Cardiovascular medicine has been in the vanguard of new therapeutic development since 1955, when President Dwight Eisenhower’s myocardial infarction (MI) in office captured worldwide attention. Many forces contribute to this positioning of cardiovascular medicine among specialties, including the alignment of patient care needs, multidisciplinary translational research, market forces, industrial production, and public health priorities. Another enabling feature is a regulatory environment that is rapidly becoming more harmonized as the process of development of new therapeutics becomes a more global endeavor. However, despite advances in translational discoveries and enormous investment in development programs, the number of new compounds that receive regulatory approval has slowly declined. A thorough understanding of new cardiovascular therapeutic development is essential for navigating an increasingly complex economic and regulatory environment and for managing the forces that contribute to challenges in development programs.
Overview of the Drug Development Process
Phase I to IV Paradigm
For a promising candidate drug to become commercially available, the developer must demonstrate efficacy and safety. Although some preliminary assessments can be performed in the preclinical setting, the principal purpose of preclinical laboratory and animal model studies is to provide data showing that the new drug will not expose human subjects to unreasonable risks when used in limited, early-stage clinical studies. (Investigation of the effects of a drug in human subjects is governed by rules that fall within the oversight responsibility of the U.S. Food and Drug Administration [FDA] and are discussed in the next section.)
Additional safety and pharmacokinetic information is gathered during phase I development. In this phase, the new compound is administered to healthy human volunteers. Rates of elimination and pharmacodynamic measurements are often obtained to provide information about absorption, bioavailability, half-life, elimination, and other biomarkers. In addition, there is close monitoring for safety signals and major toxicity.
Based on the preliminary measures of effect observed in phase I, the new drug is administered to affected subjects in phase II, which provides information on dosing as a prelude to establishing both effectiveness and safety. Several potential phase II designs may be used, including dose-escalation, “drop-the-loser,” and parallel-group studies. At the end of phase II, the goal is to have determined the preferred dose for use in larger phase III trials. The penalty for using the wrong dose, or for not identifying the correct dose, can have substantial implications for later phases.
In phase III, the new drug is administered to a large number of patients in a manner similar to its intended use in an attempt to demonstrate safety and effectiveness. The high prevalence of cardiovascular disease (approximately 1.25 million new and recurrent acute coronary syndromes are diagnosed annually in the United States ) allows most phase III trials to demonstrate efficacy using conventional statistics. New treatments that offer only modest improvements over existing therapy may require more complex statistical methods, prompting the FDA to develop guidance documents for adaptive and noninferiority clinical trial designs. The information compiled in phases I through III is then submitted for evaluation by a regulatory authority and forms the basis for marketing approval. Once approved, the drug can be marketed commercially.
Often interest continues in refining the precision of estimates of a particular drug’s safety and effectiveness, even after initial regulatory approval. Phase IV trials may seek to refine dosing, expand the drug indication to additional populations that were less well represented in earlier development work, or provide ongoing safety surveillance. Overall, the resources required to sustain this pipeline are considerable. Between 1994 and 2003, annual biomedical research funding in the United States increased from $37.1 billion to $94.3 billion, yet FDA approvals dropped from 36 to 23 new molecular entities per year. Thousands of candidate molecules are scanned in the drug discovery process, yet only 8% of new molecular entities will successfully emerge from preclinical assessments to a commercial launch. The process of discovering and developing a new molecular entity on average requires approximately 13.5 years, not including the time required to identify the drug target ( Figure 2-1 ).
Cycle of New Therapeutic Development
Beyond phase I through IV trials, which provide key evidence to support or repudiate a new therapy, other aspects to the product life cycle exist ( Figure 2-2 ). In the cycle of clinical therapeutic development, new concepts resulting from discovery and translational research advance through the phase I through IV paradigm to create evidence that supports clinical decision making. The overall evidence, which compares the efficacy and safety of different therapeutic strategies against one another, not just against placebo, forms the basis for clinical practice guidelines. Implementation of the guidelines is subject to their acceptance by the clinical community and to societal willingness to accept the nonclinical consequences of new treatment paradigms, such as cost. Key performance indicators provide education and feedback for the guidelines and help identify critical needs for additional therapeutic strategies. Assessments of performance and outcomes drive subsequent rounds of evidence synthesis and therapeutic innovation.
