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Clinical Trials, Clinical Research Organizations, Phases I–IV, and Investigator-Initiated Trials

To obtain approval to market a new drug in the United States, Canada, the European Union, and most other countries, a series of clinical trials on patients is required. The extent of the trials depends on the drug (already approved for other uses or formulations, a new breakthrough product, expected to be very toxic, etc.), the disease or indication treated (severe diseases such as advanced cancer vs. mild allergies, diseases with no known treatments, rare diseases with few patients afflicted, etc.), the nature of the patients studied (healthy, very ill, young, old, etc.), experience in other countries where it is already sold, and other factors.

After the appropriate pharmacology and toxicology testing in vitro and in animals, development of small-scale and sometimes (even at this early stage) larger-scale manufacturing procedures, and other preparatory testing, the drug is ready to be used in humans in the so-called first in man, or first in humans, study. In the United States, a company (sometimes an individual or an academic center) submits an Investigational New Drug Application (IND) to the Food and Drug Administration (FDA) (or the equivalent to a health authority outside the United States) containing the preparatory data. This is, in most cases, data that are proprietary and not available to the public. In addition, the submitter includes in the package a protocol for a clinical trial in humans.

Drug trials are heavily regulated, and multiple layers of protections and precautions have been developed to protect the subjects. These include investigational review boards, data safety monitoring boards, sponsor and health authority scrutiny, and some level of public notification and publicizing of the study on the internet (clinical trial registries). Trials are divided into four phases, although there is usually some overlap.

Phase I trials actually belong to human pharmacology, in contrast to animal pharmacology. These are the first steps in determining the profile of both the beneficial and the untoward effects in humans. They are designed mainly to find the maximum tolerated dose and the pathways for metabolizing and eliminating the drug. Safety is more important in this phase than efficacy. The first study is often a single-dose trial in a small number (e.g., a dozen) of healthy, often male (to avoid any possible pregnancy issues), volunteers. If tolerated, a multiple-dose study and a rising-dose study follow. The aim of phase I trials is to study absorption, distribution in the body, metabolism, and excretion (so-called ADME studies) as well as safety and toxicity.

Other things that may be examined include the proposed formulation to be used in subsequent trials and marketing (as they may be different) and the dosing frequency or schedule. Drug interaction studies may be done in phase I or later in phase II. If the drugs are known to be toxic or have severe and predictable ADRs, these studies are often done for ethical reasons in patients with the disease to be treated rather than in healthy volunteers (e.g., cancer chemotherapy or AIDS). Each study is short, often running no more than a few days to a few weeks at most. The trial design is usually simple and open label. They may or may not be controlled. Several phase I studies often take a year or so and may include around 100 patients in total.

There is usually no benefit to the subjects in the trial, and they participate either because of generosity of spirit or because they are paid. Because there is no gain to the individual subjects, all efforts are made to minimize the risk of toxicity. Serious adverse events are usually rare in phase I trials. Subjects are often “housed” for these studies in special clinical research centers run by academic medical centers or clinical research organizations (CROs). Note that the term subjects in this context usually refers to “normal people,” not patients. The term patients is usually used to refer to people with the disease in question and not “normal” people. Hence, phase I trials usually involve healthy subjects, and phase II, III, and IV trials involve patients. This distinction is not always followed, and some use the terms interchangeably.

Adverse events seen in phase I trials are always noteworthy because the subjects are usually normal and a low starting dose of the drug in question is usually used. Because few subjects are studied in phase I, any AE should be investigated thoroughly. SAEs and the rare death seen in phase I trials should be looked at immediately, and if the event is severe, stopping further dosing or enrollment should be considered. Note that the FDA now requires all serious AEs (whether labeled or not, whether felt to be due to the drug or not) to be submitted as expedited reports. In addition to the toxicity of the drug preparation, subjects have been known to hide serious medical problems or medical history to participate in the study, especially if the subjects are compensated.

Phase II trials are done after the drug has successfully passed through all or parts of phase I trials. Phase II trials are usually performed in patients afflicted with the disease for which that drug was developed. Whereas phase I trials are usually done for safety, phase II trials are done for both efficacy and safety. The goal is to find the minimal effective dose that retains efficacy with the minimum of AEs. These studies may also continue the ADME investigations of phase I as well as develop safety and efficacy markers and tests for subsequent larger phase III trials. The studies may include up to hundreds of patients and are usually double blinded. They may run several weeks or months.

Sponsors and investigators participating in phase II trials must pay particular attention to toxicity because unexpected SAEs and even deaths may occur. Severe and unexpected toxicity may force the immediate stopping of the study or a midstream alteration of the protocol and informed consent to decrease toxicity. Patients in phase II trials usually are not compensated for their participation.

