pecially important to individuals intolerant of even small changes in plasma concentrations.

In a statement adopted by its national Board of Di- rectors in May 1987, the EFA took the position that changing one formulation of an anticonvulsant to another should require the prior expressed permis- sion of the treating physician and the agreement of the patient.

This position reflects the concern of the EFA’s Pro- fessional Advisory Board that there are small but pharmacokinetically significant differences in the bio- equivalence of antiepileptic medications produced by different manufacturers (whether generic or brand) that can adversely affect blood levels of individuals with epilepsy, resulting in either loss of seizure con- trol or toxic side-effects. For example, the FDA has long recognized that prompt-release generic pheny- toin sodium is not therapeutically equivalent to Dilan- tin.

Drugs used to treat persons with epilepsy have a narrow therapeutic index. That is, a blood level pro- viding optimal control and one that is toxic are often close. Increasing the fluctuations in blood concentra- tions between doses can result in both subtherapeutic and toxic levels. The EFA is concerned that variations in absorption from one formulation to another of the same drug (whether generic or brand) might lead to breakthrough seizures because of the difficulty in achieving therapeutic blood levels in many individu- als with epilepsy.

Current federal regulations permit generic formu- lations of a solid dosage drug to vary up to 20% from the brand product’s rate and extent of absorption, al- though the Report of the Bioequivalence Task Force of the FDA, published in January 1988, found that the mean bioavailability difference was 3.5% for all post- 1962 drugs approved over a recent two-year peri- od.

The EFA earlier this year requested the actual varia- tion findings for each FDA-approved generic formu- lation of carbamazepine, diazepam, phenytoin, and valproate (valproic acid, sodium valproate, and di- sodium valproex). Depending on the statistical find- ings of this question, the FDA might consider impos- ing tighter bioequivalence ranges for antiepileptic medications in recognition of the difficulty securing and maintaining therapeutic levels in many people with epilepsy. This alternative was mentioned as a possibility for drugs designed to treat certain disor- ders in the Report of the Bioequivalence Task Force issued last year by the FDA.

The EFA’s concerns regarding bioequivalence were thoroughly discussed at a recent meeting with Com-

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missioner Frank Young and other leading FDA offi- cials. Dr. Timothy Pedley, president-elect of the EFA and Professor of Neurology at Columbia University, and Dr. 110 Leppik, chair of EFA’s Professional Ad- visory Board and Professor of Neurology at the Uni- versity of Minnesota, together with the EFA staff, represented the Foundation.

The EFA was pleased to learn that the FDA agrees that different classes of drugs may require different standards for equivalency and, in the case of antiepi- leptic drugs, tighter limits than are allowed under existing regulations.

Commissioner Young informed the EFA that a Task Force on Anticonvulsant Drugs has been assembled. It will consider whether a tighter bioequivalency standard needs to be adopted for drug that are intend- ed to treat certain health conditions such as epilepsy and that have a narrow therapeutic range. The FDA has also expanded its review of generic drugs to in- clude all antiepileptic drugs. This action was in re- sponse to a request made to the FDA on September 6, 1988, by the EFA and subsequently by Congressman John Dingell, chair of the Subcommittee on Oversight and Investigations of the House Energy and Com- merce Committee.

Reports in the literature also indicate concerns about generic substitution of antiepileptic drugs. In- stances of therapeutic failure of generic drugs intend- ed to treat epilepsy and other health conditions have been reported in the ]oumal of the American Medical As- sociation, The Archives of Neurology, Lancet, and Neurol- OgY.

The American Academy of Pediatrics reviewed the use of generics in 1987 and concluded that “the lack of data on bioavailability and bioequivalence in children precludes blanket support of generic prescribing for infants and children.” Recently, the American Acad- emy of Family Physicans (AAFP) issued a White Pap- er that concludes: ‘Review of the medical literature and of the definitions and claims of the FDA have raised serious concerns about generic drugs which can no longer be ignored.” The AAFP cautions against the use of generic drugs for certain segments of the population (pregnant women, the elderly) and for certain health conditions (asthma, congestive heart failure, diabetes mellitus, psychiatric disorders, and others). The statement says, in part, that “bioavail- ability does not necessarily equal therapeutic equiva- lence,” and that “drugs approved by the FDA as ge- nerically equivalent frequently have not been found to be as safe and effective as their brand name counter- parts.”

