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W4244504443 abstract "Monotherapy has multiple advantages over polytherapy, including fewer side effects and drug–drug interactions, better patient compliance, less teratogenicity, and lower cost. Schmidt (1) demonstrated that when patients receiving standard polytherapy had one drug removed, 83% maintained the previous level of seizure control, 36% had fewer seizures, and 5% became seizure free. In addition, side effects decreased. Similarly, studies by Schmidt (2) and Mattson et al. (3) revealed that a second AED adds only marginal benefit. In their studies, only 11–13% of patients had a substantial decrease in seizures, and side effects increased. FDA monotherapy approval is particularly important for the newer AEDs, which have potential advantages of better tolerability, improved safety, less teratogenicity, and simpler pharmacokinetics, which cannot be realized when the new drugs are combined with older drugs that do not share these advantages. In addition, it is established practice to treat newly diagnosed patients with a single drug; therefore absence of a monotherapy license precludes anything but off-label use of new AEDs as initial therapy. Currently, prescribing these drugs as “off-label” can present obstacles to insurance reimbursement and increase physician concern regarding legal liability. At present, most AEDs obtain initial FDA approval through an “add-on” clinical trial design. The fact that a new AED can reduce seizures when added to other therapy is not currently accepted as proof that it will have an antiepileptic effect when given alone. It is the policy of the regulatory bodies to request proof of efficacy in the monotherapy state. Aside from regulatory concerns, availability of monotherapy data also is desirable, because an “add-on” trial may exaggerate the side-effect profile of a new AED because of pharmacokinetic and pharmacodynamic drug interactions and additive toxicity. Some serious safety concerns also may be heightened or reduced when drugs are used in adjunctive therapy, as compared with monotherapy. To understand truly what side effects can be expected when a drug is used alone, it is essential to test it under that condition. Trial designs should answer important clinical questions, as well as regulatory ones. At present there is great controversy as to whether it is possible for a drug to be effective in adjunctive therapy conditions, but not in monotherapy. But in either case, there are still important reasons to test efficacy in monotherapy. First, drugs may appear more or less effective when combined than when used separately, depending on whether mechanisms of action of the combined drugs are synergistic or redundant. Certain populations (particularly the newly diagnosed) also can be tested only under monotherapy conditions. One approach that can be used to prove effectiveness of monotherapy is an active-control comparison trial, in which a new AED is compared to a well-established AED that has “substantial evidence” of effectiveness, such as carbamazepine (CBZ) or phenytoin (PHT) (4). The design schema can be seen in Fig. 1. This approach permits comparison of a new drug with the “standard of care.” Because both arms of the study are equally as likely to be effective, equipoise is maintained. In addition, such trials may be continued for long durations. At present, active control comparison trials are not accepted as proof of efficacy in the United States and will not lead to a monotherapy indication. The reasons are complex, and will be discussed at length in subsequent sections. Essentially the reluctance to give credibility to this trial design results from a concern about assay sensitivity. Assay sensitivity can be defined as the ability of a given trial design to show a difference, where one truly exists. Most of these trials, when they have been performed, have led to a “draw,” where the two AEDs under study perform equally (6–11). This leads to concerns about scientific validity. Were the two treatments really the same, or did the trial design fail to distinguish the difference? Assay sensitivity has not been demonstrated for the active control comparison trial of AEDs when performed in newly diagnosed patients. According to Temple and Ellenberg (12), “Active-control equivalence trials can be informative and have been used successfully and appropriately in many therapeutic areas in which assay sensitivity is not in doubt. These trials are often credible and have been widely used in such areas as treatment of cancer, infectious disease, and some cardiovascular conditions (for example, acute myocardial infarction treated with thrombolysis).” Active control equivalence trial schema. The most straightforward way to demonstrate AED effectiveness as monotherapy is a placebo control design; however, this approach leaves at least half the patients in the trial without AED protection and exposes them to the risk of additional seizures and their