Clinical Trials in New Drug Development

The November 2012 issue of this journal contained a commentary entitled “The 50th Anniversary of the Kefauver‐Harris Amendments: Efficacy Assessment and the Randomized Clinical Trial” that explained the importance of the amendments in the development of the randomized clinical trials (RCTs) that are used to provide compelling evidence of a new drug's efficacy.1 It also emphasized the relevance and importance to practicing physicians of a fundamental understanding of the role of clinical trials in new drug development. Clinical research informs clinical practice and evidence‐based medicine. Preapproval clinical trials bring new drugs to market and provide the information contained within each drug's prescribing information (label). This information concerning the drug's safety and therapeutic benefit, which is the best available information at the time of approval, guides treatment decisions at the individual patient level. Clinical trials also generate the evidence contained within treatment practice guidelines, which have a broader reach across populations of patients. Clinical trials conducted after the drug's approval, along with spontaneous safety reporting and active postmarketing surveillance, provide additional information that may lead to changes to the drug's label over time as the drug's use in clinical practice increases.

This paper provides an overview of clinical trial categorization in new drug development and the nature of trials falling within each category. Specific examples focus on antihypertensive agents.

Safety, Efficacy, and Benefit‐Risk Balance

When a regulatory agency reviews the marketing application for a new drug, it will determine whether there is compelling evidence that the drug is safe and effective for its intended use. It is therefore appropriate to discuss the meaning of these terms in the context of biopharmaceutical medicine. Defining efficacy is straightforward: Assessments measure the degree to which the drug accomplishes its intended effect, eg, the degree to which an antihypertensive agent lowers blood pressure. Statistical analysis will reveal whether a trial has provided compelling evidence of statistically significant efficacy, where the term compelling is operationalized by a set of statistical conventions that all interested parties have agreed to honor. Equally importantly, medical judgment will be guided by additional statistical analyses employing confidence intervals to determine whether the magnitude of the efficacy is great enough to warrant the drug's approval, ie, there is evidence of clinically significant efficacy.2, 3

Defining safety is less straightforward. One might initially think that safety is synonymous with the absence of risk; however, this is not the case. A useful operational definition of safety was provided in 2008 by the US Food and Drug Administration's (FDA's) Sentinel Initiative:4

Using medical products brings benefits and risks. Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of benefit expected in a specific population and within the context of alternatives available.

While the words “acceptable risks” may at first sight seem disconcerting, we simply cannot guarantee that a drug carries no risk to anyone. This is not a new realization. For example, in 1986, Herxheimer5 wrote as follows:

If we want to benefit from medicine, we must accept some risks. We first need to consider the risks when deciding whether or not to use the medicine. When we have decided to take the medicine, because the likely benefit sufficiently outweighs the risks, we have to understand how to minimize these risks. The user thus needs two quite separate kinds of information about possible harm: first, a realistic assessment of benefits and risks when the drug is properly used; second, what precautions and circumspections “proper use” requires.

It is the responsibility of those of us conducting clinical research to design, execute, analyze, interpret, and present the results of clinical trials to the highest standards to provide robust data to regulatory agencies. Regulators then examine these data to assess the drug's benefit‐risk balance when making their approval decision. The benefit‐risk balance must be favorable, ie, the benefits must be considered to outweigh the risks. If a drug is approved, a summary of benefits and risks will be provided in the drug's label. Prescribing physicians such as readers of this journal then have the responsibility to use appropriate “precautions and circumspections”5 when prescribing a given drug, making benefit‐risk judgments at the individual patient level.

Regulation and Classification of Clinical Trials

Piantadosi6 provided the following succinct definition: “A clinical trial is an experiment testing a medical treatment on human subjects.” Since the term human subjects can be uncomfortable to some readers, we have used the term participants. The participation of humans means that we must execute every aspect of clinical research to the highest ethical standards, and protection of participants' welfare is our paramount concern.7 Regulatory agencies worldwide govern how trials are to be conducted. These agencies include the FDA,8 the European Medicines Agency (EMA),9 and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).10 While not a regulatory agency itself, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)11 brings together regulatory agencies and biopharmaceutical industry representatives from Europe, Japan, and the United States “to discuss scientific and technical aspects of drug registration,” ie, marketing approval. Its mission is “to achieve greater harmonisation to ensure that safe, effective, and high quality medicines are developed and registered in the most resource‐efficient manner.”11

