Antihypertensive Drug Development: A Regulatory Perspective

Chapter 47

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Antihypertensive Drug Development: A Regulatory Perspective Mehul G. Desai, Norman Stockbridge, Douglas C. Throckmorton, and Robert Temple

Antihypertensive drugs have been one of the most intensely studied therapies in clinical medicine. This is not surprising considering that hypertension affects more than 50 million people in the United States alone and requires lifelong treatment. It affects individuals of both sexes and is not restricted to any particular age or ethnic group. Over the past few decades, numerous antihypertensive agents representing a variety of pharmacologic classes have been studied and approved, including diuretics, α-adrenergic receptor blockers, β-adrenergic receptor blockers, central α-agonists, direct vasodilators, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), and others. Within each class of antihypertensives, numerous products have been developed and approved. An important aspect of the search for new antihypertensive agents is the quest for drugs that are well tolerated and can be added to existing treatments. To gain regulatory approval by the U.S. Food and Drug Administration (FDA or the Agency), an antihypertensive drug, like any therapeutic agent, must demonstrate effectiveness. Effectiveness for an antihypertensive drug is established by showing that the drug lowers blood pressure (BP). BP is a surrogate endpoint. A surrogate “endpoint, or ‘marker,’ is a laboratory measurement or physical sign used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives.”1 The effect of the drug or intervention on the surrogate is expected to predict a clinical benefit of the therapy. The effect on the surrogate endpoint is not itself noticeable by the patient and is of value only if it leads to the desired clinical benefit. The law and regulations do not stipulate whether or not effectiveness must be demonstrated as an actual clinical benefit (e.g., fewer strokes, fewer myocardial infarctions, or symptomatic improvement) or as an effect on a validated surrogate endpoint for such benefit (e.g., decreased BP or decreased serum cholesterol). The law calls for evidence that the drug will do what its labeling claims it will do. However, the effect must be clinically meaningful. BP is considered a validated surrogate endpoint. An effect on BP is well supported as a predictor of clinical benefit, based on epidemiologic data, animal models, and, most importantly, numerous placebo-controlled studies. Epidemiologic evidence clearly shows that the risk of cardiovascular and cerebrovascular events increases with increases in BP. Many, large, randomized, placebo-controlled outcome trials involving a variety

of antihypertensive drug classes (e.g., diuretics, reserpine, β-adrenergic receptor blockers, CCBs, ACE inhibitors) have shown that lowering elevated BP leads to a decreased risk of cardiovascular events, notably strokes, myocardial infarctions, and death from vascular causes.2-5 This does not mean that all antihypertensive drugs will affect all outcomes similarly. For example, possible differences exist in the effects of different agents on heart failure,6 an important consequence of hypertension. It also does not mean that drugs could not differ in effects on stroke and myocardial infarction, because these disorders are influenced by factors other than BP. The possibility of such differences is regularly examined,7-10 and it is of great interest. These possible differences, however, do not undermine the observation that benefits of BP lowering have been seen in essentially all adequately sized, placebo-controlled studies with a variety of pharmacologically dissimilar agents. Because BP is a validated surrogate, approval of antihypertensive drugs continues to be based on a demonstration that a drug can produce a sustained decrease in BP with an acceptable safety profile. This greatly simplifies the development of new agents. An effect on BP is an objective, noninvasive, reproducible, titratable, and rapidly demonstrated endpoint that can be studied in placebo-controlled trials. Demonstrating that a drug is an effective antihypertensive can be accomplished using a relatively small number of patients treated for a few weeks, with longer-term open or active-control followup and a randomized withdrawal study to confirm long-term effectiveness. Long-term outcome studies in hypertension could no longer ethically use a placebo group, but instead would require an active-control, noninferiority design, a type of study that is often difficult to interpret.11,12 The aim of this chapter is to discuss regulatory aspects of drug approval of antihypertensive drugs intended for long-term use. The development of an antihypertensive new molecular entity (NME) is discussed with a focus on the steps involved in drug development from the original submission of an Investigational New Drug (IND) application to submission of a New Drug Application (NDA). An NME is a drug whose active moiety, the part of the molecule responsible for its activity (irrespective of the particular salt or ester), has not been previously marketed. The chapter also addresses the quantity and quality of evidence necessary for approval of an NME, with attention to clinical trial design and analysis. Development of combination antihypertensives is also considered, as are the issues of outcome and comparative claims for antihypertensive drugs.

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OVERVIEW OF DRUG DEVELOPMENT Clinical drug development ordinarily proceeds in a systematic manner through “phases,” as described in the Code of Federal Regulations (CFR; 21CFR312.21). Each step or phase in drug development builds on data acquired during earlier steps and in general exposes larger numbers of patients for longer periods of time. The goal of drug development is the acquisition of data that will provide the evidence needed for drug approval described in Section 505(b)(1) of the Food, Drug and Cosmetic (FD&C) Act. The law requires a showing, through adequate and well-controlled investigations, of “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling” (Section 505[d], 21USC355). The available data must also enable the applicant to provide “adequate directions for use” of the drug (Section 502[f], 21USC352). The FDA not only monitors the development process to ensure patient safety, but also interacts with the sponsor to help ensure that the studies, if successful, will provide the data needed for approval by discussing, among other things, specific study designs, study endpoints, and adequacy of planned safety databases. In the United States, the study of any NME in humans requires that an IND (notice of claimed investigational exemption for a new drug, generally called an IND application) be filed with the FDA. The submission goes to the appropriate review division within the Center for Drug Evaluation and Research (CDER), which, in the case of antihypertensive drugs, is the Division of Cardiovascular and Renal Products. An initial IND submission (1) alerts the Agency to a sponsor’s intent to initiate clinical studies in the United States, (2) provides the preliminary animal data needed to assess potential Table 47-1

targets of toxicity and to ensure that it is reasonably safe to begin drug administration to humans, (3) provides information about the manufacturing process and chemistry of the new drug, (4) describes the initial clinical study to be conducted with a focus on safety measures, and (5) provides assurance that an Institutional Review Board (IRB) will approve the study before it is initiated. If the Agency identifies no major safety issues that result in the study’s being put on “hold,” the sponsor can begin the initial clinical study of the investigational drug 30 days after submission of the IND. Often, before submitting an IND, a sponsor will meet with Agency staff for a pre-IND meeting, during which preliminary development plans are discussed. For antihypertensive drugs, sponsors often forgo such meetings, probably because the development path is relatively straightforward. After IND submission, all subsequent clinical study protocols must also be submitted to the FDA but are not subject to a 30-day waiting period. These protocols can be initiated on the day of submission to the Agency. As part of the IND submission process, the sponsor completes FDA form 1571, which describes what a typical IND application should contain. A link to the form is shown in Table 47-1. Every investigator participating in the study must also sign FDA form 1572, which, among other items, contains a list of the qualifications of the investigator, the location of the research facility where the investigation will be conducted, the name of the IRB responsible for review and approval of the protocol, and a list of certain commitments from the investigator related to the conduct of the clinical study, stating that the investigator intends (1) to conduct the study in accordance with the current protocol, (2) to conduct or supervise the described investigation personally, (3) to inform potential subjects that the drugs are being used for investigational pur-

