Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
in many countries of serious reactions from clinical trials. This phrase is very similar in meaning to the acronym SUSAR that is used for expedited clinical trial reports in the EU.
Suspected, expected, serious adverse reactions usually do not have to be submitted as expedited reports to governmental agencies. They are usually submitted periodically (e.g., yearly) or at the end of the study in the final study report. However, some regulatory jurisdictions require submission of all “serious” SARs, regardless of expectedness, if there is a reasonable possibility of a causal relationship with the product.
Expectedness represents an often highly subjective area. An event or reaction is expected if it is found in the product reference document (IB for clinical trials or the post-marketing labeling for approved drugs). More specific or more severe events or reactions, however, are considered to be unexpected. Thus, if “pneumonia” is in the brochure or product labeling and the patient has “streptococcal pneumonia”, this is considered unexpected because the “streptococcal” designation is more specific. Similarly, “fatal pneumonia” is considered unexpected if only pneumonia is labeled (see Chapter 22).
The bottom line here is that there are multiple definitions and variants floating around. They all more or less add up to the same cases being “expeditable” in the United States, European Union, and elsewhere in many, but not all situations. There are nuanced differences in the definitions of related/unrelated, but fundamentally what they come down to is that cases that are serious (death, life-threatening, hospitalization, disability/incapacity, birth defect) and related (“reasonable possibility” that the AE is due to the drug) and unexpected (not in the IB or only included in the class labeling section) are expeditable in the clinical trial setting.
Another nuance is the responsibility for the causality determination for clinical trial reports: FDA has assigned this responsibility to the sponsor (only), whereas elsewhere, either the sponsor or the investigator judgment applies. In general, one should be conservative in applying the definitions, and if one has to discuss or debate whether something is serious and/or related and/or unexpected, then it is. That is, if there is any doubt about any of these three definitions, choose the more conservative approach (serious, related, unexpected).
CHAPTER
2
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 versus 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 human” study. Permission must be requested from the regulators to proceed. In the United States, a company (sometimes an individual investigator or an academic center) submits an Investigational New Drug Application (IND) to the Food and Drug Administration (FDA). The IND contains preparatory data that support administration of the investigational medicine to humans. The EU Regulation requests a Clinical Trial Application (CTA) dossier, made available to all concerned Member States through a single submission portal (2019); one single authorization is given for all concerned countries before starting the clinical trial. Elsewhere, an equivalent data package is submitted to the local health authority. This package ordinarily contains 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. Outside the US, this administrative package is categorized as a “CTA”. In some countries, the regulator must issue a positive opinion to the applicant before the first human trial can begin and in others, there is a waiting period and if no refusal to proceed is received from the authority, the trial may begin. In such situations, “CTA” may refer to clinical trial authorization.
In rare instances, a physician may request an Emergency Use IND for a specific patient. In the US, this is handled by the FDA. 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 (e.g., clinical trial registries). Trials are divided into four phases, although there is usually some overlap.
Academic centers are doing more and more of this work as well as other earlier discovery research. The goal has been to create a multi-disciplinary approach from lab to bedside for new and better therapies. This is now called Translational Research and many medical centers now have departments of Translational Research.
Phase I trials (“First in Human” or FIH, sometimes also called “First in Man”) 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 (the 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 usually are) 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 (SAEs) are usually rare in phase I trials and, if SAEs occur, they often result in suspension or modification of the study protocol (sometimes an SAE will stop further development of a compound.) Subjects are often “housed” for these studies in special clinical research centers run by academic medical centers or clinical research organizations (CROs). These research centers provide for constant supervision and subjects are carefully monitored. Note that the term subjects in this context usually refers to “normal people”, not patients. However, the term subjects is ordinarily also used to refer to people, with the disease in question, who are enrolled in clinical trials.
Hence, phase I trials usually involve healthy subjects, and phase II, III, and IV trials involve subjects with the disease to be studied. This distinction is not always followed, and some use the terms patient and subject interchangeably.