consequences (4,13,14). Attempts have been made to circumvent this ethical problem using a “pseudo-placebo” rather than a true placebo. A pseudo-placebo is defined as a less-effective dose, which may provide the patient with some protection against severe seizures and status epilepticus, but still allows the test drug to demonstrate superior efficacy, thus confirming assay sensitivity. Ethical issues have been raised in regard to randomizing patients to a treatment that is assumed to be inferior to the optimal treatment (14,15). Despite the acceptability of such an approach to regulatory bodies, the debate about the appropriateness of such trials has made them difficult to accomplish, as evidenced by the paucity of successful monotherapy approvals. At present, the epilepsy community is trapped between issues of scientific validity and ethical concerns. Individuals may disagree in regard to assay sensitivity or the ethics of a given design, but all agree that the debate has essentially paralyzed the drug-approval system. Alternative methods are urgently needed. Prior to 1982, polytherapy was common clinical practice. There was a distinct lack of monotherapy trials, and the prevailing literature suggested that AED combinations were more efficacious than monotherapy. However, the concept of monotherapy dates back to the early days of epilepsy therapy. In a 1938 letter from Dr. Tracy Putnam regarding the treatment of an adolescent with “mostly petit mal” seizures, Dr. Putnam advocated discontinuing the boy's multiple AEDs and instituting PHT monotherapy. The Federal Food, Drug and Cosmetic act of 1938 required only “proof of safety” before allowing a drug on the market. Consequently, between 1938 and 1962, the FDA approved drugs if they were safe and there was no evidence to support ineffectiveness. However, the 1962 Kefauver–Harris Drug Amendments tightened safety requirements and required proof of efficacy as well (16). In 1987, the FDA defined the objectives of the different phases of drug development and the regulation of those phases. It required a meeting with the pharmaceutical sponsor at the end of Phase 2 to improve communication regarding specific approval indications. The 1997 Food and Drug Modernization Act states that one well-controlled clinical investigation with confirming evidence may be sufficient to verify effectiveness (17). Since 1982, clinical research has documented the benefits of monotherapy versus polytherapy. Both VA Cooperative Trials I and II revealed only limited additional benefit with polytherapy, supporting the practice of monotherapy (3,18). In these studies, patients were randomized to one of four commonly used AEDs in VA Cooperative study I, and one of two drugs in VA cooperative study II. Patients who did not become seizure free were rerandomized to a second therapy. Those still not seizure free were given combination therapy. Only a small percent improved with a polytherapy approach. Most of the standard AEDs, such as CBZ, PHT, and valproate (VPA), have blanket regulatory approvals for use in epilepsy, with no mention of monotherapy or adjunctive therapy. At the time these drugs were approved, specific trials to obtain proof of efficacy in these different circumstances were not required. In the 1990s, new drugs began to appear, mostly spurred by an active NIH drug-development program. It was only in this modern era of regulatory drug approval that proof of efficacy in monotherapy became an issue. The issues were raised in a series of commentaries written by Paul Leber, the then-director of the neuropharmacology division of the FDA, raising concern about using active-control equivalence trials for proof of efficacy (19). An NIH-sponsored workshop was held in the early 1990s to determine new approaches to trial designs for monotherapy approval. That conference led to novel designs (20). The most promising was a design relying on “therapeutic failure” as an outcome. Patients would be randomized to either active drug or low-dose VPA, which was expected to be less effective than the active study drug but would prevent convulsions or status epilepticus. As an added safety measure, patients would be removed from the trial if they experienced deterioration, as defined by well-delineated stopping rules. In addition to this design, which was to be performed in outpatients, a second design was proposed, in which true placebo could be used. This, entitled the “presurgical withdrawal to monotherapy,” would be performed in the hospital, with patients who were having their medications discontinued for the purpose of recording seizures for surgical evaluation. Both these designs are discussed in more detail in subsequent sections. In 1993, a new era began when these novel trial designs were used to allow felbamate (FBM) to receive monotherapy approval at its introduction into the marketplace. The FDA approved FBM for either monotherapy or adjunctive therapy in the treatment of partial seizures, with or without generalization, in