Useful Web Addresses

Web Address

Information Contained at That Web Address

http://www.fda.gov/

Main FDA Web site with links to many valuable informational and educational resources Center for Drug Evaluation and Research guidances International Conference on Harmonization guidances FDA forms 1571 and 1572 containing the Investigational New Drug application and investigator statement Code of Federal Regulations Database. If a specific Code of Federal Regulations reference is known, a detailed description of that regulation can be obtained. FDA Advisory Committee Calendar MedWatch Web page containing links to recent Safety Alerts for Drugs, Biologics, Devices, etc. It also contains links to the adverse event reporting forms 3500 and 3500A. Center for Drug Evaluation and Research, Freedom of Information New Drug Approval Packages (includes approval letters and posted reviews) List of drug-metabolizing enzymes and their substrates, inhibitors, and inducers

http://www.fda.gov/cder/guidance/guidance.htm http://www.ich.org/UrlGrpServer.jser?@_ID=276&@_TEMPLATE=254 http://www.fda.gov/opacom/morechoices/fdaforms/cder.html

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

http://www.fda.gov/oc/advisory/accalendar/2005/default.htm http://www.fda.gov/medwatch/index.html

http://www.fda.gov/cder/foi/nda/index.htm

http://www.fda.gov/CDER/drug/drugInteractions/default.htm

FDA, Food and Drug Administration.

Antihypertensive Drug Development: A Regulatory Perspective poses, and (4) to report to the sponsor adverse events that occur in the course of the investigation (21CFR312.53). These forms are retained by the IND’s sponsor. Substantial resources are expended by sponsors even before an IND is submitted to the FDA. Apart from the discovery process, the sponsor will have performed standard toxicology studies, animal pharmacology studies, and absorption/ distribution/metabolism/excretion (ADME) studies in animals before initial exposure of humans to the investigational drug. These types of studies may provide clues to possible safety problems in humans and can influence the kind of monitoring that may be needed during future clinical studies. The IND and the clinical studies proposed in the IND are reviewed by a team of scientists at the FDA consisting of a pharmacologist/toxicologist, a chemist, a clinical pharmacologist, a statistician, and a medical/clinical reviewer. Certain disciplines are more actively involved than others at various stages of drug development. One of the main concerns of FDA reviewers during the initial 30-day IND review period is the appropriateness of the initial dose and duration of exposure. Usually, the human starting dose is chosen by identifying the no-observed-adverse-effect level (NOAEL) dose in two animal species, a rodent and a nonrodent, and then dividing that dose by a “safety factor” of about 10 to 100, to obtain the recommended starting dose in humans. Because the initial human study is usually a single-dose or limited repeat-dose study, animal studies of relatively short duration of exposure (e.g., 2 weeks) are sufficient to support initiation of human studies. Completion of animal studies with longer durations will be needed to support initiation of clinical studies of longer duration. Generally, the duration of animal studies will be similar to the duration of the planned human study, up to 6 months. Animal studies of 6 to 12 months’ duration will support longer human studies.13 In addition, for drugs used on a longterm basis such as antihypertensives, carcinogenicity studies in rats and mice, as well as reproductive toxicity studies in rats and rabbits, are needed before marketing approval.14,15 The pharmacology/toxicology reviewer is usually the most active member of the review team during the initial IND submission for an NME, with principal responsibility for evaluating the extensive body of nonclinical data submitted to support initial human use. The chemistry reviewer is also critical, in evaluating the manufacturing process to ensure that the NME is a stable, reproducible compound and in assessing the drug’s formulation for impurities. The medical reviewer evaluates the initial phase 1 study primarily to ensure that adequate safety assessments are in place, including laboratory and electrocardiographic monitoring, that appropriate contraceptive measures are taken for women of childbearing potential, that provisions have been made for adequate subject follow-up, and that the initial dose chosen for human use is appropriate. Under the regulations, protocols for phase 1 studies may be less detailed relative to protocols for phase 2 or 3 studies, although phase 1 protocols should specify in detail only elements that are critical to safety (21CFR312.23). The Agency actively encourages the inclusion of women in the earliest clinical studies, and in fact for a study of a serious or life-threatening condition that affects both men and women, may put on hold a trial that excludes women because of their reproductive potential (21CFR312.42). The initial and subsequent phase 1 studies should provide enough information about the drug’s tolerability, pharmacokinetics (PK), and

pharmacologic effects to permit the design of well-controlled phase 2 studies. The clinical pharmacology reviewer is involved in the early IND submissions to characterize the PK profile of single and repeated doses of drug and to consider in vitro and later in vivo studies of drug-drug interactions. Later in development, it will be important to consider details of drug metabolism and excretion and the effects of impaired renal and hepatic function. PK/pharmacodynamic (PK/PD) modeling can inform the choice of doses in controlled studies. The role of the statistician is limited in the early studies submitted for the IND, but it becomes far greater in later stages of drug development, generally beginning with the end-ofphase-2 (EOP2) meetings, when discussion focuses on issues related to the statistical analysis of clinical endpoints. Better design of early (phase 2) studies, however, may be possible with the help of PK/PD modeling, use of enrichment designs,16 and more attention to studying a full range of doses. Once clinical studies are initiated, sponsors of INDs have certain obligations defined in the regulations. Some of these obligations include selecting qualified investigators, monitoring all clinical investigations being conducted under the IND, keeping investigators informed of new findings or observations related to the safe use of the new drug, submitting annual reports that update the progress of an IND, and submitting reports of serious and unexpected adverse events to all investigators and the FDA within 15 days. A critical task of the medical reviewer during the IND stage is the review of reports of serious and unexpected adverse events associated with use of the drug. Sponsors of INDs are required to submit to the Agency reports of all serious and unexpected adverse events (those adverse events not described in the investigator’s brochure) “associated with” the use of a drug (generally meaning at least possibly related to the study drug), in a timely manner on a MedWatch 3500A form (Web link available in Table 47-1), with appropriate follow-up as additional information becomes available. As experience with the NME grows, the sponsor is responsible for cautious monitoring of adverse effects and for taking any necessary steps to deal with them, including increasing safety monitoring, modifying the dose, conducting additional evaluations, and, when problems merit this, stopping the trial. The FDA regularly reviews safety reports and discusses them with sponsors as necessary. After completion of phase 1 studies and the subsequent phase 2 studies (i.e., the first studies of effectiveness), an EOP2 meeting is often held between the Agency and the IND sponsor. A critical issue is the design of phase 3 studies, the definitive, well-controlled studies of effectiveness that will serve, if successful, as the basis for marketing approval. Issues considered during such meetings include the design of the trials, the number of trials needed, the population (and demographics of the population) to be studied, the endpoints to be evaluated, the doses to be evaluated, and the total safety exposure that will be adequate. The Agency also considers any special safety evaluations that are needed. In addition to the pharmacology/toxicology, chemistry, medical, clinical pharmacology, and biostatistics reviewers, these later meetings may also include representatives from the FDA’s Office of Drug Safety. On completion of the phase 3 studies, and if the results are satisfactory, the sponsor submits an NDA to the Agency. The Agency currently recommends and eventually may require