Regulation of New Drugs: Prototypical Interface with the Food and Drug Administration
In the United States, new cardiovascular therapies are regulated by the FDA, which has three main centers: the Center for Drug Evaluation and Research (CDER), which oversees chemical drugs; the Center for Biologics Evaluation and Research (CBER), which oversees biologics; and the Center for Devices and Radiological Health, which governs medical devices. The regulatory process for devices is outlined in Chapter 3 . Rules that govern the regulatory processes for investigation and approval of new therapeutics in the United States are found in the Code of Federal Regulations (CFR), which is divided into 50 titles. FDA-regulated research is described in Title 21, and general rules for protection of human subjects are found in title 45. For drugs, the key regulations are found in 21 CFR 312.
A new drug’s eligibility for interstate commerce, including shipment across state lines for distribution to clinical research sites, depends on an approved marketing application from the FDA. When a new therapeutic compound moves from the preclinical arena (bench or animal testing) to clinical development (testing in humans), it becomes a drug subject to specific federal regulations. To be exempted from the requirements for marketing approval, the sponsor must obtain an exemption from the FDA in the form of an Investigational New Drug (IND) Application.
Before the Investigational New Drug Application
The FDA encourages sponsors to communicate with the agency to obtain guidance on the data necessary to support an IND submission. Most cardiovascular therapeutic evaluations are assigned to the Division of Cardiovascular and Renal Products (cardio-renal), although some anticoagulant products have been reviewed by the Division of Hematology Products. Pre-IND advice may be requested for many issues related to initial drug development plans, regulatory requirements for demonstrating safety and efficacy, and data requirements for an IND. These include the data needed to support the rationale for testing a drug in humans and the design of nonclinical pharmacology, toxicology, and drug activity studies, including treatment studies in animal models. Pre-IND interactions are considered preliminary communications based on early development information and generally take the form of written comments that may be supplemented by teleconferences or meetings. Additions or modifications to these communications may arise as information becomes available during follow-up, pre-IND interactions, or when an IND is established.
Types of Investigational New Drug Application
Broadly defined, there are three different types of INDs. An investigator IND is submitted by a physician, who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit an investigator IND to propose studying an unapproved drug or an approved product for a new indication or in a new patient population. An emergency use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of the typical IND. It is also used for patients who do not meet the criteria of an existing study protocol or when an approved study protocol does not exist. A treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
IND applications provide information to the FDA about animal studies, manufacturing information, and clinical development protocols. Sponsors must submit sufficient preclinical data to establish that the new compound is reasonably safe to begin initial testing in humans. Any previous experience with the compound in humans, often from data collected outside the United States, must also be included in the application. Detailed manufacturing data describing the drug’s composition, its manufacturer, its stability, and the controls used for manufacturing the new drug are reviewed to ensure that the company can adequately produce and supply consistent batches of the new drug.
Of greatest importance to clinical investigators, the IND includes detailed protocols for the anticipated clinical studies, which allow the FDA to ascertain the risks to participants in the initial trials. The IND also includes assurances that study leaders will adhere to the pertinent regulations regarding clinical trial conduct and human subject protection, including informed consent and institutional review board evaluation.
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, the FDA has an opportunity to review the IND for safety to ensure that research participants will not be subjected to unreasonable risk.
Advisory Panels
Ultimately, the FDA is responsible for evaluating IND applications that propose the marketing of new drugs or the expansion of indications for previously approved drugs. A new drug that confers substantial benefit with minimal toxicity or other risks poses no major problems for FDA regulators. In many cases, however, the risk/benefit ratio is less certain, and the pharmaceutical sponsor and the FDA may differ in their evaluations of these issues.
Since 1972, the FDA has called on panels of experts to provide advice in such situations. For cardiovascular drugs, this advice is offered by the Cardiovascular and Renal Drugs Advisory Committee (CRAC). The advisory panels do not actually decide whether drugs should be approved; rather, they provide recommendations to the FDA, which holds the legal authority to grant or deny approval. The FDA is not obliged to accept recommendations made by its advisory panels.
