How are drugs tested?
Clinical proof of efficacy and safety is required in order to obtain approval for a new drug or for expansion of the indications of an already approved drug by the European or German regulatory authorities. This requires successful completion of the different clinical trial phases. Drug testing is regulated by the German Drug Law of 1976 last amended by the 15th amendment in 2009. In addition, numerous European guidelines must be observed during a drug approval procedure.
Legal aspects of drug testing
The procedure for conducting clinical trials is regulated by §§ 40 through 42b of the German Drug Law. The GCP directive regulates the procedure for the approval and conducting of clinical trials using drugs in human subjects. The main ethical requirements regarding clinical trials are stipulated in the Declaration of Helsinki of the World Medical Association.
Moreover, the requirements in Volume 10 of the Eudralex "Clinical Trials" must be observed. Volume 10 contains the guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH brings together the activities of the European, American and Japanese regulatory authorities. The ICH guidelines facilitate better harmonization in the interpretation and application of technical guidelines and requirements for approval in order to avoid deviations in approval documents and evaluations among the various international regulatory authorities.
Clinical trial phases
Clinical trial phases
Results of pharmacological-toxicological studies in accordance with the Good Laboratory Practice (GLP) guidelines must be available in order to perform drug tests in humans—a clinical trial. A clinical drug trial is typically divided into four phases (phase I through IV).
In phase I studies, a drug is used for the first time in humans. The test subjects are typically young healthy adult volunteers. In exceptional cases only, such studies are conducted in patients for ethical reasons, e.g. when testing cytostatic drugs.
Between 20 and 80 healthy test subjects are included in the studies. The studies are usually open and have a crossover design. For example, the studies examine whether the effects observed in the animal experiment also occur in humans (proof of concept = POC) and whether additional effects can be observed. Undesired effects are carefully analyzed in order to be able to better assess the risks of the new substance. Moreover, pharmacokinetic parameters are analyzed and initial data regarding the dose-effect relationship is recorded. If the results of phase I studies justify further testing of the substance, phase II follows.
In phase II studies, a new drug is used in patients for the first time (with the exception of the testing of cytostatic drugs). Between 100 and 800 hospitalized patients with the corresponding disease are usually included in the studies. The objectives are initial testing of efficacy and tolerability, determination of dose-effect relationships with optimization of dosing, and recording of pharmacokinetic parameters in patients. The new drug is typically tested in an open and non-controlled or randomized manner in comparison to a placebo or a standard medication. The goal is to prove comparable or superior efficacy. In oncology, phase II studies are often single-arm studies. In the case of positive phase II study findings, phase III of the clinical trial follows.
The objective of phase III of a clinical trial is to biometrically prove the efficacy and safety of the new substance in several 100 to several 1000 patients. These studies are typically performed at multiple centers (multicenter) and in multiple countries in inpatients and outpatients. These studies must be controlled, i.e., in comparison to a placebo or a standard therapy. The randomized, controlled, double-blind clinical trial is the gold standard. Open studies are possible in exceptional cases.
The study protocol must contain criteria for termination of the trial in the individual case and for the entire study. Previously defined interim analyses ensure that significant differences in efficacy and tolerability are detected early and suitable measures (e.g., trial termination) can be taken. At least two independent controlled phase III clinical trials are typically required for approval of a drug.
If the results of the phase III studies are positive, the pharmaceutical company can apply for approval of the drug from the German or European regulatory authority. Phase III studies are often referred to as approval studies, which is actually incorrect, because the results of all preclinical and clinical tests of phases I through III must be submitted to the regulatory authorities for the application for approval. It is better to refer to these studies as approval-related studies.
Development doesn't end with the approval and market introduction of a drug. Comprehensive information regarding safety, tolerability, and efficacy as well as financial concerns is collected in phase IV studies, typically under the conditions of the daily clinical routine which usually differ significantly from the conditions of phase II and III studies.
These non-interventional studies (NIS) typically follow a monitoring plan defining the number of cases to be monitored, the methods of evaluation, and the questions to be answered during monitoring. There are no requirements for the treatment of patients in an NIS. They are treated under normal clinical conditions. This is important because many factors that play a role in daily practice, such as concomitant diseases, simultaneous usage of additional drugs, or adherence cannot be taken into consideration in clinical trials due to the narrow selection criteria.
The NIS includes, for example, observational studies, cohort studies, case control studies, register studies, and post-authorization safety studies (PASS).
Phase IV studies in the form of observational studies are explicitly defined in the German Drug Law, for example to identify previously undetected risks since the rate of severe undesired effects is often 1:10,000 or 1:100,000 treated patients. This underscores the importance of post-marketing surveillance.