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Hypertension Treatment in the Future that an NDA be submitted in the Common Technical Document (CTD) format.17 The CTD represents an effort by the International Conference of Harmonization (ICH) to create a core information package that can be sent to any of the three ICH regions (the United States, the European Union, and Japan) to support marketing authorization and includes a well-constructed overview of the application. The Agency’s data requirements for establishing efficacy or safety have not been changed by the CTD. The CTD leaves room for specific FDA requirements, notably the case report tabulations, case report forms, integrated summaries of safety and efficacy, and complete study reports that are outlined in the CFR (21CFR314.50). There is also an FDA guidance on integrated summaries.18 The CTD can be submitted electronically and is reviewed by an FDA review team that consists of the same disciplines that were involved in the review of the IND. Drugs that would be a significant improvement, compared with marketed products, are considered “priority” (P) applications. Details of what constitutes a “significant improvement” can be found in an FDA document called an MaPP (Manual of Policies and Procedures).19 Under agreements reached at the time of the Prescription Drug User Fee Act (PDUFA) of 1992 and its subsequent renewals, priority applications will be reviewed by 6 months after the time the application is received by the Agency. Other applications are “standard” (S) and will be reviewed within 10 months. Because of the extensive armamentarium of antihypertensive drugs currently available for use, most NDAs for antihypertensive drugs fall into the standard review category. Sometimes, during the FDA review process, NMEs that raise public health or other scientific issues may be brought before the Cardiovascular and Renal Drugs Advisory Committee (a committee of external advisors) for discussion at a meeting open to the general public. The Committee addresses specific questions posed by the FDA, often including whether there is substantial evidence of effectiveness and whether safety has been adequately assessed and shows the drug to be safe for its intended use. The Committee’s recommendations are advisory, and the Agency is not bound to accept its recommendations. After completion of the Agency’s reviews, a decision regarding approvability is conveyed to the NDA applicant or sponsor in the form of an “action letter. ” Currently, there are three types of action letters: (1) approval, (2) approvable, and (3) not approvable. When a sponsor is granted an “approval” letter, the drug can be marketed as of the date of the letter, with the labeling identified in the approval letter. Following an approval action, the primary reviews of the various disciplines as well as secondary reviews are made available to the public (link available in Table 47-1). Approvable and not-approvable actions both indicate that something further needs to be done before a drug can be approved. In that sense, they are both indicators of a deficiency in the application. The deficiency can range from a need to revise labeling to a need to conduct additional studies of effectiveness or safety. At present, the Agency sends the sponsor an “approvable” letter if the application meets most of the requirements listed for marketing approval and can be approved if “specific additional information or material is submitted or specific conditions (for example, certain changes in labeling) are agreed to by the [sponsor]” or if additional information is provided, such as additional data analyses or even an additional study

(21CFR314.110). A “not-approvable” letter is issued if the Agency believes that the drug application is insufficient to justify approval because effectiveness is not supported or safety problems appear serious. The sponsor may undertake to correct any deficiencies noted by the FDA and file a resubmission. The Agency was asked in the FDA Modernization Act (FDAMA) to develop a single “complete response” letter (to replace the approvable and not-approvable letters) that would detail deficiencies when the drug cannot yet be approved. At the time of approval, the agency may conclude that safety concerns require a risk management effort that could include further postmarketing studies, educational efforts, or specific labeling.20-22 Sponsors may also agree to carry out postmarketing (phase 4) studies, such as studies of larger doses or of combinations with other antihypertensive drugs.

CLINICAL PHARMACOLOGY Pharmacokinetics The PK of a drug comprises descriptions of the fate of the drug and its metabolites in the body, including its absorption, distribution, metabolism, and excretion. These parameters are often described by analyzing the measurement of blood and urine concentrations of the drug and its metabolites over time, including certain important parameters including the highest concentration achieved after dosing (Cmax), the time of peak concentrations (Tmax), the trough concentration before the next dose (Cmin), and area under the curve or the integration of time and concentration, representing a measure of drug exposure (AUC). Information about PK is obtained from single- and multiple-dose studies conducted in healthy subjects or in the patient population in whom the drug is intended. Areas of particular interest are those that make PK less predictable than expected (e.g., PK differences among people or nonlinearities of PK with changes in dose). For example, one expects blood levels of a drug to be proportional to the administered dose, and inversely related to body size, weight, or body surface area. It is thus of great interest when there is a nonlinear relationship such that drug levels do not change in direct proportion to the administered dose, or when substantial sex differences exist. Similarly, it is critical to know how impaired renal or hepatic function and other co-variates (e.g., age and sex) or the presence of concomitantly administered drugs affect PK. Deviations from linearity or substantial intersubject variation are particularly important for drugs with a narrow therapeutic index (drugs for which the difference between effective exposures and toxic exposures is small), and in the most extreme cases they may indicate the need for therapeutic drug monitoring. Interpretation of PK findings also requires knowledge of the activity of major metabolites. Although many useful PK findings may emerge from special studies (e.g., of drug interactions, dose-response, or people with renal or hepatic impairment) using an intensive sampling protocol, it is often of value to conduct population PK analyses using sparse sampling in studies to detect unexpected causes of nonlinearity or individuals with unusually high drug exposure. Knowledge of the PK of a drug and its active metabolites can guide both how often to administer a particular compound in later studies and the timing of certain safety data that are to be

Antihypertensive Drug Development: A Regulatory Perspective collected (e.g., electrocardiograms to assess Q-T intervals, measurements of BP or heart rate). Finally, knowing how the PK of a drug changes in a particular population, or with a co-administered drug, can be useful in determining how to modify dosage regimens to optimize use of the drug.

Metabolism and Drug-Drug Interactions The route by which a drug is metabolized or eliminated from the body is an important determinant of interindividual PK variability. Although the importance of metabolic pathways and their potential for creating individual differences in response and drug-drug interactions are now widely recognized, experience with an antihypertensive agent was an important early source of this recognition. Debrisoquine, an adrenergic blocking agent, was developed in the 1970s for the treatment of hypertension. Studies with this agent showed a positive correlation between BP lowering and the amount of unchanged drug excreted in the urine; this finding reflecting the fact that the parent compound, debrisoquine, is pharmacologically active, whereas its metabolite is not.23 The enzyme responsible for the conversion of debrisoquine to its metabolite was originally called debrisoquine hydroxylase, but it is now recognized as cytochrome P-450 2D6 (CYP2D6), one of several important oxidizing enzymes in the liver. Cytochrome P-450 2D6 is polymorphic in humans, and approximately 5% to 10% of whites have a genetic deficiency of this enzyme (often referred to as poor metabolizers). They therefore experience exaggerated responses to drugs such as debrisoquine or tricyclic antidepressants,24 as a result of greatly increased (sometimes 10-fold) drug exposure. Probably more important, because it can occur in people who have been receiving the drug and tolerating it, is that even in subjects without a genetic deficiency of CYP2D6, concomitant use of a drug that inhibits this enzyme can mimic the genetic deficiency and can lead to abrupt excess parent drug concentrations and potential toxicity. Inhibitors of CYP2D6 include fluoxetine, paroxetine, and quinidine. Inhibitors of cytochrome P-450 enzymes and other metabolic and transport systems are important, even for systems that are not genetically polymorphic such as CYP2D6. References to enzymes involved in drug disposition, their substrates, inhibitors, and inducers can be found at the links provided in Table 47-1. Terfenadine, cisapride, and astemizole, all now removed from the market, were drugs that were metabolized by CYP3A and became far more toxic when their metabolism was blocked, thus leading to Q-T prolongation and torsades de pointes arrhythmias. Routine and early evaluation of the substrate, inhibitor, and inducer status of NMEs should be conducted, and these matters are considered at length in FDA guidances.25,26 One recently approved, then subsequently withdrawn, antihypertensive illustrates the importance of metabolic inhibition. Mibefradil was a CCB antihypertensive drug approved in 1997 for the treatment of hypertension and angina. In vitro and in vivo studies clearly showed that the drug was a potent inhibitor of CYP3A, an enzyme responsible for metabolizing a variety of medications, including several 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors or statins, as well as astemizole and cisapride. The drug was labeled to describe these interactions, but mibefradil was linked to cases of torsades de pointes–type