Special studies may be done in phase I, II, III, or IV, such as drug-interaction studies (sometimes in healthy volunteers, sometimes in patients with the disease), food or alcohol interaction studies, and evaluation studies in renal failure or liver failure patients. These special studies, however, are usually required for the MA or NDA submission and so must be done at some point.

Some drugs or products (e.g., oncology drugs or herbals) may not fully undergo phase I and phase II testing as is classically done and as described above. Oncology drugs, which are often very toxic, are rarely studied in normals but are used directly in patients with malignancy. Similarly, “orphan drugs,” which are drugs developed for rare diseases, may undergo abbreviated testing.

Phase III is often divided into phases IIIA and IIIB. Phase III trials include hundreds to thousands of patients, and the whole phase may take several years to complete, depending on the treatment duration and outcomes of the disease studied. Each individual trial may include multiple sites on one or more continents and run months to a year or more. (Survival studies may take even longer because the study does not end until the last patient dies.) The goal is regulatory approval to market the drug.

Phase IIIA trials are usually the key (the old term is “pivotal”) studies to be submitted for regulatory approval, and they are incorporated in the NDA submission or “MA dossier.” The design used in these trials is usually double blind, but many other varieties are used. Depending on the drug and disease under study, the comparator is either the known and accepted therapy called the “standard of care” (e.g., obligatory in almost all cancer, infection, severe pain trials) or placebo (e.g., in treating mild headache or nasal congestion). In some cases, the FDA and other agencies may require a placebo-controlled trial. This is becoming more and more controversial in terms of the ethics of using placebo. Many health agencies often prefer trials against the standard of care rather than placebo. Although both have a place in drug development, placebo trials are felt to be less and less acceptable.

Phase IIIB trials are additional (usually) large-scale studies that may be started during the examination of the initial dossier by the health agency (the reviewing process) and may end before or after the approval for marketing (NDA or MA). Because the total elapsed review time by the health agency may take a year or more, sponsors may continue studies during this review period. These studies may focus on pharmacoeconomic or risk evaluation issues as well as cost-effectiveness and studies against competitor drugs. Sometimes surprising or unexpected results of phase IIIA studies force late changes in phase IIIB studies. As most products now have full life cycle risk evaluation and management programs in place, additional testing may be added to phase III trials to evaluate risks that are unclear or that need further evaluation. By doing such testing in phase III, it may be possible to achieve more rapid marketing approval though postmarketing studies, and other commitments for risk evaluation, management, and mitigation may continue in phase IV.

Phase IV studies include different types of studies. They are done after the approval and marketing of the drug. Note that a drug may not always be marketed immediately after approval. Sometimes the company receiving the approval may choose to sell or out-license the drug, or timing may make it wiser to wait (e.g., new seasonal allergy drugs should be marketed near the time for the allergy season to hit). The health authority may require that certain phase IV studies be done as “commitments” immediately after marketing as a requirement of marketing approval. This may be done to clarify some safety and efficacy issues that remained after phase III but which the health agency believed were not sufficient to prevent or delay marketing of the drug. In the United States, the FDA now has the legal authority to require phase IV commitments, including Risk Evaluation and Mitigation Strategies (REMS) and formal clinical or observational studies. Similarly, the EMA and member states may require further studies in their Risk Management Plans (RMPs). Failure to perform such tasks may result in penalties to the company or even withdrawal or limitation of the marketing approval.

Phase IV studies may also be marketing or pharmacoeconomic studies to aid in selling the product by studying head-on comparisons with competitor drugs. They may be studies looking at subgroups of the approved group and indication (e.g., testing a drug approved for diabetes on diabetics who are elderly or are also in heart failure). They may be done in children, not only to evaluate the usefulness and safety but also to obtain, in various markets, additional patent exclusivity.

Phase IV studies may be done for specific safety reasons to investigate an AE or a signal that has unexpectedly occurred after marketing. Such studies may be classical clinical trials or they may be observational or epidemiologic studies done in large databases. The design and size are very variable, ranging from small open-label trials to massive, multicenter, double-blind comparator trials or “large simple safety studies” with simple protocols and minimal record-keeping. Sometimes patients are compensated for participation.

So-called market-driven phase IV “seeding studies” are now forbidden in most parts of the world. These were pure marketing projects designed to encourage physicians to prescribe a particular product in place of a competitor’s product. A protocol was usually written (to justify calling the endeavor a study) but was often of poor quality. Results were not always collected by the sponsor and, if collected, were often not analyzed. Prescribers were sometimes compensated. In a more subtle way, postmarketing trials for entirely legitimate purposes may include elements aimed at getting physicians to use the new drug in place of another product (“stealth seeding trials”). By doing this, the prescriber becomes familiar with the product, and the company hopes he or she will prescribe it for other patients after the trial is completed.

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