In addition to safety aspects, observational studies can also be used to examine parameters such as quality of life, treatment progress, application behavior, or costs under the conditions of the daily routine. However, observational studies are limited in their significance due to the lack of a control group. In addition, there is a risk that they will be misused as a marketing instrument to make the new drug known to physicians.
There are different types of clinical trials, for example
In interventional studies, select patients receive a drug in a targeted manner for testing purposes. The treatment strategy is defined in the study protocol. In non-interventional studies (NIS), approved drugs are typically administered as part of routine treatment. There is no predefined study protocol.
In prospective studies, the parameters to be examined are defined at the start of the study and investigated to a defined study endpoint. In retrospective studies, data are acquired retrospectively from treatment documents or via follow-up examinations and conclusions about desired and/or undesired effects are made. The significance of prospective studies is greater than that of retrospective studies. However, the results of retrospective studies are usually available more quickly.
In controlled studies, the efficacy and tolerability of an investigational product are compared directly to a placebo or another medication. In non-controlled studies, e.g. in observational studies, all patients receive the same investigational product. The significance of controlled studies is much higher than that of non-controlled studies.
In controlled studies, patients are randomized into treatment and control groups to avoid errors caused by intentional or unintentional patient selection for one of the groups. This can be achieved using various randomization techniques. In non-randomized studies, there is a risk that the groups will be distributed unevenly, e.g., more older or severely ill patients could be included in one group than in the other group, thus limiting the significance of the study.
In open studies, the physician and patient know whether the patient is receiving the study drug or the comparator. In single-blind studies, only the physician knows which medication the patient is receiving and in double-blind studies, neither the physician nor the patient knows which drug is being used. The double-blind study yields the most reliable and most objective statements about desired and undesired effects of a drug. However, there are types of drugs or undesired effects that do not allow proper blinding, e.g. severe reddening of the skin upon administration of niacin preparations.
Exploratory studies (phase II) are primarily used to formulate hypotheses, while confirmatory studies (phase III) serve to confirm hypotheses.
Endpoints in clinical trials
In the case of the endpoints, i.e. the target parameters, of clinical studies, a differentiation is made between hard and soft criteria. The hardest endpoint is death. Further hard endpoints are the recurrence of a disease (relapse rate) or remission (complete retrogression of all signs of disease).
The top study objective is the primary endpoint of a clinical trial. Therefore, the survival rate or the relapse rate can be defined as the primary endpoint, for example.
The secondary endpoints are the second-tier study objectives. A study with proof of efficacy only for the secondary endpoints did not reach its objective since achieving a secondary endpoint is not considered confirmatory but rather only as hypothesis-generating.
Oncology as a special case: Overall survival versus progression-free survival
Overall survival (OS) is the hardest possible endpoint in clinical trials and is thus the gold standard among efficacy endpoints. However, analysis of overall survival can require long follow-up periods that can delay the development of new substances. In addition, particularly in the investigation of substances in the first-line treatment of cancers, patients are subsequently treated with additional drugs making it difficult to evaluate the effect of the initially used drug with respect to overall survival. Therefore, other endpoints are increasingly selected, for example:
• Progression-free survival (PFS),
• Disease-free survival (DFS),
• Response rate (RR),
• Clinical benefit,
• Toxicity or
• Benefits reported by the patient
Overall survival (OS) is a valid and robust clinical parameter that correlates with the primary objective of the patient. However, it must be possible for the physician and patient to switch to other active treatments during the course of the disease. This affects overall survival and the time to progression of the disease so that the effect of the initially examined drug is difficult to evaluate.
Progression-free survival is also a valid and robust clinical parameter. PFS results are available more quickly than OS results and they are not affected by subsequent treatments provided that the treatment is complete before progression of the disease. In the case of progression-free survival as an endpoint, the improvement of symptoms due to treatment typically correlates with the quality of life of the patient. Regulatory authorities increasingly accept progression-free survival and response rate as endpoints in approval-related clinical studies with oncological drugs.
Regulatory authorities require the OS as the primary endpoint when the study drug is presumably more toxic than the comparator, when no recognized treatments for additional treatment are available, and when the time from disease progression to death is expected to be short. If a different endpoint is selected, this must be justified. According to regulatory authorities, the PFS is an acceptable primary endpoint when additional treatment options that could affect OS are available.
Registration of clinical trials
In 2004, the International Council of Medical Journal Editors (ICMJE) decided only to publish studies recorded in a public register from the start of the trial to ensure reports are also available for studies with unexpected or undesired results. [Author: Dr. Susanne Heinzl]