arrhythmias when it was given, despite labeling, to patients receiving astemizole and cisapride (substrates for the enzyme CYP3A). More surprising was the extent of serious interactions with certain statin drugs. Although other CYP3A inhibitors were associated with rare cases of rhabdomyolysis when these drugs were taken with statins, mibefradil use quickly resulted in numerous reports of rhabdomyolysis when it was co-administered with simvastatin. In retrospect, it was probably the use of mibefradil for cardiovascular conditions that made its use with statins so common. Other potent CYP3A inhibitors (e.g., antifungals, such as ketoconazole) were less likely to be used concomitantly with statins. Because of its metabolic liability, mibefradil was soon withdrawn from the market.

Special Populations Studies to characterize the PK of a drug in special populations, such as male and female patients, the elderly, and patients with renal or hepatic impairment (depending on how the drug is metabolized and excreted), should be carried out during drug development.27-31 Factors such as sex, age, renal or hepatic impairment, and others are important determinants of interindividual differences in drug exposure and may identify a population at risk of drug-related adverse events. Nearly all ACE inhibitors undergo predominantly renal elimination. Labeling of these drugs therefore suggests a starting dose at the low end of the dosage range in patients with renal impairment (or elderly patients, who often have a degree of renal impairment), with titration to higher doses as needed. This is intended primarily to avoid dose-related adverse events such as hypotension.

Food Effects and Absorption Food intake concomitant with oral drug administration can have marked effects on drug bioavailability, particularly for drugs with large first-pass effects or drugs in controlledrelease forms. A controlled-release formulation of nisoldipine is an example of an antihypertensive whose PK profile is significantly altered in the setting of concomitant food intake. Administration of nisoldipine with a high-fat meal increases the peak plasma concentration by up to threefold, whereas the total exposure is reduced by about 25%.32 This phenomenon, referred to as dose dumping, in effect converts the extendedrelease formulation into an immediate-release formulation, thus eliminating the 24-hour antihypertensive coverage of nisoldipine while exposing the patient to the risks of an acutely exaggerated hypotensive response. A similar phenomenon can occur when controlled-release formulations of nifedipine are taken with high-fat meals. Studying food effects of drugs should be a routine part of most new drug development programs,33 unless the drug is an immediaterelease, rapidly dissolving product that is not significantly metabolized.

Pharmacodynamics The approval of antihypertensive drugs is based on their PD effect, that is, lowering BP. Many currently approved antihypertensive agents have additional effects (e.g., diuretics to treat edema, ␤ -blockers or CCBs to treat angina), and, in many

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Hypertension Treatment in the Future cases, an earlier PD effect represents the drug’s mechanism of BP lowering (e.g., ACE inhibition for an ACE inhibitor). Evaluating the PD effects of antihypertensives other than their effects on BP may be of interest and can be used to suggest a therapeutic dose range for the other effects or to anticipate adverse effects. Studies of the drug’s mechanism-based biomarkers (e.g., exercise-induced heart rate for ␤ -blockers, urinary sodium excretion for diuretics, ACE activity or plasma renin activity for ACE inhibitors, and angiotensin II activity for ARBs) can be useful in selecting dose ranges for later controlled BP trials, although they are not a substitute for those clinical dose-response studies. The dose-response and duration of these effects can be initially characterized in healthy subjects, but eventually they should be assessed in the target population. It is often useful to relate PD effects to plasma concentrations through a PK/PD model or an exposureresponse model. A wide range of doses should be studied to characterize these relationships adequately. Exposure response data can sometimes facilitate development of new formulations. The immediate-release formulation of metoprolol was originally approved as a twice-daily treatment for hypertension and angina. Subsequently, a once-daily extended-release formulation was developed and approved, based on PK/PD studies in a relatively small number of healthy volunteers showing that the effects of the immediate-release and controlled-release products on exercise heart rate were similar (e.g., maximal reduction in exercise heart rate [Emax], plasma concentration of metaprolol that produces 50% Emax [EC50]).34 It was also shown that the plasma concentrations with the extended-release formulation remained higher than a level that produced clinically relevant reductions in exercise-induced tachycardia for the duration of the dosing interval, a finding indicating that this drug could be expected to provide 24-hour antihypertensive effectiveness.

CLINICAL EFFICACY General Principles The evidence needed to support the effectiveness of a new antihypertensive agent is based on the general requirements set forth in the FD&C Act as amended in 1962. The amended law required “substantial evidence of effectiveness,” which it defined as evidence from “adequate and well-controlled investigations.” The plural of investigations was intended. More recently, the FDAMA of 1997 amended the definition of substantial evidence to state that the Agency may determine that “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to represent substantial evidence (Section 505[d], 21USC355). The law also requires that a drug label provide adequate directions for use. In practical terms, data from at least two studies, usually more, are needed and expected, considering what needs to be known about how to use antihypertensive drugs appropriately, including a good dose-response assessment and use with other antihypertensive drugs.

Study Design The CFR describes criteria for an adequate and wellcontrolled study (21CFR314.126). The CFR identifies five