Labeling
Once the FDA has determined that a new therapeutic compound is potentially approvable, much attention is given to how the product is labeled to ensure truth and accuracy. The drug label directly affects the statements that can be made by the sponsor in future claims, promotions, and advertisements for the new drug. In general, labels must summarize the essential scientific information required for safe and effective use of the drug and must be based on as much supporting human experience data as possible. By regulation, all express or implied claims in labeling must be supported by substantial evidence (21 CFR 201.56[a][3]). As a consequence, the dosing and indications described in the label usually reflect the doses and populations that were used in the phase III clinical trials submitted for regulatory approval.
In some instances, certain statements about a drug or class of drugs are required by regulation to be included in the label. For example, 21 CFR 310.517 mandates that labeling for sulfonylurea class oral hypoglycemics must include specific warnings. In other instances, labels for all drugs within a class contain identical statements (class labeling) to describe a risk or effect that is typically associated with the class based on the pharmacology or chemistry of the drug class. For example, the boxed warning about the risk of using an angiotensin-converting enzyme inhibitor during the second and third trimesters of pregnancy is uniformly presented in all labeling for this class of drugs.
Until recently, the labeling for antihypertensive products included only the information that the drugs were indicated to reduce blood pressure; it did not include information on the clinical benefits related to cardiovascular outcomes expected from blood pressure reductions. In 2005, CRAC discussed class labeling for cardiovascular outcome claims for drugs indicated to treat hypertension. The committee voiced a broad consensus in favor of antihypertensive agent labeling changes that would describe the cardiovascular outcome benefits expected from lowering blood pressure. Subsequently, in 2008, the FDA formulated a drug-labeling industry guidance for cardiovascular outcome claims for drugs indicated for hypertension.
Sitagliptin was the first in a class of diabetic drugs (dipeptidyl peptidase-4 inhibitors) designed to increase endogenous insulin secretion and suppress glucagon release. In October 2006, the FDA approved sitagliptin based on clinical studies showing that the drug reduced glycated hemoglobin A1c levels compared with placebo. At that time, hemoglobin A1c was regarded as the primary efficacy endpoint for glucose reduction. In 2007, cardiovascular events associated with rosiglitazone prompted additional discussion at the FDA regarding the types of evidence required for new diabetes drugs to obtain approval. In July 2008, the Endocrinologic and Metabolic Drugs Advisory Committee was asked whether sponsors of a drug or biologic should conduct a long-term cardiovascular trial or provide equivalent evidence to exclude unacceptable cardiovascular risks, even in the absence of a cardiovascular safety signal during phase II and phase III development. Of the 16 voting members, 14 voted yes. In December 2008, the FDA issued guidance regarding the evaluation of cardiovascular risk for diabetes therapies. The guidance asks manufacturers to demonstrate that new therapies for type 2 diabetes do not unacceptably increase cardiovascular risk. The subsequent reviews of saxagliptin and liraglutide were evaluated closely for cardiovascular safety outcomes and exemplify the regulatory shift from sole evaluation of surrogate biomarkers, such as hemoglobin A1c, to a broader evaluation of clinical safety events.
Postmarketing Surveillance
Although phase III pivotal studies may evaluate the safety of a new compound in thousands of patients, additional adverse effects may remain undetected at the time of initial regulatory approval. Consequently, postmarketing surveillance and risk-assessment programs are essential for identifying safety signals that are not apparent before approval. The FDA uses the data from postmarketing surveillance to update drug labeling and, on rare occasions, to reevaluate the approval or marketing decision (21 CFR 314.80).
The Adverse Event Reporting System (AERS) is a computerized database designed to support the FDA’s postmarketing safety surveillance program. AERS includes voluntary reports submitted by health professionals and the public through the MedWatch program, as well as reports from manufacturers that are required by regulation. Reports in AERS are evaluated by the Center for Drug Evaluation and Research Office of Surveillance and Epidemiology to detect safety signals. These analyses may prompt the FDA to improve product safety by taking regulatory action, such as by updating a product’s labeling information, sending out a notification (“Dear Health Care Professional”) letter, or reevaluating an approval decision.