adults with epilepsy. FBM received monotherapy approval supported by trials that included a study of FBM against low-dose VPA (15 mg/kg/day) as well as a short-term presurgical monotherapy trial (21–24). Based on this approval, FBM was used in many patients as first-line therapy, and 100,000 patients were given it within 1 year. Unfortunately, although FBM was a good drug, serious safety concerns have subsequently limited its use. Essentially, the approval of FBM as monotherapy “set the bar” for subsequent new AEDs; failure to gain a monotherapy approval was seen as a significant competitive disadvantage. From this point on, every drug-development plan contained a strategy for gaining monotherapy approval. In 1998, lamotrigine (LTG) received an FDA indication for conversion to monotherapy in adults with partial seizures who are receiving treatment with a single enzyme-inducing AED (25). Unlike the approval for FBM, the wording on the LTG approval was very specific, as follows: “The safety and effectiveness of LTG have not been established as initial monotherapy, for conversion to monotherapy from non–enzyme-inducing AEDs, or for simultaneous conversion to monotherapy from two or more AEDs”(26). Clearly, such wording would mean that all use in newly diagnosed patients would be off-label. The motivation for the wording was unclear. Would the therapeutic-failure designs lead only to an approval for patients converted to monotherapy? An alternative explanation would be that LTG, which has different pharmacokinetics in monotherapy and polytherapy, was a special case, and this strict wording would not necessarily be applied to other AEDs for which a similar monotherapy trial program was used. The FDA granted oxcarbazepine (OCBZ) simultaneous adjunctive and monotherapy approval for partial seizures in adults, and for adjunctive therapy in children aged 4–16 years, based on six multicenter randomized double-blind controlled trials. Four of these trials demonstrated efficacy of OCBZ as monotherapy. Two compared OCBZ with placebo; one included newly diagnosed and recent-onset patients with partial seizures, and the other studied patients with refractory epilepsy preparing for epilepsy surgery. Two other trials used a randomized withdrawal design that compared a high dose (2,400 mg) with a low dose (300 mg). Again, the bar was raised to include not only monotherapy approval, but approval for use in the newly diagnosed population. Yet, even as it appeared that the regulatory hurdles for monotherapy approval had been surmounted for both newly diagnosed patients and patients with refractory epilepsy, new concerns emerged. One was an ethical concern. Editorials questioned whether it was appropriate for studies to randomize epilepsy patients to intentionally suboptimal treatment. Some were concerned that this violated the principle of equipoise, which is laid out in the Helsinki agreement (14,27). This principle expounds that “in any medical study, every patient—including those in the control group, if any—should be assured of the best proven diagnostic and therapeutic method.” Clearly that is not the intent of the therapeutic-failure design. In addition, questions were raised in regard to the clinical validity of the therapeutic-failure design. At the same time, the availability of a number of new AEDs, and the tendency of these trials to be performed after approval, meant that fewer patients were willing to agree to possible randomization to less effective treatment. The last therapeutic failure study was performed ∼5 years ago. Although these trials are still contemplated, clearly they no longer represent an ideal drug-development strategy. The difficulties encountered in the United States were not so acutely felt in Europe, where active-control equivalence trials were considered an acceptable form of evidence to prove effectiveness in monotherapy. Many such trials were performed in the 1990s (6,8–11), leading to the granting of several monotherapy licenses. However, even in Europe, there was increasing concern regarding appropriate methods for these trials and whether they provide sufficient proof of monotherapy effectiveness. In 2000, the Committee for Proprietary Medicinal Products (CPMP), the body that governs drug approval in Europe, issued new guidelines. These guidelines identified randomized, double-blind, active-controlled trials as the “best study design” but acknowledged that trials resulting in a no-difference outcome could pose problems in interpretation. Figure 2 demonstrates what the CPMP considers an acceptable trial design. Although the document did not explicitly mandate a trial demonstrating superiority, such an expectation might be inferred from the wording. Active control equivalence trial design compatible with the committee for proprietary medicinal products (CPMP). In preparation for this workshop, the Practice Committee of the AES distributed a one-page survey to 3,000 clinician members of the AES in December 2000 and January 