to refer to any person enrolled in any study phase to be referred to as a study subject. These two terms will be used interchangeably in this book to refer to an individual in a trial. The preferred use is “subject” for anyone in a study and “patient” for anyone otherwise seeking or receiving care in the healthcare system.
Adverse events (AEs) 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 consideration should be given to stopping further dosing or enrollment.
Some countries now require that the next subject is dosed only when the previous subject ends the surveillance period scheduled in the protocol; this allows the avoidance of tragic adverse experiences in several subjects at the same time. Note that the FDA now requires all SAEs (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 tolerance and 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 number of AEs and safety issues. These studies may also continue the ADME investigations of phase I. In addition, they may also be used to 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 and controlled. They may run several weeks or months.
Sponsors and investigators participating in phase II trials must pay particular attention to toxicity because unexpected SAEs, including 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. Patients in phase II trials usually are not compensated for their participation, although they routinely receive study medication and study-related medical care.
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 MAA 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 II testing as is classically done and as described above. Oncology drugs, which are often very toxic, are rarely studied in normal subjects, but are used directly in patients with malignancy. Similarly, “orphan drugs”, which are drugs developed for rare diseases, may undergo abbreviated testing. The FDA Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US, or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug. A similar situation exists in the EU where an orphan drug designation is given to products aimed at treating diseases that afflict no more than 5 in 10,000 people or where the potential profit is insufficient to justify research and development costs.
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.)
For oncology products, protocols are often designed to follow patients for disease progression-free survival after completion of treatment for a set timeframe, such as five years. Certain advanced therapies, e.g., gene-based therapies, may also require long-term follow-up for delayed appearance of AEs. Based on a variety of scientific criteria, FDA guidance suggests consideration of a minimum of 15 years for follow-up in gene therapy protocols.
The goal in phase III is to obtain sufficient clinical trial data to support regulatory approval to market the drug. However, it may be possible to obtain product approval prior to completion of all follow-up activities.
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 “MAA 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, each study arm will get the currently accepted therapy (“standard of care”) plus the study drug and the comparator is the “standard of care”. This is usually obligatory in almost all cancer, infection, severe pain trials. There are many variants of this model that are used. 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 if there is an established standard of care. Many health agencies and payers often require 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. In infectious diseases, for example, it is considered ethically unacceptable to exclude an active comparator from the protocol.
Phase IIIB trials are additional (usually) large-scale studies that may be started during the examination and review of the initial dossier by the health agency 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 post-marketing studies and other commitments (or requirements) for risk evaluation, management, and mitigation may continue in phase IV. Alternatively, FDA permits selective safety data collection of non-serious events in late phase studies for products that have an otherwise well-characterized safety profile. Examples where this has been permitted are primarily in line extensions for oncology products.
Other approaches to making clinical trials more efficient include adaptive clinical trial designs, which permit modification of protocol parameters (or statistical procedures) after study initiation according to a prescribed schedule. There are several types of adaptive designs that can be applied in various settings while maintaining the integrity and validity of the study.
In some jurisdictions, Health Technology Assessment (HTA) data are required to demonstrate product value before payers, e.g., governments, insurance companies, etc., will reimburse for use of the product, even after approval for marketing by the appropriate drug regulator. This can be a complicated exercise that impacts commercial viability of the product. For example, in England the National Institute for Health and Care Excellence (NICE) and in France the French National Authority for Health, review UK/French approved products to see if they improve outcomes and add to patient care. If they determine that a product does not do this, their recommendation may determine whether the product is reimbursed by the UK or French National Health Service. That is, the drug is approved in England/France but may not be reimbursed by insurance.