Biopharmaceutical clinical trials are typically classified into various phases, with any given trial being identified as belonging to one of them. A common system includes four temporal phases: phases I, II, III, and IV. However, as ICH Guideline E812 noted, “It is important to recognise that the phase of development provides an inadequate basis for classification of clinical trials because one type of trial may occur in several phases.” The guideline provides an alternate 4‐item system, one that employs more informative nomenclature relating to study objectives. This system includes human pharmacology, therapeutic exploratory, therapeutic confirmatory, and therapeutic use trials. Guideline E8 hence combines these systems as indicated by the headings of the next 4 sections.

Phase I (Most Typical Kind of Study: Human Pharmacology)

An enormous amount of work spanning several years is completed in the new drug development process before clinical trials commence. This work comprises a drug's nonclinical development program. Nonclinical development comprises in silico,13 in vitro, ex vivo, and in vivo testing, including investigations conducted at the intracellular, cellular, isolated tissue, isolated organ, and intact animal levels.14 No animal model is a perfect predictor of the precise effects of a drug in humans, but these data nonetheless constitute the rational basis for determining what drug doses we administer to the individuals participating in first‐in‐human clinical trials.

Human pharmacology trials assess the safety of the drug, obtain a thorough knowledge and understanding of the drug's pharmacokinetic profile and potential interactions with other drugs (drug‐drug interactions), and estimate pharmacodynamic activity. These trials are typically conducted by clinical pharmacologists. They include relatively small numbers of participants, but a lot of assessments are completed for each one.

Acute single‐dose studies are conducted first. Short‐term studies of various doses are then conducted, followed by longer‐term studies of various doses. Eventually, dose‐finding studies are conducted to determine the maximum tolerated dose of the drug. Human pharmacology trials are informative with regard to providing answers to questions concerning any side effects, their characteristics, and whether they are consistent to any notable degree across participants.

Phase II (Most Typical Kind of Study: Therapeutic Exploratory)

Participants in these trials have the disease or condition of clinical concern, eg, hypertension, thus facilitating initial assessments of a drug's safety and efficacy in the intended patient population. They are conducted by researchers trained in clinical trial methodology and operational execution.

Often, several hundred participants take part in these trials. Some of them receive the drug being developed (the investigational drug), and some receive a control treatment, which can be a placebo or an active comparator. The nature of these trials is therefore comparative, since responses to the drug are compared with responses to the control treatment in order to investigate the drug's comparative efficacy.

Some authors have voiced the opinion that these trials provide the most accurate assessment of efficacy, since they are conducted in an extremely tightly controlled manner. While we agree, however, this environment is not typical of those in which the drug will eventually be used if approved. Therapeutic confirmatory and therapeutic use trials provide more realistic assessments with regard to the drug's benefit to large numbers of patients in real‐world therapeutic settings.15

Phase III (Most Typical Kind of Study: Therapeutic Confirmatory)

Therapeutic confirmatory studies are conducted as RCTs, as discussed previously in this journal.1 Several thousand participants with the disease or clinical condition for which the drug is being developed take part. These trials are often required to specifically include certain subgroups of participants that are representative of patients who will receive them in clinical practice if the drug is approved. For example, EMA's 2010 guideline for the development of new antihypertensive agents states that the number of participants 75 years and older “should be sufficient to assess both efficacy and safety in this group and specific attention should be paid to them.”16

As for therapeutic exploratory trials, the nature of these trials is comparative. The drug's treatment effect, the representation of the drug's efficacy, is calculated as “mean response to the drug treatment minus mean response to the control treatment.” An example of a therapeutic confirmatory study in the field of hypertension was published by Bakris and colleagues.17 This study was an RCT comparing the single‐pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension. It was conducted as part of a phase III program in support of a marketing application for the single‐pill combination. Additional safety data are also gained from trials like this, adding to the safety data portfolio already accumulated.

Upon completion of therapeutic confirmatory trials, sponsors submit a marketing application to regulatory agencies. If an agency determines that there is compelling evidence of beneficially balanced safety and efficacy, it will approve the drug for use in its jurisdiction.