2001. The estimated completion time of the survey was 1 min. Five hundred thirty-four physicians completed the survey's eight questions, including 238 adult epileptologists, 116 adult neurologists, 109 pediatric epileptologists, and 71 pediatric neurologists. Ninety-two percent of the respondents admitted prescribing drugs off-label. One third of those who did not cited insufficient knowledge of the drugs and fear of liability as the reasons. Eighty-two percent of general neurologists and 68% of the epileptologists believed that monotherapy labeling was valuable. Sixty-two percent of the general neurologists, but only 46% of the epileptologists thought that FDA labeling influenced practice patterns, suggesting that neurologists are more sensitive to FDA labeling than are epileptologists. Seventy-seven percent agreed that “The ideal therapy for epilepsy is monotherapy for each patient.” However, only 19% agreed with the statement, “New drugs must go through monotherapy trials before they are used as monotherapy.” Eighty-six percent believed that comparison monotherapy trials provide useful information. The survey also generated many interesting comments. For example: Very few trials study and report data regarding seizure 100% reduction. Let's see more of that. Also, let's see more trials comparing the new ones head-to-head. -There are virtually no adequate monotherapy trials of any of the new AEDs and none at all in kids. -I feel all AEDs are effective as monotherapy and use them as such when appropriate. I feel equivalency trials should be accepted by FDA. Placebo trials are unethical. -If off-label liability and third party payment for Rx issues were not a problem, then it (FDA monotherapy approval) would not be necessary. Maybe this is where efforts could be focused. -“Novel” trial designs are necessary to evaluate monotherapy potential of these agents on surgical candidates, newly diagnosed, and up/down titration trials. The survey revealed that >90% of physicians prescribe AEDs off-label. However, it appeared that some physicians did not appreciate the difference between FDA regulatory indications and “legal” use of AEDs as monotherapy. Physicians clearly need more education in this area. Several regulatory authorities have created regulations that affect the approval of AEDs for use in monotherapy. These include the CPMP in Europe, the FDA in the United States, and the International Conference on Harmonization (ICH), which was convened to try to bring convergence to the views of the various regulatory authorities. Each of these is discussed in turn. Distinct differences exist between regulatory agencies in the United States and Europe regarding monotherapy approval. The CPMP in Europe introduced new guidelines in 2000 to address monotherapy approval (28). The CPMP allows monotherapy approval for an AED when it shows comparable efficacy and safety to another active control drug. Previously untreated patients are the population of choice for monotherapy trials. The FDA requires superiority designs in which the test drug outperforms a control and does not currently accept comparative trials with no-difference outcome for monotherapy AED approvals. This is because of absence of proof of assay sensitivity, as discussed earlier. The CPMP considers randomized, double-blind active-control trials in previously untreated patients with epilepsy that “demonstrate at least a similar benefit/risk balance of the test product as compared to an acknowledged standard product at its optimal use” as “the best study design.” In reality, active-control trials in previously untreated patients are usually designed to show noninferiority to control by a specified margin. Flexible or fixed-dose trials with more than one arm to establish the lower end of the clinically effective dose range as well as the optimal effective dose in monotherapy also are considered valid trial designs. A potential problem with the comparative drug trial design is the “no difference outcome,” in which both drugs produce similar results. This type of result appears to suggest that both drugs are equally effective, but also may indicate that both drugs are equally ineffective. To circumvent this problem of no-difference outcome, the CPMP noted, “a number of innovative designs have been proposed and their use should be justified by the applicant.” These remedies include, “inclusion of a placebo group or several doses of the test drug, or placebo-controlled withdrawal phase at the end, or an initial short period of comparison to placebo.” (CPMP ICH E10. 