The EFA shares AAFP’s concerns that, although an individual generic drug may be chemically safe, switch-

ing a person from one formulation to another may be harmful, since different formulations of a drug can af- fect both the rate and extent of drug entry into the bloodstream. The EFA has requested that AAFP in- clude epilepsy in the list of critical diseases for which there should never be mandatory substitution of a generic drug.

PBI Carbamazepine Recall In 1988, 53 million tablets of generic carbamaze-

pine manufactured by Pharmaceutical Basics, Inc. (PBI) were recalled after it was discovered that this product failed dissolution tests. The details of this recall and its consequences continue to surface. Al- though two individuals who had been taking the PBI carbamazepine died between the time that the prob- lem with the product was reported to the FDA and the issuance of the recall notice, the FDA has assured the EFA that it believes that there was no direct cause- and-effect relationship between the defective generic carbamazepine and these deaths. Epilepsy-related mortality is an infrequent occurrence, and it is often difficult to document the causal factor. The EFA is not in a position to comment on the 1988 deaths of these two individuals. However, these reports underscore important questions about the FDA procedures for recalling defective antiepileptic drugs.

The recent press accounts of the events surround- ing last year’s recall of generic carbamazepine reveal that PBI initially informed the FDA of the dissolution problem on August 3,1988. It took seven weeks of negotiation between the FDA and PBI before agree- ment was reached regarding the details of the recall. This delay occurred, in part, because the FDA lacks the legal authority to order a recall.

In September 1988, after hearing of a possible prob- lem with the particular formulation of generic car- bamazepine manufactured by PBI, the EFA immedi- ately contacted the FDA. The FDA confirmed that it was negotiating with PBI over the details of the recall.

The EFA, in correspondence to the FDA dated Sep- tember 16,1988, urged the FDA to classify this recall as a Class I event given the serious consequences that can result from loss of seizure control. A Class I recall is appropriate for “a situation in which there is a strong likelihood that the use of, or exposure to, a violative product will cause serious, adverse health conse- quences or death.“ Such a classification requires the drug manufacturer to distribute news of the recall to local pharmacies and physicians.

The FDA issued a press release on September 21,

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1988, notifying the general public that PBI had volun- tarily recalled 53 million tablets of its generic car- bamazepine. The FDA explained that the product was recalled because “they do not dissolve well and thus may not enter the bloodstream as expected.” The FDA stated in its press release that it had “received 15 reports of problems, including some expected sei- zures, which may be related to this manufacturing problem.”

The FDA had classified this recall as a Class II event. This classification is used for situations “in which the use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.” PBI notified its distributors of the recall. The FDA issued a press advisory.

The EFA notified all of its past and present mem- bers of this recall and published a detailed report in the National Spokesman.

Guidelines for Future Recalls Upon learning of the reported deaths, the EFA re-

newed its request to the FDA to classify future recalls of antiepileptic drugs as a Class I event. The EFA believes that epilepsy-related mortality demands that future recalls be handled as a life-threatening event.

Deleterious consequences often follow the loss of seizure control. Status epilepticus is a foremost con- cern because it has significant morbidity and mortality rates. In addition, many states require suspension of an individual’s driver’s license for a period of six months to one year following a seizure. This event can result in serious financial and emotional losses to the person with epilepsy and his or her family.

The FDA must rely on the threat of liability suits and adverse public opinion to convince drug companies to comply with the agency’s request that a drug be recalled. In the PBI case, the company initially insist- ed that less than 10 million tablets were defective rath- er than the 53 million the FDA sought to have re- called.

This episode, along with the difficulties experienced in October when the FDA sought the cooperation of Bolar Pharmaceutical regarding removal of its generic nitrofurantoin from the market, has spotlighted the need to strengthen the FDA’s authority regarding re- calls. Chairman Dingell has indicated that his Com- mittee, which has jurisdiction over the FDA, will look into legislation to increase the enforcement authority of the FDA.

Adverse Reaction Reports The EFA is also concerned that the existing mech-

anism through which adverse reaction reports are voluntarily filed with the FDA needs strengthening. It is apparent that the statistics available to the FDA are not sufficient.