kinds of control groups that can be used: placebo, no treatment, dose-response, active/positive, and historical. The choice among these control groups is discussed in much more detail in an ICH guidance document.12 Until recently, with the advent of ambulatory BP monitoring (ABPM), only a placebo-controlled study, a dose-response study, or an active-controlled study showing superiority of the test drug would have been considered satisfactory evidence of effectiveness of an antihypertensive agent. Active-controlled noninferiority studies would be difficult to interpret, given the substantial early “placebo response” in most hypertension trials.11,12 Although the reasons for placebo response in hypertension studies are not fully documented, it is thought that the response can be attributed, at least in part, to digit preference, a tendency to read high at entry, when BP must be greater than some entry value, and then reading appropriately or low once treatment begins. In a placebo-controlled trial, this effect is simply subtracted, because the effect measured is the drugplacebo difference. In an active-controlled trial, however, this is not possible, and it is not uncommon for active-controlled trials to show changes from baseline of 20/15 mm Hg, a difference far larger than the difference between drug and placebo seen in placebo-controlled trials. An active-controlled noninferiority study would have to base its analysis on a noninferiority margin (the actual effect of the control drug in the study) of typically 4 to 5 mm Hg. Attempting to show that, for example, a difference of half that (e.g., 2 mm Hg) had been ruled out when the change from baseline is, for example 20/15 mm Hg, would be a significant challenge. As discussed in more detail later, ABPM, unlike manual cuff pressure measurements, appears to show little or no fall in BP in the placebo group, thus making active-controlled trials potentially feasible. Placebo-controlled studies in hypertension commonly include more than one dose of the study drug (Fig. 47-1A). This is a very informative design, capable not only of providing unequivocal evidence of effectiveness, either by pairwise comparison with placebo or demonstration of a slope, but also of relating efficacy and adverse effects to dose. With a group of such studies, pooled data usually allow analyses of dose-response for relevant population subsets, including demographic subsets and BP severity subsets. A potential concern with a placebo-controlled design is denial of known effective treatment to patients enrolled in such a study. Although it is recognized that long-term placebo-controlled studies in hypertension cannot be ethically conducted, shortterm (e.g., duration of 8 to 12 weeks) placebo-controlled studies appear acceptable. A meta-analysis of 25 randomized shortterm placebo-controlled studies in more than 6400 patients demonstrated no increased risk of death, stroke, myocardial infarction, or heart failure in patients randomized to placebo.35 The FDA also conducted a meta-analysis of short-term hypertension studies, referred to as the Placebo in Hypertension Adverse Reaction Meta-analysis (PHARM) project.36 It also showed no significant increase in the risk of irreversible morbidity or harm in patients treated with placebo. Nonetheless, because the effects of most antihypertensives are fully developed within a few days to a couple of weeks, it appears prudent to limit studies to relatively short durations. New antihypertensive agents are commonly studied for their additive effects on top of standard agents, although this has not been explicitly required (see Fig. 47-1B). A common

Antihypertensive Drug Development: A Regulatory Perspective

Washout

Single blind, placebo run-in

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Figure 47–1 A and B, Placebo-controlled, fixeddose, dose-response study. C, Active-controlled versus new drug study (new drug could have several doses). D, Randomized withdrawal study. E, Factorial study.

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example of such a study is a comparison of the study drug and placebo, each added to a fixed dose of a diuretic. This is a placebo-controlled study and supports the effectiveness of the new agent, just as does a study that does not include the diuretic.37 In long-term extension studies, other drugs are added to attain adequate BP control, thus allowing informal observation of other concomitant use. Later in this chapter, studies in support of a fixed-dose combination antihypertensive are discussed in more detail. An active-controlled study (see Fig. 47-1C) showing superiority of the study drug over an active-control agent with respect to BP lowering can also be used to demonstrate effectiveness of the new drug. It could also support a labeling claim of superiority if the control drug is used properly, at its highest dose, and in an optimal regimen.12,38 However, such a study provides neither a good estimate of effect size of the new drug relative to placebo nor a good assessment of the actual adverse effect rate (i.e., drug rate minus placebo rate). A labeling claim of greater effectiveness, based on BP lowering, is most credible for drugs of the same pharmacologic class, because differences in efficacy among classes are more difficult to interpret in full, given differences in side effects. In contrast, studies that compare drugs for effects on clinically relevant outcomes (e.g., mortality, stroke, and coronary heart disease), when they are used at equieffective doses, are of great interest, and convincing results could appear in labeling. Outcome claims in hypertension are discussed in more detail later in this chapter. As discussed earlier, a dose-response study can be informative about both effectiveness and dose response. In a randomized, fixed-dose, dose-response study, the design

described in the 21CFR314.126 and identified in ICH E439 as optimal, patients are randomized to two or more fixed doses in a parallel group study. The fixed doses can be reached in steps. Such a study design may or may not incorporate a placebo and could include an active control as well. Doses should be spaced adequately (e.g., threefold increments) to increase the likelihood of seeing differences in BP response. Although a dose-response study with a nonzero slope is sufficient to demonstrate a drug effect even without a placebo, conducting such a study (in the absence of a placebo group) is ill advised. In the absence of a slope for the active treatments, the study is entirely uninformative, even if all doses would have been superior to placebo, had one been included. It is not uncommon in hypertension studies for all doses to have effect sizes close to each other. Including a placebo arm ensures that a study will have assay sensitivity, but, in addition, it allows dose-placebo pairwise comparisons that provide information on the particular doses, including the lower doses, that are effective. A dose-response study with a nonzero slope, in the absence of a placebo group, may need further evaluation to determine whether the lower doses are actually useful. Recognition of the limitations of titration designs and acceptance of the randomized fixed dose-response study (ICH E4) have obscured the potential value of titration designs, properly analyzed.40 Sheiner and colleagues used such a design, combined with analysis of individual dose-response curves that, if accompanied by a placebo group, could provide an initial estimate of the dose-response curve for effectiveness, as well as unequivocal evidence of effectiveness.41 Such a titration design would be very useful as an initial controlled study

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Hypertension Treatment in the Future that would ensure titration to an adequate dose and guide subsequent dose-response studies. As their name implies, dose-response studies describe dose response but do not themselves indicate what the starting or maximal doses should be, because these are matters of judgment. When a drug is well tolerated, starting doses are usually chosen to give a substantial fraction of the drug’s full effect. Only if there are dose-related toxicity concerns (e.g., ␣ -blockers and hypotension, diuretics and hypokalemia) will a much lower starting dose be recommended in general or for certain patients. A study design that can be used to help demonstrate efficacy and that is important to proper demonstration of the durability of effect after long-term use is the randomized withdrawal study (see Fig. 47-1D). In a randomized withdrawal study, all patients initially receive therapy with the study drug for some period of time (e.g., 6 months to 1 year or more, depending on how long an effect duration is to be evaluated) as part of a single-arm, open-label safety study or as part of an active-controlled comparison. At the end of the open-label study period, patients are randomized in a blinded manner either to continued use of study drug or to placebo (withdrawal of study drug, which can be down-titrated if there is concern about withdrawal effects). After a relatively short period (e.g., 2 weeks), BP effects between the two groups can be reassessed. Alternatively, patients can be monitored closely and discontinued from the study as soon as their BP rises to a predetermined level. In both cases, a withdrawaltype study that shows increased BP in the placebo-controlled group demonstrates that the study drug was continuing to have an effect. This durability of effect would otherwise be difficult to establish, because a long-term placebo-controlled study in hypertension would be ethically unacceptable.

Study Population Patients enrolled in an antihypertensive efficacy study should be representative of the population for which the therapy may be targeted. Although regulations and guidances (except for ICH E7,42 which suggests 100 people >65 years old) do not specifically state the percentage of subjects in a clinical study that should be of a particular subgroup (e.g., age ≥65 years, female, or black), a draft guidance urges reasonable participation of each group.43 Moreover, the legal requirement (Section 502[f], 21USC352) to provide adequate directions for use in labeling suggests that the population studied ought to be representative of those that will receive the drug. There are several examples in which a particular subgroup has not had the same BP response as that of the whole group. The smaller antihypertensive effect of drugs directly affecting the reninangiotensin system (␤ -blockers, ACE inhibitors, and ARBs) in black subjects is well recognized. In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, a randomized, blinded, active-controlled study comparing losartan with atenolol in hypertensive patients with electrocardiographically documented left ventricular hypertrophy, statistical heterogeneity was observed in the primary endpoint with respect to race.44 In this study, black patients responded more favorably to atenolol, whereas white patients responded more favorably to losartan in terms of a reduction in the composite primary endpoint of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction.