2000) It is unclear whether a drug would receive approval in Europe for use in monotherapy based on an active-control trial alone, if the test drug were found to have equivalent efficacy to a standard. Most likely, additional proof of efficacy would be required, as implied in the earlier statement. However, unlike in the United States, active-control studies are considered necessary, even if not sufficient, for monotherapy approval. The ICH also established new guidelines for AED trial designs. Regulators and industry in the United States, Europe, and Japan have subscribed to these nonbinding guidelines. The guidelines make specific recommendations in regard to selection of control groups. The document indicates a clear preference for placebo control, as it “controls for all potential influences on the actual or apparent course of the disease other than the pharmacologic action of the test drug. These influences include spontaneous change (natural history of the disease and regression to the mean), subject or investigator expectations, the effect of being in a trial, use of other therapy, and subjective elements of diagnosis or therapy.” Included in the discussion of active control as a potential control group is the statement that demonstration of equivalent efficacy as the active control establishes efficacy of the test treatment “only if it can be assumed that the active control was effective under the conditions of the trial, as two treatments would also look similar if neither were [was] effective in the trial”(29). The following is an extensive discussion of assay sensitivity. Assay sensitivity refers to the ability of a study to detect a meaningful difference between two treatments if there really is a difference between the two treatments. It is not only a question of whether the active control is effective, but also of whether one has properly designed the trial. According to the ICH guideline, for a noninferiority or equivalence trial to be used as evidence of efficacy, two determinations must be made. The first is that there must be “historical evidence of sensitivity to drug effect,” that is, that similarly designed trials have “regularly distinguished effective treatments from less effective or ineffective treatments.” They state unequivocally that “without this determination, demonstration of efficacy from showing of non-inferiority is not possible and should not be attempted. In addition, there must be demonstration of “appropriate trial conduct.” These two determinants are critical to the issue of proper conduct of monotherapy trials that use an active comparator. Essentially, the ICH guideline says that equivalence trials using an active comparator must be preceded by placebo-controlled trials with the same design. The ICH also discusses ethical issues related to selection of a control group. They state, “In cases where an available treatment is available for the condition under study in a proposed trial …” and “… where an available treatment is known to prevent serious harm, such as death, or irreversible morbidity in the study population, it is generally inappropriate to use a placebo control… In other situations, when there is no serious harm, it is generally considered ethical to ask patients to participate in a placebo-controlled trial, even if they may experience discomfort as a result, provided the setting is non-coercive, and patients are fully informed about available therapies and the consequences of delaying treatment.” In other words, the ICH guideline clearly lays out the ethical considerations in selecting a placebo or pseudo-placebo for patients with epilepsy. Withholding or removing treatment may cause discomfort, but not risk of “serious harm.” The conference was attended by several representatives of the U.S. FDA. The following statements are taken from a presentation by Russ Katz, Director of the Neuropharmacology Division of the FDA. In general, when the FDA considers a new drug application, they “act on the evidence before them.” Based on the results of adjunctive AED trials, the FDA has granted indications for adjunctive treatment. FDA labeling also reflects the ages and seizure types of the trials' participants. For a monotherapy indication, in the setting in which an AED has already obtained adjunctive therapy approval, the FDA ordinarily asks for a single additional trial that demonstrates monotherapy effectiveness. The FDA approach for AED approval also applies to other neurologic diseases such as Parkinson's, as well as cardiovascular, renal, and oncologic drug approvals. In general, clinical trials do not mirror clinical practice. They are experiments designed to demonstrate a “proof of principle,” that the drugs are effective. Placebo-controlled, active-control equivalence, and active-control superiority trials are three types of monotherapy trial designs. The FDA believes that placebo-control trials, designed to demonstrate a difference between a test drug and placebo, are the easiest to interpret. There are several types of placebo trial designs, including randomized withdrawal, low dose versus high dose, and multiple-dose trials. Populations may include newly diagnosed patients and presurgical patients. Although placebo-control trials are ideal from a scientific perspective, they present ethical concerns because of the possibility of increased seizures and their sequelae. Active-control equivalence trials have the advantage