The EFA has asked for a summary of all adverse re- action reports involving the following major antiepi- leptic medications (brand and generic): (1) Depakene (valproic acid); (2) Depakote (divalproex sodium); ‘(3) Dilantin (phenytoin); (4) phenobarbital; (5) Teg- retol (carbamazepine); (6) Valium (diazepam); and (7) Zarontin (ethosuximide).

Investigation of Generic Drug Manufacturers Investigations of the generic drug industry are

being conducted by the FDA, the Inspector General of the Department of Health and Human Services, the Department of Justice, and the Subcommittee on Oversight and Investigations of the House Energy and Commerce Committee. These investigations, which began during the summer of 1988, arose be- cause of complaints voiced by Mylan Laboratories (a generic drug manufacturer) of discriminatory treat- ment in the approval process by the generic drug sec- tion of the FDA.

These investigations have served to highlight the concerns of the epilepsy community and to raise seri- ous new questions regarding the manufacturing pro- cedures used by some generic companies.

In a recent letter responding to EFAS concerns, Chairman Dingell wrote that “the Subcommittee’s investigation into the generic drug approval process at the FDA leaves us with no confidence that the Agency has the ability, or that a significant portion of the generic drug industry has the integrity, to assure that the manufacture of extremely sensitive medica- tions is consistent with maximization of the public health.”

At a September 1989 hearing, Congressman Dingell found that substantive problems existed with 11 ge- neric drug companies-seven of which market anti- epileptic medications. To date, there have been no re- ports of safety problems with these particular drugs. The manufacturers and the specific generic formula- tions they produce are as follows: Barre-National (phenobarbital); Bolar Pharmaceutical (phenytoin and primodone); Par Pharmaceutical (diazepam, lora- zepam, and valproic acid), Pharmaceutical Basics, Inc. (carbamazepine, diazepam, lorazepam, and pheno- barbital); Quantum Pharmics (diazepam); Sidmak

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EFA COMMENTARY

Laboratories (carbamazepine and phenytoin); and Vitarine Pharmaceuticals (phenobarbital). The EFA has asked the FDA to keep the Foundation informed if any problems arise with any of these products.

In a subsequent development, Congressman Din- gel1 informed the EFA that the FDA failed to notice two different formulations contained in Par’s Abbreviated New Drug Application (ANDA) for valproic acid and that its random testing failed to detect that a third formulation was being marketed; that Superpharm and Quantum may have made misrepresentations in their ANDAs for diazepam; and that FDA field com- pliance staff have questions about the ANDAs sub- mitted by Superpharm and Quantum for loraze- pam.

Expanding the FDA Inquiry In response to deficiencies found by the House

Subcommittee on Oversight and Investigations, the FDA announced on August 17,1989, that it was going to review the country’s 30 top-selling generic medica- tions including diazepam, lorazepam, and phenobar- bital.

The EFA, in its September 6,1989, letter to Commis- sioner Young, requested that the FDA expand this study to include, at a minimum, carbamazepine, phenytoin, and valproic acid if not all antiepileptic medications. Congressman Dingell wrote to Com- missioner Young asking the FDA not only to expand its generic drug surveillance program to include all antiepileptic drugs but all drugs designed to treat health conditions where the therapeutic range of the medication may be critical. The FDA has informed the EFA that it would comply with our request.

Quality Control and Surveillance The current congressional and departmental inves-

tigations of the FDA, as reported in the press, only serve to strengthen existing concerns and raise seri- ous new questions about the overall integrity of the manufacturing procedures used by some generic companies and the oversight mechanisms established by the FDA.

The House Subcommittee, at its July hearing, iden- tified serious inadequacies in the FDA’s generic drug approval process. The Subcommittee found that no system exists to monitor the quality and integrity of drug approval or disapproval decisions; no system to assign applications for review; no definite timelines for lab testing; and no monitoring system to ensure that established guidelines are uniformly applied and reviewed.

Congressman Dingell, joined by Congressman Thomas Bliley, senior Republican member of the Subcommittee, issued a call for a thorough review of the overall drug approval process.