Dose Selection, Dosing Interval, and Dose Titration Studying a relatively wide range of doses should be routine practice in hypertension drug development. As explained in ICH E4,39 it is critical to describe the dose-response curve of a drug for favorable and unfavorable effects. With this information, it is possible to choose an appropriate starting dose and a dose beyond which there appears to be no further important benefit (this is a more accurate description of the goals of a dose-response study than seeking the so-called maximum effective dose and minimum effective dose). Some major historical errors in dose finding have occurred. Hydrochlorothiazide (HCTZ) and chlorthalidone were used at daily doses of 100 mg in major outcome studies in the 1960s and 1970s.45-47 In retrospect, the selection of a high diuretic dose in these outcome studies was clearly an error, because subsequent dose-response studies of chlorthalidone revealed that BP lowering was maximal at a dose of 25 mg once daily,48 and no additional BP lowering was observed with titration of chlorthalidone to doses as high as 200 mg once daily.49 However, dose-dependent decreases in serum potassium and dose-dependent increases in blood glucose and uric acid occurred at the higher doses. These effects appear to have been consequences of the use of excessive doses. The findings from these studies and from subsequent confirmatory studies led to a revision in the product labeling, thus leading to lower starting doses and lower recommended doses. The excess doses and resulting hypokalemia, in all probability, led to a decrease in the cardiovascular benefit in the early outcome trials using thiazide diuretics.2,10,40,50 Demonstrating that an antihypertensive drug or drug regimen is effective requires demonstrating that BP is lowered meaningfully throughout the time period between one administered dose and the next, sometimes referred to as the interdosing interval. Showing that BP is reduced at “trough” (usually the time just before the next dose) is thus part of establishing antihypertensive efficacy for the proposed regimen. If an antihypertensive drug does not produce an effect of this duration, it is being administered too infrequently. Captopril, an ACE inhibitor approved for the treatment of hypertension in a dosing regimen twice daily or three times daily, was evaluated by the Agency for potential approval in a once-daily dosing regimen. That regimen was ultimately not approved by the Agency, however, because there was only a clinically trivial reduction in sitting diastolic BP at trough. Some short-acting dihydropyridine CCBs have also failed to retain an adequate trough effect when they are given once daily, a problem resolved for felodipine by development of a controlled-release dosage form. As a general matter, although no specific rule or guidance exists, it has been expected that the effect at trough should be at least 50% to 70% of the peak effect (with both effects measured as placebo-subtracted values). It is also important to characterize the appropriate titration interval between dose increments. Although BP effects during a dosing interval generally depend on plasma concentrations of the drug, the full antihypertensive effects of a drug are often delayed, and may increase over time, even though plasma concentrations are stable. The reasons for this are not clear. Consequently, during a study, BP measurements should be assessed serially (e.g., weekly after study drug

Antihypertensive Drug Development: A Regulatory Perspective initiation) to determine when a plateau or steady state effect with respect to BP is reached relative to the initiation of therapy.

Endpoints The Agency has not defined a minimum magnitude of BP lowering that must be attained by a drug for it to be approved. In theory, an antihypertensive that reduced mean BP on average by as little as 2 mm Hg could be considered approvable if the drug had no significant safety issues, although most antihypertensive drugs currently approved produce substantially greater mean BP reductions, and it is difficult to imagine that such a drug would be considered very useful. If used, such a drug could also create a delay for patients to receive other, more effective antihypertensives. Approval of such a drug would make most sense if the drug provided a novel mechanism, so it could be added to maximal medical therapy in a patient not at goal BP. A more interesting possibility, however, is that a drug could have a small effect in the general population, but a sizeable effect in some patients, possibly, but not necessarily, a genetically or proteomically definable subset of the population. Even if that subset were only a small fraction of the population, such a drug, if properly targeted, could be useful for the responsive subset. In general, mean BP change in a population, rather than the response rate (i.e., percentage of the population that reaches a prespecified goal BP or has a change of a specified magnitude), has been used as the metric to evaluate antihypertensive efficacy. Although the response rate, relative to comparator, generally tracks mean BP changes, it depends on the starting BP and the non–drug-related component of response (i.e., digit preference), and thus it may be misleading. Moreover, the management of hypertension involves the addition of antihypertensive drugs in a sequential manner until adequate BP lowering is achieved, often requiring two or more medications, because single agents frequently will not enable a patient to achieve a desired goal. All antihypertensive agents are labeled for use alone or in combination to lower BP. How low a BP to target is determined by the treating physician based on a patient’s co-morbidities and other factors. In contrast, in some cases it could be useful to examine the distribution of responses rather than simply the mean response, for example, when there are responder and nonresponder subsets, as would be the case for low-renin and high-renin patients in responding to ACE inhibitors, ARBs, or ␤ -blockers. In those cases, mean responses and the distribution of responses have shown a larger effect of these drugs in whites. It would also be important to look at the combined effects of drugs. Despite the smaller response of blacks to monotherapy with drugs that work through the renin-angiotensin system, the response of blacks and whites to combinations of diuretics and ACE inhibitors, ARBs, and ␤ -blockers is the same.51 Diastolic BP at trough has been the primary outcome measure in hypertension trials, but this no longer seems sensible. Changes in systolic BP are of at least equal interest and importance. Lowering systolic BP has been shown to improve cardiovascular morbidity and mortality in elderly patients.3,4 In practice, every agent shown to reduce diastolic BP has also reduced systolic BP. Nonetheless, it is possible that drugs could differ in their effects on systolic and diastolic BP, and it is of interest to evaluate this possibility routinely.

AMBULATORY BLOOD PRESSURE MONITORING BPs obtained in an office setting, using a mercury (cuff) sphygmomanometer, have been the basis of the epidemiologic evidence establishing the risks associated with an elevated BP and the measurement tool used in outcome studies that have demonstrated the benefits of lowering BP. ABPM is an alternative way to obtain BP measurements in both clinical and research settings, and it may have important advantages, including an ability to examine different patterns of BP control. ABPM has opened several new design possibilities in the study of antihypertensive drugs. ABPM provides a characterization of the time course of BP effects throughout the dosing interval, in contrast to the “sparse sampling” of BPs that is the best one can do with clinic cuff pressure measurements. There also appears to be essentially no change in BP in placebotreated patients, thus leading to the possibility that a separate placebo group would not be needed for the purposes of demonstrating efficacy.52 By obtaining BPs unaccompanied by the presence or interpretation of medical personnel, ABPM also appears to avoid the “white-coat effect” and digit preference effect, thus decreasing the likelihood of enrolling pseudohypertensive subjects into clinical trials. Although BP measurements averaged over the last few hours of the interdosing interval (or trough) and the first few hours (for peak) appear most relevant for demonstrating efficacy (a drug with no effect during the morning hours would not seem desirable, even if it had a substantial mean effect over the day), it remains possible that drugs with similar trough and peak effects could have differential 24-hour effects, and some patterns could potentially prove more advantageous. Even though hypertension studies utilizing ABPM do not need a placebo-control arm, it remains advisable to include an active control in an ABPM study of a new antihypertensive drug, to help characterize the population being studied and to determine the BP-lowering ability of the new agent relative to a familiar control agent. An antihypertensive development program for an NME would not ordinarily be able to rely exclusively on ABPM active-control data, because the safety database needs controlled (preferably placebo-controlled) observations to assess adverse event rates. It seems possible, however, that comparison of a drug with multiple well-characterized, active controls could serve this purpose, certainly for longer-term safety observations.