that all patients are treated with “active” drug, either a standard or investigative AED. (However, this trial design does not necessarily protect patients against seizures, because the investigative AED may not be effective or “active.” In addition, one must have external information that confirms the effectiveness of the “active drug.” This information requires a stable estimate of the active drug's treatment effect in a similar patient population and in a similar dose. Consequently, according to the FDA, active-control trials are a subset of historical control trials, which provide only weak evidence for effectiveness. Active-control superiority trials have the advantage of demonstrating a difference between treatments. However, a low dose of the investigational drug or active comparator may allow patients to have increased seizures, presenting similar ethical problems as those of placebo-control trials. In the rare situation in which the active control exacerbates the seizure disorder, active-control superiority trials may produce spurious results. To date, the FDA has required monotherapy trials to support monotherapy indications. Active-control equivalence trials represent a viable alternative if robust information concerning the effectiveness of the comparator is available. In addition, a drug must demonstrate efficacy before one can consider the benefits of its side-effect profile. This conference on AEDs and monotherapy could have historical significance in large part because it addresses the tension between patient care and protection with industrialization and scientifically sound methodologies of clinical research. Although science and industry bring new discoveries to our patients, we may be losing the proper balance between economics, technology, academic rewards, and other pressures that influence clinical research. As physicians, we must address these issues if we are to protect our patients. Just after World War II, the scientific method began to influence clinical care with the first randomized clinical trial, an evaluation of streptomycin for pulmonary tuberculosis. At the same time, the Nuremberg code spelled out ethical guidelines for clinical research as a response to the Nazi human experiments. The code states that “the degree of risk … should never exceed that determined by the humanitarian importance of the problem to be solved.” Since then, the World Medical Association Declaration of Helsinki has prescribed ethical principles for clinical trials, first in 1964, and amended in 1975, 1983, 1989, and 1996. The Helsinki Declaration contains 12 basic principles, including careful assessment of risk, informed consent, and independent committee assessment. The most often quoted statement in the Helsinki Declaration is, “In any medical study, every patient—including those of the control group, if any—should be assured of the best proven diagnostic and therapeutic method (30).” Despite these guidelines, scientific experiments that abuse human beings have occurred in the United States as well as abroad. Researchers injected live cancer cells into elderly patients at Kingsbrook, and the U.S. Public Service allowed men in Tuskegee infected with syphilis to go untreated to learn more about the disease's natural history. These experiments were blatantly unethical and have been condemned in the literature beginning with Beecher's landmark article in 1996, entitled “Ethics and Clinical Research (31).” As a result of our growing awareness of the importance of ethics in clinical research, we now pursue phased investigations, advancing from animal to human studies and evaluating safety and then efficacy. One of the limitations in demonstrating efficacy of a new treatment is the placebo effect. Shapiro (32) defined a placebo (from the Latin, “to please”) as “any therapeutic procedure that is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but is objectively without specific activity for the condition being treated.” Psychodynamically effective in ≤35% of all patients and conditions, its effects can be measured by factors such as an increase in endogenous cerebrospinal fluid opioids in patients with chronic pain, increase in tissue oxygenation of ischemic limbs, and a decrease in blood pressure in patients with hypertension. Because of these profound placebo effects, the FDA considers the placebo-controlled trial the “gold standard” for proving that a specific treatment has an effect. Under most circumstances, the FDA requires positive placebo-controlled trials for new drugs regardless of whether this requires withholding standard treatment. This standard has been evolving since 1962, when Congress extended the FDA mandate to ascertain effectiveness as well as drug safety. According to Sackett (33), “Validity has become a nonnegotia" @default.
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W4244504443 title "A Workshop on Antiepileptic Drug Monotherapy Indications" @default.
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