Phase IV (Variety of Studies: Therapeutic Use)

Therapeutic use studies are conducted once the drug is on the market. They may be optional studies, or studies required by a regulatory agency as a condition of approving the drug for marketing. In the former case, the biopharmaceutical company sponsoring a trial may wish to know more about the drug's performance in patients who were not well represented in preapproval trials, eg, patients with compromised liver function and patients taking several concomitant medications. In addition, other sponsors such as an institute within the National Institutes of Health may want to explore a drug's place in current treatment practice guidelines, comparing its safety and/or efficacy with other treatment options or combinations of various treatment options. In the latter case, the regulatory agency approving the drug for marketing felt that, based on the drug's benefit‐risk balance as indicated by the data they had to review at that time, the drug could be marketed and hence offer immediate benefit to patients, but it also felt that it would be advantageous to require the sponsor to provide additional safety and/or efficacy information that could be used to refine the drug's label if necessary. In these cases, the drug often receives a restricted initial label.

The SHEP, ALLHAT, and ACCOMPLISH Trials

Readers of this journal will be familiar with these trials. Of specific relevance in the present context is that, while they were all therapeutic‐use RCTs, the designs of the trials differed such that the most appropriate control treatment was employed in each case to best answer the research question of interest. The Systolic Hypertension in the Elderly Program (SHEP)18, 19 was conducted as a multicenter, randomized, double‐blind, placebo‐controlled trial of chlorthalidone for isolated systolic hypertension. The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)20 employed a multicenter, randomized, double‐blind, active‐controlled design to compare chlorthalidone with each of 3 alternative antihypertensive treatments with regard to the incidence of nonfatal myocardial infarction and coronary heart disease death in hypertensive patients with at least one other risk factor for coronary heart disease. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial21 was also a multicenter, randomized, double‐blind, active‐controlled clinical trial, but one that differed from ALLHAT in that the combination therapy benazepril plus amlodipine was compared with benazepril plus hydrochlorothiazide with regard to reduction of cardiovascular events in high‐risk hypertensive patients.

Postmarketing Surveillance

A landmark report from the Institute of Medicine of the National Academies22 emphasized the importance of postmarketing evaluations, commenting as follows:

The approval decision does not represent a singular moment of clarity about the risks and benefits associated with a drug – preapproval clinical trials do not obviate continuing formal evaluations after approval.

The limited sample size of even the largest preapproval clinical trials means that there is a (very) low probability of observing (very) rare but potentially important events. The “rule of threes” is instructive here.23 The sample size, ie, the number of individuals participating in a clinical trial, that would be needed to be 95% confident that a single case of an identified adverse event of interest would be seen is approximately 3 times the reciprocal of the frequency of the event in the general population. That is, for an event that occurs in 1/1000 individuals, a sample size of 3000 participants would provide 95% confidence of observing at least 1 event. For adverse events that are considerably more rare (eg, rhabdomyolysis, Torsades de Pointes), much larger sample sizes would be needed (30,000 and 300,000 for events with frequencies of 1/10,000 and 1/100,000, respectively), and trials of this magnitude are infeasible from both cost and time perspectives. Therefore, it is probabilistically (very) unlikely that adverse events with a (very) low frequency of occurrence will be observed during these trials. They are much more likely to surface once the drug is widely used by very large numbers of patients; hence, the critical role of therapeutic use clinical trials and postmarketing surveillance.

Concluding Comments

New drug development is a lengthy, expensive, and complex endeavor. While precise quantification of time and cost differs on a case‐by‐case basis, meaningful estimates at this point in time are 10 to 15 years and US$ 1 billion. There are therefore many ongoing initiatives to increase the speed and reduce the cost of drug development. New drug development is a very meaningful pursuit: biopharmaceutical medicines have improved health and quality of life on a global scale that is unrivaled by any other medical intervention.15 There are still many unmet medical needs, however, and many new drugs to be developed. We hope that physicians who have not previously been investigators/principal investigators at sites running clinical trials might consider doing so in the future.

Disclosures

The authors report no specific funding in relation to the preparation of this paper. No editorial support was used.