In his September 26 letter to the EFA, Chairman Dingell requested EFA’s assistance in drafting legisla- tion that would effectively address the problems iden- tified with the therapeutic bioavailability of antiepi- leptic drugs.

It should be noted that the FDA is being seriously hampered by lack of adequate resources. Its staff has been reduced from nearly 8,200 in 1979 to 7,360 at present. If the FDA is to do its job of monitoring the safety, efficacy, and quality control of drugs and process new drug applications in a timely manner, the human and other necessary support resources will have to be restored. The EFA and other organizations in Washing- ton are working toward this end.

Improved Product Labeling The recent controversy points to the need for the

FDA to initiate the product identification recom- mendations that Congressman Henry Waxman and former Congressman Tony Coelho proposed to Commissioner Young in a November 1988 letter. Congressmen Waxman and Coelho suggested that “all drug products should be marked with identifiers that disclose the manufacturer and the active ingredient.” This proposal stemmed from discussions held during the 1988 EFA National Conference involving repre- sentatives of the EFA, led by Dr. Timothy Pedley and Congressmen Coelho and Waxman.

The EFA has strongly supported this proposal. It would provide consumers with the information nec- essary to identify the manufacturer of the drug prod- uct that they are about to use. It would also enable individuals with epilepsy who have achieved control of their seizures using a specific generic product, to guarantee that subsequent refills of the generic medi- cation have been produced by the same manufac- turer.

Mandatory Substitution The EFA, as reflected in its May 1987 statement, be-

lieves it is critical that substitution occur only with the informed consent of both the consumer and the phy- sician.

Many states have adopted guidelines governing Medicaid reimbursement which encourage substitu- tion of generic products for the brand name drug. States have done so in an attempt to slow the growth of Medicaid expenditures because generic drug prod-

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drugs developed to treat specific epilepsy syndromes such as status epilepticus and the serious disorders of childhood as eligible under the Subpart E (severely debilitating/life-threatening) regulations.

The Subpart E regulations, issued in October 1988, are designed to expedite FDA review of applications of new drugs intended to treat life-threatening and severely debilitating health conditions. (Impetus for the issuance of Subpart E regulations came, in large part, from the AIDS community.)

The EFA believes this regulatory initiative will prove to be an important incentive in the ongoing search for more effective and less toxic antiepileptic medi- cations especially for those individuals whose lives are most at stake because they continue to suffer from intractable seizures. It has been more than 11 years since the last major antiepileptic drug was approved by the FDA for marketing in the United States.

The Foundation’s position regarding inclusion of epilepsy under the Subpart E regulations was dis- cussed at length during the recent meeting held with Commissioner Young. The EFA’s representatives, again, urged inclusion of drugs intended to treat status epilepticus and specific syndromes that have high morbidity and mortality rates. For example, mortality rates for status epilepticus range from lo- 30% and for neonatal seizures, 35%. Morbidity in these groups is even higher.

The EFA and its Professional Advisory Board are working with the FDA and Congress to secure an- swers to the many questions that have been raised re- garding the safety and effectiveness of all antiepileptic drugs but, especially at this time, generic formula- tions.

ucts typically sell for 30-35% less than the name brand product. This trend toward mandatory substi- tution is growing and now involves insurance com- panies, hospitals, and health maintenance organiza- tions.

Many EFA affiliates have worked with state agen- cies to ensure that physicians have the ability to over- ride substitution requirements when, in their judg- ment, the individual with epilepsy should be given the brand name medication. To do otherwise estab- lishes a second-class health care delivery system for Americans dependent on Medicaid.

The EFA has also urged Congress to consider re- quiring pharmacists to notify the consumer whenever any of the following substitutions occur: (1) when a generic drug manufactured by one company is substi- tuted for the generic drug that was provided when the prescription was previously filled; (2) when a generic formulation is substituted for the brand name drug; or (3) when the brand name is substituted for a generic product.

The AAFP, in its recently adopted report on ge- nerics, similarly opposed any mandatory substitution provisions.

Severity of Epilepsy Many of the procedures at the FDA can be traced to

the apparent perception by the FDA that the conse- quences of epilepsy are not serious or life-threaten- ing. This has been reflected in the Agency’s reluctance to: (1) designate future recalls of antiepileptic drugs as a Class I rather than Class II event; and (2) classify

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