Dronedarone is an antiarrhythmic agent similar to amiodarone, often used for suppression of atrial fibrillation. Few direct comparisons of dronedarone and amiodarone exist, although each drug has been evaluated extensively against placebo. The safety profile of dronedarone led to regulatory approval by the FDA and other regulatory authorities, although indirect analyses suggested that dronedarone was less effective for the prevention of atrial fibrillation compared with amiodarone. The FDA approval included a risk evaluation and mitigation strategy, as well as additional requirements for postmarketing drug safety surveillance. After approval, the FDA received several case reports of hepatic failure in patients treated with dronedarone, including two postmarketing reports of acute hepatic failure requiring transplantation. A notification letter was issued by the manufacturer to communicate these additional risks to clinicians, and the labeling was subsequently revised.
Exemptions from Investigational New Drug Application and Practice of Medicine
In the practice of medicine, it is not uncommon for some therapeutic agents to become de facto standards of care on an empirical basis before there is a labeled indication for that particular use. The government has long permitted physicians to prescribe or administer any legally marketed product within the practice of medicine, which is generally regulated by state laws. If physicians use a drug for an indication not in the approved labeling, they should base their decision on sound scientific evidence as part of good medical practice.
The FDA may consider some research studies exempt from specific regulations governing new therapeutic agents. In general, research protocols may be eligible for exemption from the IND requirements by evaluating drugs 1) that are already approved by the FDA, 2) that do not significantly increase the risk or decrease the acceptability of risk to study subjects, 3) that use the drugs in a manner consistent with their approved labeling, and 4) that are not intended to be reported to the FDA in support of a labeling or advertising change.
Investigator-Initiated Investigational New Drug Application
Many research protocols involving new drugs, or new uses for existing drugs, do not meet the criteria for exemption from regulation and therefore require investigator-initiated INDs. Changes to established dosing, drug delivery systems, routes of administration, or concomitant therapy (such as a new combination product) may result in the need for an IND. An investigator IND is submitted by a physician who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed. Investigator-initiated research comprises a much larger share of INDs than pharmaceutical company–sponsored research. Academic institutions and individual practitioners submitted approximately 3.5 INDs for every commercial IND submitted between 1986 and 2005. If the investigator also assumes the role of sponsor for a new drug, additional documentation and reporting to the FDA are required. These include safety and adverse event reports within the required timeframes and an annual report within 60 days of the anniversary date on which the IND went into effect. The sponsor is also expected to select qualified investigators, perform ongoing monitoring, and ensure compliance. If the investigator is using a commercially manufactured drug and secures permission from the manufacturer, it is possible to reference the existing Drug Master File at the FDA for details of the manufacturing data.
CDER Versus CBER: Key Differences for Biologics
The FDA regulates biologic products—blood components and products made from blood, such as clotting factors, gene therapy, tissues for transplantation, and vaccines—through CBER. Biologic products introduced into interstate commerce are regulated under 21 CFR 600-680. Since its inception in 1987, CBER has been closely tied with CDER, and the two centers have weathered several rounds of reorganization over the ensuing decades. Most recently, the oversight for biopharmaceuticals—proteins extracted from animals or microorganisms that are intended for therapeutic use, including recombinant versions of these products, except clotting factors—was transferred from CBER to CDER. Biopharmaceutical development often has different challenges compared with that of traditional chemical drugs, including variations in potency, less correlation between animal and human models, and unique uncertainties with regard to mechanisms of action and potential risks to human subjects. As the development of biopharmaceuticals has become more common, the regulatory practices of CDER and CBER have become remarkably harmonized, in part due to active efforts between the two centers to share regulatory decisions and standardize review processes. Consequently, future regulation of biologics is likely to resemble traditional pharmaceutical development more closely. An evolving area of interest concerns biosimilar compounds, for which the factors of identity and potency are still less certain than those for generic chemical drugs.
When regulatory pathways were well defined and agents from both centers were developed in parallel, CDER and CBER regulatory standards did not differ. CDER’s regulatory requirements for bivalirudin, a direct thrombin inhibitor for the treatment of postinfarction angina with angioplasty, were nearly identical to those used by CBER for abciximab, a biopharmaceutical glycoprotein IIb/IIIa inhibitor seeking the same indication.
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