OUTCOME LABELING CLAIMS FOR ANTIHYPERTENSIVES As noted earlier, approval of antihypertensives is based on an effect on BP. With few exceptions, and for several reasons, antihypertensive labeling makes no reference to outcome claims, even though an effect on outcome is the reason for the use of these drugs. First, antihypertensive outcome studies do not evaluate the effect of a single drug. Rather, although they may start with an antihypertensive of particular interest, the addition of other drugs, usually in a planned sequence, is needed to reach a prespecified goal BP. How much of the benefit observed can be attributed to the single starting agent is invariably a complex question. It is, in contrast, relatively easy to conclude that the observed effects on outcomes with a

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Hypertension Treatment in the Future wide variety of interventions compared with placebo are evidence of the benefit of lowering BP per se. Comparisons of individual drugs or classes, or of “old” versus “new,” are at present of great interest, both through individual studies7,8 and overviews,9,10 but results are not consistent, and differences are clearly small except when agents differ in effects on particular conditions, such as heart failure or diabetic nephropathy. A second problem is that most newer drugs, for which there could be commercial interest in outcome claims, have not been the subject of placebo-controlled trials, because these trials can no longer be ethically conducted. Interpreting the noninferiority studies in hypertension that can be conducted may initially seem simple, given the many historical placebo-controlled studies, but, in fact, such comparisons are not straightforward. The effect size may have been modified by many new effective treatments for hypertension-related comorbidities, such as lipid-lowering treatments, postinfarction treatment with ␤ -blockers and ACE inhibitors, effective treatment of heart failure, aspirin, thrombolytics, and revascularization procedures (e.g., angioplasty, bypass). These therapies would generally not have been available during the placebo-controlled studies that form the basis for establishing a noninferiority margin.11,12 For these reasons, outcome claims in labeling of antihypertensive drugs are few. The claim for the reduction in the risk of stroke with losartan in patients with hypertension and left ventricular hypertrophy was based on a comparison of losartan and atenolol that significantly favored the former. Although the Agency did not allow a superiority claim relative to atenolol, it did conclude that losartan had clearly been shown to reduce the risk of stroke. There is considerable irony in the present situation. Treatment of BP is recognized as critical because of welldocumented effects in clinical trials on stroke, myocardial infarction, mortality, and other adverse cardiovascular outcomes, yet labeling usually remains silent about these benefits for the reasons given previously. Discussion at a recent Cardiovascular and Renal Drugs Advisory Committee led to support of an attempt to develop a general statement for inclusion in labeling for all antihypertensive drugs regarding the effect of BP lowering on these outcomes.53

FIXED-COMBINATION ANTIHYPERTENSIVE DRUG DEVELOPMENT

monotherapies are compared with the combination product (see Fig. 47-1E). Years ago, this was typically accomplished in a single three-arm study using relatively high doses, often the maximum labeled dose of each agent. This study design documented the contribution of each component when the agents were from different pharmacologic classes (one would not want to combine half doses of two ACE inhibitors or diuretics), but the design did not reveal anything about lowerdose combinations. This was not a major problem, however, because, in general, single drugs were used at full doses before a second drug was added (“stepped care”), and the appropriate combination product could be substituted for the titrated doses. More recently, effectiveness of antihypertensive drug combinations has been evaluated in a multidose factorial study design that compares several doses of each component and their combinations (Fig. 47-2). This design can detect shifts in the dose-response curve of the individual drugs and can support the value of lower-dose combinations, given that practice has moved from stepped care to considerations of side effect minimization by use of submaximal doses of two agents, at least partly because of the recognition that full doses of diuretics posed problems. As noted later, in some cases this has led to recommended use of combinations as initial therapy. An alternative to the factorial study is the performance of two add-on studies (see Fig. 47-1B), each conducted in patients not responding adequately to an optimal regimen of one component. For example, patients whose BP is not adequately controlled on an optimal regimen of drug A would be randomized to A and B versus A alone. Similarly, patients whose BP is not adequately controlled on an optimal regimen of drug B would be randomized to A and B versus B alone. For either study, it would be possible to randomize subjects to one or more doses of the add-on agent. Combination drug products should not distort the use of the components by forcing use of inappropriate doses. A full range of fixed-dose combinations should therefore be made available, including the lowest and highest doses of each com-

Drug B Placebo Low Medium High dose dose dose

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The underlying goal of combination drug product development is to make drug intake more convenient and thereby to improve patient adherence, although such improvement has never been demonstrated. Two active drugs can be combined when “each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug” (21CFR300.50). There are several ways to demonstrate the contribution of antihypertensive components to the BP effect, and the Agency has not expressed a particular preference for one or another. Most common is a factorial design study, in which the two

High dose

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Figure 47–2 Example of 4 × 4 factorial design involving three doses of drugs A and B in addition to placebo. In developing a combination antihypertensive, it is critical to know that the blood pressure–lowering effects of drugs A and B are additive when both drugs are used at their maximal or near maximal labeled doses. Additional cells within the factorial table should also be studied to characterize the surface response of blood pressure lowering and to ensure that the dose-response curve of the initial or starting drug is not affected by the add-on drug. The cells marked by “X” represent cells that, if studied, could help to demonstrate that a combination antihypertensive product was effective.

Antihypertensive Drug Development: A Regulatory Perspective ponent, and all or most combinations of doses in between. Most combination antihypertensives are indicated for the treatment of hypertension with the labeling stating that the fixed-dose combination is not indicated for initial therapy, but rather for patients who have been titrated to the doses in the combination to be used. However, three exceptions to this labeling exist. The first example is a combination of the ␤ 1-selective adrenergic blocker, bisoprolol, and a thiazide diuretic, HCTZ. A 12-cell (placebo and three doses of bisoprolol; placebo and two doses of HCTZ) factorial design study demonstrated that each component of the combination contributed to the antihypertensive effect.54 Of particular interest was the low-dose combination of 2.5 mg bisoprolol and 6.25 mg HCTZ. This combination lowered BP better than 25 mg HCTZ and had an effect similar to that of 40 mg bisoprolol. The low-dose combination, however, avoided dose-related bisoprolol adverse events, including somnolence, dyspepsia, diarrhea, and asthenia, as well as the dose-related HCTZ adverse effect of hypokalemia. Labeling therefore identified the low-dose combination as a reasonable initial therapy. A second combination antihypertensive drug product approved for first-line use is the recently approved combination of losartan and HCTZ for administration in patients with more severe hypertension in whom the need for faster BP control outweighs the risks of initiating treatment with combination therapy. A randomized, double-blind study comparing the combination with losartan monotherapy was conducted in patients with sitting diastolic BPs higher than 110 mm Hg.55 The primary endpoint in this study was the percentage of patients who reached the goal BP of less than 140/90 mm Hg. Slightly less than 10% of the patients in the losartan monotherapy arm reached the goal, whereas twice as many reached the goal in the combination arm of the study, a statistically significant difference. In this particular population of hypertensive patients, the benefit of reaching BP goal in a relatively short time was judged to outweigh the risk of exposing only approximately 10% of patients to an unnecessary second drug. The initial treatment indication was not extended to patients with lower BPs, because the number of patients in the monotherapy arm to reach the goal would be much greater than 10%, with less reason therefore to give a potentially unnecessary drug. There was no evidence from the studies conducted that initiating treatment with the combination product led to an increased risk of adverse events such as syncope or symptomatic hypotension, although the number of such events that occurred was small. In the third case, the fixed-dose combination of captopril and HCTZ was approved for first-line use because it permitted once-daily use of captopril, whereas captopril monotherapy required administration twice or three times daily to give acceptable BP control at trough. In some combination drug products that include an antihypertensive agent, the endpoint targeted by each component is different, such as the combination of amlodipine, a dihydropyridine CCB that lowers BP, and atorvastatin, an HMGCoA reductase inhibitor that lowers cholesterol. In developing a fixed-dose combination of these two drugs, it was not necessary to show that each component had an effect on both endpoints because such an effect was neither anticipated nor needed. A possible PK interaction should be assessed, and it may be necessary, depending on the information available, to

show that there is no PD interaction, for example, that the BP-lowering effect of amlodipine was not decreased in the presence of atorvastatin, and that the cholesterol-lowering effect of atorvastatin was not decreased in the presence of amlodipine. There are, moreover, considerable data showing that statin outcome effects are similar in patients who are, and who are not, receiving antihypertensives and a variety of other drugs, such as aspirin, so PD studies may not be necessary.

SAFETY As a rule, it does not take very many patients to document and characterize the BP effects of a new antihypertensive agent, including dose-response and interactions with other drugs. The absence of a serious adverse event in a database of a few hundred patients treated for a few weeks, however, would provide very limited reassurance as to safety. Given the availability of many antihypertensives, as well as the potentially large treatment population, the Agency needs to be reasonably sure that the new agent does not have unacceptable toxicity. The ICH E1 guidance suggests approximately 1500 patient exposures for a new drug that is intended for long-term use, with at least 600 patients treated for 6 months.56 Between 1998 and 2002, three approved antihypertensive NDAs evaluated between 2800 and 3400 patients (Internal FDA data).57 The database for an unfamiliar class of drugs would probably be larger than the database for another member of a familiar class. Any suggestion of a safety problem would lead to the need for larger databases. The safety assessment typical of all new drugs, including clinical observations over time, with special attention to deaths (rare in short-term hypertension studies) and other serious adverse events, and laboratory observations (hematology, chemistry, urinalysis, electrocardiograms) are expected of antihypertensive drugs. Assessments of effects on the Q-T interval would also be expected, because these predict an ability to cause torsades de pointes–type ventricular arrhythmias, which have been seen with antihypertensive and antianginal agents such as sotalol and bepridil. Understanding the drug’s metabolism, the potential for drug-drug interactions, and drug-disease interactions is also expected. One safety assessment relatively specific for antihypertensive drugs is an evaluation of orthostatic hypotension. Experiences with certain antihypertensives, including ␤ -blockers and central ␣ -agonists, suggest a need to look for withdrawal and rebound effects. Given the abundance of therapeutic options available for the treatment of hypertension, a new antihypertensive with clinically significant adverse events (e.g., Q-T prolongation, hepatotoxicity) will face difficulties during the approval process. If the drug is a member of a familiar class, such toxicity is likely to render it not approvable. Dilevalol, a ␤-blocker (with other properties), and tasosartan, an ARB, were not approved because of concerns about hepatotoxicity, an adverse effect not shared by other members of their respective therapeutic classes. Demonstrating an advantage over available therapy, however, could possibly have overcome such concerns. A recent example is omapatrilat, the first member of a new class of antihypertensive agents that simultaneously inhibits both ACE and neutral endopeptidase (NEP). Based on its pharmacologic properties, angioedema, an adverse

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Hypertension Treatment in the Future effect characteristic of all ACE inhibitors, was not an unexpected finding with omapatrilat. However, this drug appeared to cause angioedema at an unacceptably higher rate than other ACE inhibitors and perhaps with greater severity. The sponsor of omapatrilat conducted a large study to show that the increased rate of angioedema with a lower dose of omapatrilat was not more than twice that of enalapril, but the 25,000-patient study showed a risk of angioedema that was 3.2-fold that of enalapril, with some severe cases requiring hospitalization.57 These findings were not considered acceptable to the Cardiovascular and Renal Drugs Advisory Committee and the Agency in the absence of some documented advantage. The risk, however, could possibly be acceptable if omapatrilat were able to lower BP meaningfully in a patient population resistant to multiple other antihypertensives. Minoxidil is approved for such patients despite substantial toxicity.

ANTIHYPERTENSIVE THERAPY AND PEDIATRICS The FDAMA of 1997 and the Best Pharmaceuticals for Children Act (BPCA) of 2002 allow the FDA to seek studies of drugs in the pediatric population, with the incentive of an additional 6 months of marketing exclusivity for completion of the requested studies. The Pediatric Research Equity Act of 2003 allows the FDA to require pediatric studies before approval, but the FDA usually defers such requirements until some postmarketing data are available, and then it usually makes the request for studies under the BPCA. These requests, referred to as “written requests,” ask sponsors to show an effect on BP, as well as dose-response information, pediatric PK information, and longer-term safety information. Because several classes of antihypertensive agents, when used as monotherapy, have much smaller effects in the black population than they do in whites, a high priority is placed on evaluating the effects of race in studies of these drugs in children. Therefore, written requests for antihypertensive drugs call for 40% to 60% of the population to be black. To qualify for exclusivity, the study must either show an effect on its prespecified primary endpoint (regardless of the effect size) or rule out a clinically meaningful effect. This latter requirement is implemented by having the observed variance be small enough that it would have been possible to exclude, with 95% confidence, an effect as large as 3 mm Hg had the true mean effect been nil. If no placebo group is used, and no dose response is seen, a randomized withdrawal study can be used to establish whether the drug had an effect.

CONCLUSION Hypertension is one of the most data-rich therapeutic areas within the FDA. This chapter describes some of the main aspects of antihypertensive drug regulation and discusses evidence needed by the Agency to make an informed decision with respect to benefit and risk. A future challenge to the Agency will be developing labeling for antihypertensives that describes the established outcome benefits of BP lowering. At a recent meeting of the Cardiovascular and Renal Drugs Advisory Committee,53

members acknowledged that lowering BP is a very wellestablished surrogate endpoint, and incorporating outcome data from trials into antihypertensive drug labels would be a worthwhile endeavor. Finally, because it is unethical to conduct long-term placebocontrolled trials in hypertension, future studies evaluating clinical outcomes can be expected to use active-controlled noninferiority designs. Such studies pose challenging medical and statistical issues, including the choice of a noninferiority margin and the applicability or relevance of evidence in the setting of a constantly changing standard of care.

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